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  1. Anabolic effects of IGF-1 signaling on the skeleton

    Science.gov (United States)

    Tahimic, Candice G. T.; Wang, Yongmei; Bikle, Daniel D.

    2013-01-01

    This review focuses on the anabolic effects of IGF-1 signaling on the skeleton, emphasizing the requirement for IGF-1 signaling in normal bone formation and remodeling. We first discuss the genomic context, splicing variants, and species conservation of the IGF-1 locus. The modulation of IGF-1 action by growth hormone (GH) is then reviewed while also discussing the current model which takes into account the GH-independent actions of IGF-1. Next, the skeletal phenotypes of IGF-1-deficient animals are described in both embryonic and postnatal stages of development, which include severe dwarfism and an undermineralized skeleton. We then highlight two mechanisms by which IGF-1 exerts its anabolic action on the skeleton. Firstly, the role of IGF-1 signaling in the modulation of anabolic effects of parathyroid hormone (PTH) on bone will be discussed, presenting in vitro and in vivo studies that establish this concept and the proposed underlying molecular mechanisms involving Indian hedgehog (Ihh) and the ephrins. Secondly, the crosstalk of IGF-1 signaling with mechanosensing pathways will be discussed, beginning with the observation that animals subjected to skeletal unloading by hindlimb elevation are unable to mitigate cessation of bone growth despite infusion with IGF-1 and the failure of IGF-1 to activate its receptor in bone marrow stromal cell cultures from unloaded bone. Disrupted crosstalk between IGF-1 signaling and the integrin mechanotransduction pathways is discussed as one of the potential mechanisms for this IGF-1 resistance. Next, emerging paradigms on bone-muscle crosstalk are examined, focusing on the potential role of IGF-1 signaling in modulating such interactions. Finally, we present a future outlook on IGF research. PMID:23382729

  2. IGF-1 signaling mediated cell-specific skeletal mechano-transduction.

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    Tian, Faming; Wang, Yongmei; Bikle, Daniel D

    2018-02-01

    Mechanical loading preserves bone mass and stimulates bone formation, whereas skeletal unloading leads to bone loss. In addition to osteocytes, which are considered the primary sensor of mechanical load, osteoblasts, and bone specific mesenchymal stem cells also are involved. The skeletal response to mechanical signals is a complex process regulated by multiple signaling pathways including that of insulin-like growth factor-1 (IGF-1). Conditional osteocyte deletion of IGF-1 ablates the osteogenic response to mechanical loading. Similarly, osteocyte IGF-1 receptor (IGF-1R) expression is necessary for reloading-induced periosteal bone formation. Transgenic overexpression of IGF-1 in osteoblasts results in enhanced responsiveness to in vivo mechanical loading in mice, a response which is eliminated by osteoblastic conditional disruption of IGF-1 in vivo. Bone marrow derived stem cells (BMSC) from unloaded bone fail to respond to IGF-1 in vitro. IGF-1R is required for the transduction of a mechanical stimulus to downstream effectors, transduction which is lost when the IGF-1R is deleted. Although the molecular mechanisms are not yet fully elucidated, the IGF signaling pathway and its interactions with potentially interlinked signaling cascades involving integrins, the estrogen receptor, and wnt/β-catenin play an important role in regulating adaptive response of cancer bone cells to mechanical stimuli. In this review, we discuss recent advances investigating how IGF-1 and other interlinked molecules and signaling pathways regulate skeletal mechano-transduction involving different bone cells, providing an overview of the IGF-1 signaling mediated cell-specific response to mechanical stimuli. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:576-583, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  3. Telomerase activity promotes osteoblast differentiation by modulating IGF-signaling pathway

    DEFF Research Database (Denmark)

    Saeed, Hamid; Qiu, Weimin; Li, Chen

    2015-01-01

    -regulation of several components of insulin-like growth factor (IGF) signaling. Specifically, a significant increase in IGF-induced AKT phosphorylation and alkaline phosphatase (ALP) activity were observed in hMSC-TERT. Enhanced ALP activity was reduced in presence of IGF1 receptor inhibitor: picropodophyllin....... In addition, telomerase deficiency caused significant reduction in IGF signaling proteins in osteoblastic cells cultured from telomerase deficient mice (Terc (-/-)). The low bone mass exhibited by Terc (-/-) mice was associated with significant reduction in serum levels of IGF1 and IGFBP3 as well as reduced...... skeletal mRNA expression of Igf1, Igf2, Igf2r, Igfbp5 and Igfbp6. IGF1-induced osteoblast differentiation was also impaired in Terc (-/-) MSC. In conclusion, our data demonstrate that impaired IGF/AKT signaling contributes to the observed decreased bone mass and bone formation exhibited by telomerase...

  4. Human GH Receptor-IGF-1 Receptor Interaction: Implications for GH Signaling

    Science.gov (United States)

    Gan, Yujun; Buckels, Ashiya; Liu, Ying; Zhang, Yue; Paterson, Andrew J.; Jiang, Jing; Zinn, Kurt R.

    2014-01-01

    GH signaling yields multiple anabolic and metabolic effects. GH binds the transmembrane GH receptor (GHR) to activate the intracellular GHR-associated tyrosine kinase, Janus kinase 2 (JAK2), and downstream signals, including signal transducer and activator of transcription 5 (STAT5) activation and IGF-1 gene expression. Some GH effects are partly mediated by GH-induced IGF-1 via IGF-1 receptor (IGF-1R), a tyrosine kinase receptor. We previously demonstrated in non-human cells that GH causes formation of a GHR-JAK2-IGF-1R complex and that presence of IGF-1R (even without IGF-1 binding) augments proximal GH signaling. In this study, we use human LNCaP prostate cancer cells as a model system to further study the IGF-1R's role in GH signaling. GH promoted JAK2 and GHR tyrosine phosphorylation and STAT5 activation in LNCaP cells. By coimmunoprecipitation and a new split luciferase complementation assay, we find that GH augments GHR/IGF-1R complex formation, which is inhibited by a Fab of an antagonistic anti-GHR monoclonal antibody. Short hairpin RNA-mediated IGF-1R silencing in LNCaP cells reduced GH-induced GHR, JAK2, and STAT5 phosphorylation. Similarly, a soluble IGF-1R extracellular domain fragment (sol IGF-1R) interacts with GHR in response to GH and blunts GH signaling. Sol IGF-1R also markedly inhibits GH-induced IGF-1 gene expression in both LNCaP cells and mouse primary osteoblast cells. On the basis of these and other findings, we propose a model in which IGF-1R augments GH signaling by allowing a putative IGF-1R-associated molecule that regulates GH signaling to access the activated GHR/JAK2 complex and envision sol IGF-1R as a dominant-negative inhibitor of this IGF-1R-mediated augmentation. Physiological implications of this new model are discussed. PMID:25211187

  5. Comparison of IGF-1 (insulin like growth factor-1) levels in bovine serum sampled three times during the day using validated equine IGF-1 elisa

    OpenAIRE

    Mrkun J.; Kosec M.; Zrimšek Petra

    2009-01-01

    Cows in negative energy balance exhibit reduced fertility, mediated by metabolic signals that influence the reproductive system. Measurement of IGF-1 contributes to the diagnosis of negative energy balance. The aim of this study was to investigate possible variations in IGF-1 levels in samples taken at different times of the day. Equine IGF-1 ELISA was used for measuring IGF-1 in bovine samples. Statistical analysis was applied to the results. Using scatter diagrams fitted with Deming regress...

  6. IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling.

    Science.gov (United States)

    Yoneyama, Yosuke; Lanzerstorfer, Peter; Niwa, Hideaki; Umehara, Takashi; Shibano, Takashi; Yokoyama, Shigeyuki; Chida, Kazuhiro; Weghuber, Julian; Hakuno, Fumihiko; Takahashi, Shin-Ichiro

    2018-04-11

    Insulin-like growth factor-I receptor (IGF-IR) preferentially regulates the long-term IGF activities including growth and metabolism. Kinetics of ligand-dependent IGF-IR endocytosis determines how IGF induces such downstream signaling outputs. Here, we find that the insulin receptor substrate (IRS)-1 modulates how long ligand-activated IGF-IR remains at the cell surface before undergoing endocytosis in mammalian cells. IRS-1 interacts with the clathrin adaptor complex AP2. IRS-1, but not an AP2-binding-deficient mutant, delays AP2-mediated IGF-IR endocytosis after the ligand stimulation. Mechanistically, IRS-1 inhibits the recruitment of IGF-IR into clathrin-coated structures; for this reason, IGF-IR avoids rapid endocytosis and prolongs its activity on the cell surface. Accelerating IGF-IR endocytosis via IRS-1 depletion induces the shift from sustained to transient Akt activation and augments FoxO-mediated transcription. Our study establishes a new role for IRS-1 as an endocytic regulator of IGF-IR that ensures sustained IGF bioactivity, independent of its classic role as an adaptor in IGF-IR signaling. © 2018, Yoneyama et al.

  7. Independent regulation of skeletal growth by Ihh and IGF signaling.

    Science.gov (United States)

    Long, Fanxin; Joeng, Kyu-Sang; Xuan, Shouhong; Efstratiadis, Argiris; McMahon, Andrew P

    2006-10-01

    The insulin-like growth factors (IGFs) play a major role in regulating the systemic growth of mammals. However, it is unclear to what extent their systemic and/or local functions act in concert with other local growth factors controlling the sizes of individual organs. We have specifically addressed whether growth control of the skeleton by IGFs interacts genetically with that by Indian hedgehog (Ihh), a locally produced growth signal for the endochondral skeleton. Here, we report that disruption of both IGF and Ihh signaling resulted in additive reduction in the size of the embryonic skeleton. Thus, IGF and Ihh signaling appear to control the growth of the skeleton in parallel pathways.

  8. Curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway.

    Science.gov (United States)

    Tian, Binqiang; Zhao, Yingmei; Liang, Tao; Ye, Xuxiao; Li, Zuowei; Yan, Dongliang; Fu, Qiang; Li, Yonghui

    2017-08-01

    We have previously reported that curcumin inhibits urothelial tumor development in a rat bladder carcinogenesis model. In this study, we report that curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway. Curcumin inhibits IGF2 expression at the transcriptional level and decreases the phosphorylation levels of IGF1R and IRS-1 in bladder cancer cells and N-methyl-N-nitrosourea (MNU)-induced urothelial tumor tissue. Ectopic expression of IGF2 and IGF1R, but not IGF1, in bladder cancer cells restored this process, suggesting that IGF2 is a target of curcumin. Moreover, introduction of constitutively active AKT1 abolished the inhibitory effect of curcumin on cell proliferation, migration, and restored the phosphorylation levels of 4E-BP1 and S6K1, suggesting that curcumin functions via suppressing IGF2-mediated AKT/mTOR signaling pathway. In summary, our results reveal that suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway is one of the mechanisms of action of curcumin. Our findings suggest a new therapeutic strategy against human bladder cancer caused by aberrant activation of IGF2, which are useful for translational application of curcumin.

  9. Investigation on the role of IGF-1 signal transduction in the biological radiation responses

    Energy Technology Data Exchange (ETDEWEB)

    Jung, U Hee; Jo, Sung Kee; Park, Hae Ran; Oh, Soo Jin; Cho, Eun Hee; Eom, Hyun Soo; Ju, Eun Jin

    2009-05-15

    Effects of {gamma}-irradiation on the IGF-1 related gene expressions and activations in various cell lines - Various expression patterns of IGF-1 and IGF-1R following {gamma}-irradiation were observed according to the cell lines - The increased expressions of IGF-1 and IGF-1R were observed in Balb/3T3 and NIH/3T3 cells - Among the IGF-1 downstream signaling molecules, the phosphorylated ERK5 were not changed by {gamma}-irradiation in all three examined cell lines, whereas the phosphorylated p65 were increased by {gamma} -irradiation in all cell lines. The role of IGF-1 and p38 signaling in {gamma}-irradiated mouse embryonic fibroblast (MEF) cells - In MEF cells, IGF-1 signaling molecules were decreased and p21/phosphorylated p38 were increased by {gamma}-irradiation - The experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 signaling is involved but not essential in radiation-induced cell growth arrest and senescence and that p38 MAP kinase play a important role in this cellular radiation response. The role of IGF-1 and p38 signaling in {gamma}-irradiated mouse fibroblast (NIH/3T3) cell - In NIH/3T3 cells, IGF-1 signaling molecules and p21/phosphorylated p38 were increased by {gamma} -irradiation. - However, the experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 and p38 signaling do not play a crucial role in radiation-induced cell growth arrest and senescence in NIH/3T3 cells. Effects of {gamma}-irradiation on the expressions and activations on the genes related to the IGF-1 signaling in mouse tissues - In {gamma}-irradiated mice, the increased expressions of IGF-1 and IGF-1R were observed in the lung and kidney at 2 months after irradiation, and in all the tissues examined (lung, liver and kidney) at 6 months after irradiation. - In the lung of {gamma}-irradiated mice at 6 months after irradiation, the increases of IGF-1R, phosphorylated FOXO3a, p65, p38, p21 were observed. - The

  10. Investigation on the role of IGF-1 signal transduction in the biological radiation responses

    International Nuclear Information System (INIS)

    Jung, U Hee; Jo, Sung Kee; Park, Hae Ran; Oh, Soo Jin; Cho, Eun Hee; Eom, Hyun Soo; Ju, Eun Jin

    2009-05-01

    Effects of γ-irradiation on the IGF-1 related gene expressions and activations in various cell lines - Various expression patterns of IGF-1 and IGF-1R following γ-irradiation were observed according to the cell lines - The increased expressions of IGF-1 and IGF-1R were observed in Balb/3T3 and NIH/3T3 cells - Among the IGF-1 downstream signaling molecules, the phosphorylated ERK5 were not changed by γ-irradiation in all three examined cell lines, whereas the phosphorylated p65 were increased by γ -irradiation in all cell lines. The role of IGF-1 and p38 signaling in γ-irradiated mouse embryonic fibroblast (MEF) cells - In MEF cells, IGF-1 signaling molecules were decreased and p21/phosphorylated p38 were increased by γ-irradiation - The experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 signaling is involved but not essential in radiation-induced cell growth arrest and senescence and that p38 MAP kinase play a important role in this cellular radiation response. The role of IGF-1 and p38 signaling in γ-irradiated mouse fibroblast (NIH/3T3) cell - In NIH/3T3 cells, IGF-1 signaling molecules and p21/phosphorylated p38 were increased by γ -irradiation. - However, the experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 and p38 signaling do not play a crucial role in radiation-induced cell growth arrest and senescence in NIH/3T3 cells. Effects of γ-irradiation on the expressions and activations on the genes related to the IGF-1 signaling in mouse tissues - In γ-irradiated mice, the increased expressions of IGF-1 and IGF-1R were observed in the lung and kidney at 2 months after irradiation, and in all the tissues examined (lung, liver and kidney) at 6 months after irradiation. - In the lung of γ-irradiated mice at 6 months after irradiation, the increases of IGF-1R, phosphorylated FOXO3a, p65, p38, p21 were observed. - The patterns of altered expressions showed significant

  11. Regulation of IGF-1 signaling by microRNAs

    Directory of Open Access Journals (Sweden)

    Hwa Jin eJung

    2015-01-01

    Full Text Available The insulin-like growth factor 1 (IGF-1 signaling pathway regulates critical biological processes including development, homeostasis, and aging. Dysregulation of this pathway has been implicated in a myriad of diseases such as cancers, neurodegenerative diseases, and metabolic disorders, making the IGF-1 signaling pathway a prime target to develop therapeutic and intervention strategies. Recently, small non-coding RNA molecules in ~22 nucleotide length, microRNAs (miRNAs, have emerged as a new regulator of biological processes in virtually all organ systems and increasing studies are linking altered miRNA function to disease mechanisms. A miRNA binds to 3’UTRs of multiple target genes and coordinately down-regulates their expression, thereby exerting a profound influence on gene regulatory networks. Here we review the components of the IGF-1 signaling pathway that are known targets of miRNA regulation, and highlight recent studies that suggest therapeutic potential of these miRNAs against various diseases.

  12. Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles

    OpenAIRE

    Tazearslan, Cagdas; Huang, Jing; Barzilai, Nir; Suh, Yousin

    2011-01-01

    Dampening of insulin/insulin like growth factor-1 (IGF1) signaling results in extension of lifespan in invertebrate as well as murine models. The impact of this evolutionarily conserved pathway on modulation of human lifespan remains unclear. We previously identified two IGF1R mutations (Ala-37-Thr and Arg-407-His) that are enriched in Ashkenazi Jewish centenarians as compared to younger controls and are associated with reduced activity of the IGF1 receptor as measured in immortalized lymphoc...

  13. Role of Ubiquitination in IGF-1 Receptor Signaling and Degradation

    OpenAIRE

    Sehat, Bita; Andersson, Sandra; Vasilcanu, Radu; Girnita, Leonard; Larsson, Olle

    2007-01-01

    BACKGROUND: The insulin-like growth factor 1 receptor (IGF-1R) plays numerous crucial roles in cancer biology. The majority of knowledge on IGF-1R signaling is concerned with its role in the activation of the canonical phosphatidyl inositol-3 kinase (PI3K)/Akt and MAPK/ERK pathways. However, the role of IGF-1R ubiquitination in modulating IGF-1R function is an area of current research. In light of this we sought to determine the relationship between IGF-1R phosphorylation, ubiquitination, and...

  14. Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia.

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    Toshiki Hirakawa

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs, the expression of insulin-like growth factor-1 (IGF1 and IGF1 receptor (IGF1R was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9 was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2 and hypoxia (1% O2. IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed αSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC.

  15. Role of IGF-I Signaling in Muscle Bone Interactions

    Science.gov (United States)

    Bikle, Daniel D; Tahimic, Candice; Chang, Wenhan; Wang, Yongmei; Philippou, Anastassios; Barton, Elisabeth R.

    2015-01-01

    Skeletal muscle and bone rely on a number of growth factors to undergo development, modulate growth, and maintain physiological strength. A major player in these actions is insulin-like growth factor I (IGF-I). However, because this growth factor can directly enhance muscle mass and bone density, it alters the state of the musculoskeletal system indirectly through mechanical crosstalk between these two organ systems. Thus, there are clearly synergistic actions of IGF-I that extend beyond the direct activity through its receptor. This review will cover the production and signaling of IGF-I as it pertains to muscle and bone, the chemical and mechanical influences that arise from IGF-I activity, and the potential for therapeutic strategies based on IGF-I. PMID:26453498

  16. Novel cross-talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses

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    Sacco, Antonella; Morcavallo, Alaide; Vella, Veronica; Voci, Concetta; Spatuzza, Michela; Xu, Shi-Qiong; Iozzo, Renato V.; Vigneri, Riccardo; Morrione, Andrea; Belfiore, Antonino

    2015-01-01

    The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian development and growth, and is frequently deregulated in cancer contributing to tumor initiation and progression. Discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine-kinase, is as well frequently overexpressed in cancer and implicated in cancer progression. Thus, we investigated whether a functional cross-talk between the IGF-IR and DDR1 exists and plays any role in cancer progression. Using human breast cancer cells we found that DDR1 constitutively associated with the IGF-IR. However, this interaction was enhanced by IGF-I stimulation, which promoted rapid DDR1 tyrosine-phosphorylation and co-internalization with the IGF-IR. Significantly, DDR1 was critical for IGF-IR endocytosis and trafficking into early endosomes, IGF-IR protein expression and IGF-I intracellular signaling and biological effects, including cell proliferation, migration and colony formation. These biological responses were inhibited by DDR1 silencing and enhanced by DDR1 overexpression. Experiments in mouse fibroblasts co-transfected with the human IGF-IR and DDR1 gave similar results and indicated that, in the absence of IGF-IR, collagen-dependent phosphorylation of DDR1 is impaired. These results demonstrate a critical role of DDR1 in the regulation of IGF-IR action, and identify DDR1 as a novel important target for breast cancers that overexpress IGF-IR. PMID:25840417

  17. Rosiglitazone Inhibits Adrenocortical Cancer Cell Proliferation by Interfering with the IGF-IR Intracellular Signaling

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    Luconi Michaela

    2008-07-01

    Full Text Available Rosiglitazone (RGZ, a thiazolidinedione ligand of the peroxisome proliferator-activated receptor (PPAR-γ, has been recently described as possessing antitumoral properties. We investigated RGZ effect on cell proliferation in two cell line models (SW13 and H295R of human adrenocortical carcinoma (ACC and its interaction with the signaling pathways of the activated IGF-I receptor (IGF-IR. We demonstrate a high expression of IGF-IR in the two cell lines and in ACC. Cell proliferation is stimulated by IGF-I in a dose- and time-dependent manner and is inhibited by RGZ. The analysis of the main intracellular signaling pathways downstream of the activated IGF-IR, phosphatidyl inositol 3-kinase (PI3K-Akt, and extracellular signal-regulated kinase (ERK1/2 cascades reveals that RGZ rapidly interferes with the Akt and ERK1/2 phosphorylation/activation which mediates IGF-I stimulated proliferation. In conclusion, our results suggest that RGZ exerts an inhibitory effect on human ACC cell proliferation by interfering with the PI3K/Akt and ERK1/2 signaling pathways downstream of the activated IGF-IR.

  18. The Direct Binding of Insulin-like Growth Factor-1 (IGF-1) to Integrin αvβ3 Is Involved in IGF-1 Signaling*

    OpenAIRE

    Saegusa, Jun; Yamaji, Satoshi; Ieguchi, Katsuaki; Wu, Chun-Yi; Lam, Kit S.; Liu, Fu-Tong; Takada, Yoko K.; Takada, Yoshikazu

    2009-01-01

    It has been proposed that ligand occupancy of integrin αvβ3 with extracellular matrix ligands (e.g. vitronectin) plays a critical role in insulin-like growth factor-1 (IGF-1) signaling. We found that expression of αvβ3 enhanced IGF-1-induced proliferation of Chinese hamster ovary cells in serum-free conditions (in the absence of vitronectin). We hypothesized that the direct integrin binding to IGF-1 may play a role in IGF-1 signaling. We demonstrated that αvβ3 specifically and directly bound ...

  19. Impaired Insulin/IGF Signaling in Experimental Alcohol-Related Myopathy

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    Elizabeth Silbermann

    2012-08-01

    Full Text Available Alcohol-related myopathy (Alc-M is highly prevalent among heavy drinkers, although its pathogenesis is not well understood. We hypothesize that Alc-M is mediated by combined effects of insulin/IGF resistance and oxidative stress, similar to the effects of ethanol on liver and brain. We tested this hypothesis using an established model in which adult rats were pair-fed for 8 weeks with isocaloric diets containing 0% (N = 8 or 35.5% (N = 13 ethanol by caloric content. Gastrocnemius muscles were examined by histology, morphometrics, qRT-PCR analysis, and ELISAs. Chronic ethanol feeding reduced myofiber size and mRNA expression of IGF-1 polypeptide, insulin, IGF-1, and IGF-2 receptors, IRS-1, and IRS-2. Multiplex ELISAs demonstrated ethanol-associated inhibition of insulin, IRS-1, Akt, and p70S6K signaling, and increased activation of GSK-3β. In addition, ethanol-exposed muscles had increased 4-hydroxy-2-nonenal immunoreactivity, reflecting lipid peroxidation, and reduced levels of mitochondrial Complex IV, Complex V, and acetylcholinesterase. These results demonstrate that experimental Alc-M is associated with inhibition of insulin/IGF/IRS and downstream signaling that mediates metabolism and cell survival, similar to findings in alcoholic liver and brain degeneration. Moreover, the increased oxidative stress, which could be mediated by mitochondrial dysfunction, may have led to inhibition of acetylcholinesterase, which itself is sufficient to cause myofiber atrophy and degeneration.

  20. Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis

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    Brian T. O’Neill

    2015-05-01

    Full Text Available Insulin and insulin-like growth factor 1 (IGF-1 are major regulators of muscle protein and glucose homeostasis. To determine how these pathways interact, we generated mice with muscle-specific knockout of IGF-1 receptor (IGF1R and insulin receptor (IR. These MIGIRKO mice showed >60% decrease in muscle mass. Despite a complete lack of insulin/IGF-1 signaling in muscle, MIGIRKO mice displayed normal glucose and insulin tolerance. Indeed, MIGIRKO mice showed fasting hypoglycemia and increased basal glucose uptake. This was secondary to decreased TBC1D1 resulting in increased Glut4 and Glut1 membrane localization. Interestingly, overexpression of a dominant-negative IGF1R in muscle induced glucose intolerance in MIGIRKO animals. Thus, loss of insulin/IGF-1 signaling impairs muscle growth, but not whole-body glucose tolerance due to increased membrane localization of glucose transporters. Nonetheless, presence of a dominant-negative receptor, even in the absence of functional IR/IGF1R, induces glucose intolerance, indicating that interactions between these receptors and other proteins in muscle can impair glucose homeostasis.

  1. Essential role of flotillin-1 palmitoylation in the intracellular localization and signaling function of IGF-1 receptor.

    Science.gov (United States)

    Jang, Donghwan; Kwon, Hayeong; Jeong, Kyuho; Lee, Jaewoong; Pak, Yunbae

    2015-06-01

    Here, we explored flotillin-1-mediated regulation of insulin-like growth factor-1 (IGF-1) signaling. Flotillin-1-deficient cells exhibited a reduction in the activation of IGF-1 receptor (IGF-1R), ERK1/2 and Akt pathways, and the transcriptional activation of Elk-1 and the proliferation in response to IGF-1 were reduced in these cells. We found that IGF-1-independent flotillin-1 palmitoylation at Cys34 in the endoplasmic reticulum (ER) was required for the ER exit and the plasma membrane localization of flotillin-1 and IGF-1R. IGF-1-dependent depalmitoylation and repalmitoylation of flotillin-1 sustained tyrosine kinase activation of the plasma-membrane-targeted IGF-1R. Dysfunction and blocking the turnover of flotillin-1 palmitoylation abrogated cancer cell proliferation after IGF-1R signaling activation. Our data show that flotillin-1 palmitoylation is a new mechanism by which the intracellular localization and activation of IGF-1R are controlled. © 2015. Published by The Company of Biologists Ltd.

  2. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

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    Radhakrishnan Sridhar

    2010-05-01

    Full Text Available Abstract Background Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene, a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. Methods We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Results Resveratrol (100-150 μM exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G0/G1-S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. Conclusions For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and

  3. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

    International Nuclear Information System (INIS)

    Vanamala, Jairam; Reddivari, Lavanya; Radhakrishnan, Sridhar; Tarver, Chris

    2010-01-01

    Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene), a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity) and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Resveratrol (100-150 μM) exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G 0 /G 1 -S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and activation of p53, suggesting its potential role as a

  4. Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration.

    Science.gov (United States)

    Deochand, Chetram; Tong, Ming; Agarwal, Amit R; Cadenas, Enrique; de la Monte, Suzanne M

    2016-01-01

    Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer's disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking. This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins. Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs. CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312-IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased AβPP-Aβ, and reduced ASPH protein, which is a target of insulin/IGF-1 signaling. Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal.

  5. Igf1r signaling is indispensable for preimplantation development and is activated via a novel function of E-cadherin.

    Directory of Open Access Journals (Sweden)

    Ivan Bedzhov

    Full Text Available Insulin-like growth factor I receptor (Igf1r signaling controls proliferation, differentiation, growth, and cell survival in many tissues; and its deregulated activity is involved in tumorigenesis. Although important during fetal growth and postnatal life, a function for the Igf pathway during preimplantation development has not been described. We show that abrogating Igf1r signaling with specific inhibitors blocks trophectoderm formation and compromises embryo survival during murine blastocyst formation. In normal embryos total Igf1r is present throughout the membrane, whereas the activated form is found exclusively at cell contact sites, colocalizing with E-cadherin. Using genetic domain switching, we show a requirement for E-cadherin to maintain proper activation of Igf1r. Embryos expressing exclusively a cadherin chimera with N-cadherin extracellular and E-cadherin intracellular domains (NcEc fail to form a trophectoderm and cells die by apoptosis. In contrast, homozygous mutant embryos expressing a reverse-structured chimera (EcNc show trophectoderm survival and blastocoel cavitation, indicating a crucial and non-substitutable role of the E-cadherin ectodomain for these processes. Strikingly, blastocyst formation can be rescued in homozygous NcEc embryos by restoring Igf1r signaling, which enhances cell survival. Hence, perturbation of E-cadherin extracellular integrity, independent of its cell-adhesion function, blocked Igf1r signaling and induced cell death in the trophectoderm. Our results reveal an important and yet undiscovered function of Igf1r during preimplantation development mediated by a unique physical interaction between Igf1r and E-cadherin indispensable for proper receptor activation and anti-apoptotic signaling. We provide novel insights into how ligand-dependent Igf1r activity is additionally gated to sense developmental potential in utero and into a bifunctional role of adhesion molecules in contact formation and signaling.

  6. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition.

    Science.gov (United States)

    Moll, Lorna; Ben-Gedalya, Tziona; Reuveni, Hadas; Cohen, Ehud

    2016-04-01

    The discovery that the alteration of aging by reducing the activity of the insulin/IGF-1 signaling (IIS) cascade protects nematodes and mice from neurodegeneration-linked, toxic protein aggregation (proteotoxicity) raises the prospect that IIS inhibitors bear therapeutic potential to counter neurodegenerative diseases. Recently, we reported that NT219, a highly efficient IGF-1 signaling inhibitor, protects model worms from the aggregation of amyloid β peptide and polyglutamine peptides that are linked to the manifestation of Alzheimer's and Huntington's diseases, respectively. Here, we employed cultured cell systems to investigate whether NT219 promotes protein homeostasis (proteostasis) in mammalian cells and to explore its underlying mechanisms. We found that NT219 enhances the aggregation of misfolded prion protein and promotes its deposition in quality control compartments known as "aggresomes." NT219 also elevates the levels of certain molecular chaperones but, surprisingly, reduces proteasome activity and impairs autophagy. Our findings show that IGF-1 signaling inhibitors in general and NT219 in particular can promote proteostasis in mammalian cells by hyperaggregating hazardous proteins, thereby bearing the potential to postpone the onset and slow the progression of neurodegenerative illnesses in the elderly.-Moll, L., Ben-Gedalya, T., Reuveni, H., Cohen, E. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition. © FASEB.

  7. The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

    Energy Technology Data Exchange (ETDEWEB)

    Munoz, Juan Pablo; Collao, Andres; Chiong, Mario; Maldonado, Carola; Adasme, Tatiana; Carrasco, Loreto; Ocaranza, Paula; Bravo, Roberto; Gonzalez, Leticia; Diaz-Araya, Guillermo [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Facultad de Ciencias Quimicas y Farmaceuticas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Hidalgo, Cecilia [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Lavandero, Sergio, E-mail: slavander@uchile.cl [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Facultad de Ciencias Quimicas y Farmaceuticas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile)

    2009-10-09

    Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-induced MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal {alpha}-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.

  8. The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

    International Nuclear Information System (INIS)

    Munoz, Juan Pablo; Collao, Andres; Chiong, Mario; Maldonado, Carola; Adasme, Tatiana; Carrasco, Loreto; Ocaranza, Paula; Bravo, Roberto; Gonzalez, Leticia; Diaz-Araya, Guillermo; Hidalgo, Cecilia; Lavandero, Sergio

    2009-01-01

    Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-induced MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal α-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.

  9. Elevated IGFBP3 levels in diabetic tears: a negative regulator of IGF-1 signaling in the corneal epithelium.

    Science.gov (United States)

    Wu, Yu-Chieh; Buckner, Benjamin R; Zhu, Meifang; Cavanagh, H Dwight; Robertson, Danielle M

    2012-04-01

    To determine the ratio of IGFBP3:IGF-1 in normal and diabetic human tears, and in telomerase-immortalized human corneal epithelial cells (hTCEpi) cultured under elevated glucose conditions and to correlate these changes with total and phosphorylated levels of IGF-1R. Tear samples were collected noninvasively from diabetic subjects and non-diabetic controls; corneal sensitivity was assessed using a Cochet-Bonnet Aesthesiometer. Conditioned media were collected following culture of hTCEpi cells in normal (5 mM) and elevated (25 mM) glucose conditions; mannitol was used as an osmotic control. IGFBP3, IGF-1, and phosphorylated IGF-1R levels were assessed by ELISA. IGFBP3 and IGF-1R mRNA were assessed by real-time polymerase chain reaction (PCR). Total and phosphorylated IGF-1R expression in whole cell lysates was assessed by western blot. There was a 2.8-fold increase in IGFBP3 in diabetic tears compared to non-diabetic controls (P=0.006); IGF-1 levels were not significantly altered. No difference in corneal sensitivity was detected between groups. The concentration of IGFBP3 in tears was independent of IGF-1. Consistent with human tear measurements in vivo, IGFBP3 secretion was increased 2.2 fold (Ptears compared to normal controls blocked phosphorylation of the IGF-1R by IGF-1 (Ptears may attenuate IGF-1R signaling in the diabetic cornea. A long-term increase in IGFBP3 may contribute to epithelial compromise and the pathogenesis of ocular surface complications reported in diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Determination of LongR3-IGF-I, R3-IGF-I, Des1-3 IGF-I and their metabolites in human plasma samples by means of LC-MS.

    Science.gov (United States)

    Thomas, Andreas; Walpurgis, Katja; Delahaut, Philippe; Fichant, Eric; Schänzer, Wilhelm; Thevis, Mario

    2017-08-01

    According to the regulations of the World Anti-Doping Agency (WADA), growth promoting peptides such as the insulin-like growth factor-I (IGF-I) and its synthetic analogues belong to the class of prohibited compounds. While several assays to quantify endogenous IGF-I have been established, the potential misuse of synthetic analogues such as LongR 3 -IGF-I, R 3 -IGF-I and Des1-3-IGF-I remains a challenge and superior pharmacokinetic properties have been described for these analogues. Within the present study, it was demonstrated that the target peptides can be successfully detected in plasma samples by means of magnetic beads-based immunoaffinity purification and subsequent nanoscale liquid chromatographic separation with high resolution mass spectrometric detection. Noteworthy, the usage of a specific antibody for LongR 3 -IGF-I enables the determination in low ng/mL levels despite the presence of an enormous excess of endogenous human IGF-I. In addition, different metabolism studies (in-vitro and in-vivo) were performed using sophisticated strategies such as incubation with skin tissue microsomes, degradation in biological fluids (for all analogues), and administration to rats (for LongR 3 -IGF-I). Herewith, several C-and N-terminally truncated metabolites were identified and their relevancy was additionally confirmed by in-vivo experiments with rodents. Especially for LongR 3 -IGF-I, a metabolite ((Des1-11)-LongR 3 -IGF-I) was identified that prolonged the detectability in-vivo by a factor of approximately 2. The method was validated for qualitative interpretation considering the parameters specificity, identification capability, recovery (26-60%), limit of detection (0.5ng/mL), imprecision (IGF-I was used as internal standard to control all sample preparation steps. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action.

    Science.gov (United States)

    Rabiee, Atefeh; Krüger, Marcus; Ardenkjær-Larsen, Jacob; Kahn, C Ronald; Emanuelli, Brice

    2018-07-01

    Insulin/IGF-1 action is driven by a complex and highly integrated signalling network. Loss-of-function studies indicate that the major insulin/IGF-1 receptor substrate (IRS) proteins, IRS-1 and IRS-2, mediate different biological functions in vitro and in vivo, suggesting specific signalling properties despite their high degree of homology. To identify mechanisms contributing to the differential signalling properties of IRS-1 and IRS-2 in the mediation of insulin/IGF-1 action, we performed comprehensive mass spectrometry (MS)-based phosphoproteomic profiling of brown preadipocytes from wild type, IRS-1 -/- and IRS-2 -/- mice in the basal and IGF-1-stimulated states. We applied stable isotope labeling by amino acids in cell culture (SILAC) for the accurate quantitation of changes in protein phosphorylation. We found ~10% of the 6262 unique phosphorylation sites detected to be regulated by IGF-1. These regulated sites included previously reported substrates of the insulin/IGF-1 signalling pathway, as well as novel substrates including Nuclear Factor I X and Semaphorin-4B. In silico prediction suggests the protein kinase B (PKB), protein kinase C (PKC), and cyclin-dependent kinase (CDK) as the main mediators of these phosphorylation events. Importantly, we found preferential phosphorylation patterns depending on the presence of either IRS-1 or IRS-2, which was associated with specific sets of kinases involved in signal transduction downstream of these substrates such as PDHK1, MAPK3, and PKD1 for IRS-1, and PIN1 and PKC beta for IRS-2. Overall, by generating a comprehensive phosphoproteomic profile from brown preadipocyte cells in response to IGF-1 stimulation, we reveal both common and distinct insulin/IGF-1 signalling events mediated by specific IRS proteins. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action

    DEFF Research Database (Denmark)

    Rabiee, Atefeh; Krüger, Marcus; Ardenkjær-Larsen, Jacob

    2018-01-01

    Insulin/IGF-1 action is driven by a complex and highly integrated signalling network. Loss-of-function studies indicate that the major insulin/IGF-1 receptor substrate (IRS) proteins, IRS-1 and IRS-2, mediate different biological functions in vitro and in vivo, suggesting specific signalling...... properties despite their high degree of homology. To identify mechanisms contributing to the differential signalling properties of IRS-1 and IRS-2 in the mediation of insulin/IGF-1 action, we performed comprehensive mass spectrometry (MS)-based phosphoproteomic profiling of brown preadipocytes from wild type......, IRS-1-/-and IRS-2-/-mice in the basal and IGF-1-stimulated states. We applied stable isotope labeling by amino acids in cell culture (SILAC) for the accurate quantitation of changes in protein phosphorylation. We found ~10% of the 6262 unique phosphorylation sites detected to be regulated by IGF-1...

  13. The dipeptide Pro-Asp promotes IGF-1 secretion and expression in hepatocytes by enhancing JAK2/STAT5 signaling pathway.

    Science.gov (United States)

    Wang, Songbo; Wang, Guoqing; Zhang, Mengyuan; Zhuang, Lu; Wan, Xiaojuan; Xu, Jingren; Wang, Lina; Zhu, Xiaotong; Gao, Ping; Xi, Qianyun; Zhang, Yongliang; Shu, Gang; Jiang, Qingyan

    2016-11-15

    It has been implicated that IGF-1 secretion can be regulated by dietary protein. However, whether the dipeptides, one of digested products of dietary protein, have influence on IGF-1 secretion remain largely unknown. Our study aimed to investigate the effects of the dipeptide Pro-Asp on IGF-1 secretion and expression in hepatocytes and to explore the possible underlying mechanisms. Our findings demonstrated that Pro-Asp promoted the secretion and gene expression of IGF-1 in HepG2 cells and primary porcine hepatocytes. Meanwhile, Pro-Asp activated the ERK and Akt signaling pathways, downstream of IGF-1. In addition, Pro-Asp enhanced GH-mediated JAK2/STAT5 signaling pathway, while inhibition of JAK2/STAT5 blocked the promotive effect of Pro-Asp on IGF-1 secretion and expression. Moreover, acute injection of Pro-Asp stimulated IGF-1 expression and activated JAK2/STAT5 signaling pathway in mice liver. Together, these results suggested that the dipeptide Pro-Asp promoted IGF-1 secretion and expression in hepatocytes by enhancing GH-mediated JAK2/STAT5 signaling pathway. Copyright © 2016. Published by Elsevier Ireland Ltd.

  14. The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS. Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling.

    Science.gov (United States)

    Beitner-Johnson, D; Blakesley, V A; Shen-Orr, Z; Jimenez, M; Stannard, B; Wang, L M; Pierce, J; LeRoith, D

    1996-04-19

    The Crk proto-oncogene product is an SH2 and SH3 domain-containing adaptor protein which we have previously shown to become rapidly tyrosine phosphorylated in response to stimulation with insulin-like growth factor I (IGF-I) in NIH-3T3 cells. In order to further characterize the role of Crk in the IGF-I signaling pathway, NIH-3T3 and 293 cells were stably transfected with an expression vector containing the Crk cDNA. The various resultant 3T3-Crk clones expressed Crk at approximately 2-15-fold higher levels than parental 3T3 cells. In 3T3-Crk cells, Crk immunoreactivity was detected in insulin receptor substrate-1 (IRS-1) immunoprecipitates. Stimulation with IGF-I resulted in a dissociation of Crk protein from IRS-1. In contrast, the association of the related adaptor protein Grb2 with IRS-1 was enhanced by IGF-I stimulation. Similar results were obtained in stably transfected 293-Crk cells, which express both IRS-1 and the IRS-1-related signaling protein 4PS. In these cells, IRS-1 and 4PS both associated with Crk, and this association was also decreased by IGF-I treatment, whereas the association of Grb2 with IRS-1 and 4PS was enhanced by IGF-I. Overexpression of Crk also enhanced IGF-I-induced mitogenesis of NIH-3T3 cells, as measured by [3H]thymidine incorporation. The levels of IGF-I-induced mitogenesis were proportional to the level of Crk expression. These results suggest that Crk is a positive effector of IGF-I signaling, and may mediate its effects via interaction with IRS-1 and/or 4PS.

  15. IGF-1 Receptor and adhesion signaling: an important axis in determining cancer cell phenotype and therapy resistance.

    Directory of Open Access Journals (Sweden)

    Orla T Cox

    2015-07-01

    Full Text Available IGF-1R expression and activation levels generally cannot be correlated in cancer cells, suggesting that cellular proteins may modulate IGF-1R activity. Strong candidates for such modulation are found in cell-matrix and cell-cell adhesion signaling complexes. Activated IGF-1R is present at focal adhesions, where it can stabilize β1 integrin and participate in signaling complexes that promote invasiveness associated with epithelial mesenchymal transition (EMT, and resistance to therapy. Whether IGF-1R contributes to EMT or to non-invasive tumor growth may be strongly influenced by the degree of ECM engagement and the presence or absence of key proteins in IGF-1R-cell adhesion complexes. One such protein is PDLIM2, which promotes both cell polarization and EMT by regulating the stability of transcription factors including NFκB, STATs and beta catenin. PDLIM2 exhibits tumor suppressor activity, but is also highly expressed in certain invasive cancers. It is likely that distinct adhesion complex proteins modulate IGF-1R signaling during cancer progression or adaptive responses to therapy. Thus, identifying the key modulators will be important for developing effective therapeutic strategies and predictive biomarkers.

  16. Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer.

    Science.gov (United States)

    Wang, Xinjing; Zhu, Qinyi; Lin, Yingying; Wu, Li; Wu, Xiaoli; Wang, Kai; He, Qizhi; Xu, Congjian; Wan, Xiaoping; Wang, Xipeng

    2017-10-24

    Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14 + Tie2 + , TEMs) as key contributors to angiogenesis and metastasis of EOC. Tissue slides were evaluated by immunofluorescence for the presence of total tissue macrophages and TEMs. The correlation between microvascular density (MVD) values and the TEMs number or ratio was calculated in both ovarian cancer tissues and peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood of female healthy donors, benign cysts patients, and EOC patients using flow cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by ELISA in serum samples of EOC patients, benign cysts patients, and ascites samples of EOC patients. The effects of Ang2 on the migration and the cytokine expression of TEMs were further examined. The pro- angiogenesis activity of TEMs via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test was performed using neutralising antibody. TEMs were significantly higher in tumour foci, peripheral blood and ascites in EOC patients. The proportion of TEMs among total tissue macrophages was positively correlated with tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and metastasis. Further functional and mechanisms studies revealed that concentration of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs. Recruited TEMs promoted endothelial cell function through IGF1-activated downstream signalling. Blocking secreted IGF1 using inhibiting antibody

  17. GPER1-mediated IGFBP-1 induction modulates IGF-1-dependent signaling in tamoxifen-treated breast cancer cells.

    Science.gov (United States)

    Vaziri-Gohar, Ali; Houston, Kevin D

    2016-02-15

    Tamoxifen, a selective estrogen receptor modulator, is a commonly prescribed adjuvant therapy for estrogen receptor-α (ERα)-positive breast cancer patients. To determine if extracellular factors contribute to the modulation of IGF-1 signaling after tamoxifen treatment, MCF-7 cells were treated with IGF-1 in conditioned medium (CM) obtained from 4-OHT-treated MCF-7 cells and the accumulation of phospho-Akt (S473) was measured. CM inhibited IGF-1-dependent cell signaling and suggesting the involvement of extracellular factors (ie. IGFBPs). A significant increase in IGFBP-1 mRNA and extracellular IGFBP-1 protein was observed in 4-OHT-treated MCF-7 cells. Knockdown experiments demonstrated that both GPER1 and CREB mediate IGFBP-1 induction. Furthermore, experiments showed that 4-OHT-dependent IGFBP-1 transcription is downstream of GPER1-activation in breast cancer cells. Additionally, neutralization and knockdown experiments demonstrated a role for IGFBP-1 in the observed inhibition of IGF-1 signaling. These results suggested that 4-OHT inhibits IGF-1 signaling via GPER1 and CREB mediated extracellular IGFBP-1 accumulation in breast cancer cells. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  18. Differential Regulation of Hippocampal IGF-1-Associated Signaling Proteins by Dietary Restriction in Aging Mouse.

    Science.gov (United States)

    Hadem, Ibanylla Kynjai Hynniewta; Sharma, Ramesh

    2017-08-01

    Time-dependent alterations in several biological processes of an organism may be characterized as aging. One of the effects of aging is the decline in cognitive functions. Dietary restriction (DR), an intervention where the consumption of food is lessened but without malnutrition, is a well-established mechanism that has a wide range of important outcomes including improved health span, delayed aging, and extension of lifespan of various species. It also plays a beneficial role in protecting against age-dependent deterioration of cognitive functions, and has neuroprotective properties against neurodegenerative diseases. Insulin-like growth factor (IGF)-1 plays an important role in the regulation of cellular and tissue functions, and relating to the aging process the most important pathway of IGF-1 is the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt/PKB) signaling cascade. Although many have studied the changes in the level of IGF-1 and its effect on neural proliferation, the downstream signaling proteins have not been fully elucidated. Hence in the present investigation, the IGF-1 gene expression and the normal endogenous levels of IGF1R (IGF-1 receptor), PI3K, Akt, pAkt, and pFoxO in the hippocampus of young, adult, and old mice were determined using real-time PCR and Western blot analyses. The effects of DR on these protein levels were also studied. Results showed a decrease in the levels of IGF-1, IGF1R, PI3K, and pAkt, while pFoxO level increased with respect to age. Under DR, these protein levels are maintained in adult mice, but old mice displayed diminished expression levels of these proteins as compared to ad libitum-fed mice. Maintenance of PI3K/Akt pathway results in the phosphorylation of FoxOs, necessary for the enhancement of neural proliferation and survival in adult mice. The down-regulation of IGF-I signaling, as observed in old mice, leads to increasing the activity of FoxO factors that may be important for the neuroprotective

  19. Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling.

    Science.gov (United States)

    Shi, Haojun; Fang, Winston; Liu, Minda; Fu, Deliang

    2017-10-01

    Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor-induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin-like growth factor-1 (IGF-1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF-1-dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF-1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF-1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF-1/IGF-1R-induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF-1/IGF-1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies. © 2017 UICC.

  20. Transcriptional profiling of ErbB signalling in mammary luminal epithelial cells - interplay of ErbB and IGF1 signalling through IGFBP3 regulation

    International Nuclear Information System (INIS)

    Worthington, Jenny; Bertani, Mariana; Chan, Hong-Lin; Gerrits, Bertran; Timms, John F

    2010-01-01

    Members of the ErbB family of growth factor receptors are intricately linked with epithelial cell biology, development and tumourigenesis; however, the mechanisms involved in their downstream signalling are poorly understood. Indeed, it is unclear how signal specificity is achieved and the relative contribution each receptor has to specific gene expression. Gene expression profiling of a human mammary luminal epithelial cell model of ErbB2-overexpression was carried out using cDNA microarrays with a common RNA reference approach to examine long-term overlapping and differential responses to EGF and heregulin beta1 treatment in the context of ErbB2 overexpression. Altered gene expression was validated using quantitative real time PCR and/or immunoblotting. One gene of interest was targeted for further characterisation, where the effects of siRNA-mediated silencing on IGF1-dependent signalling and cellular phenotype were examined and compared to the effects of loss of ErbB2 expression. 775 genes were differentially expressed and clustered in terms of their growth factor responsiveness. As well as identifying uncharacterized genes as novel targets of ErbB2-dependent signalling, ErbB2 overexpression augmented the induction of multiple genes involved in proliferation (e.g. MYC, MAP2K1, MAP2K3), autocrine growth factor signalling (VEGF, PDGF) and adhesion/cytoskeletal regulation (ZYX, THBS1, VCL, CNN3, ITGA2, ITGA3, NEDD9, TAGLN), linking them to the hyper-poliferative and altered adhesive phenotype of the ErbB2-overexpressing cells. We also report ErbB2-dependent down-regulation of multiple interferon-stimulated genes that may permit ErbB2-overexpressing cells to resist the anti-proliferative action of interferons. Finally, IGFBP3 was unique in its pattern of regulation and we further investigated a possible role for IGFBP3 down-regulation in ErbB2-dependent transformation through suppressed IGF1 signalling. We show that IGF1-dependent signalling and proliferation were

  1. Interference of silibinin with IGF-1R signalling pathways protects human epidermoid carcinoma A431 cells from UVB-induced apoptosis

    International Nuclear Information System (INIS)

    Liu, Weiwei; Otkur, Wuxiyar; Li, Lingzhi; Wang, Qiong; He, Hao; Zang, Linghe; Hayashi, Toshihiko; Tashiro, Shin-ichi; Onodera, Satoshi; Xia, Mingyu; Ikejima, Takashi

    2013-01-01

    Highlights: ► Silibinin protects A431 cells from UVB irradiation-induced apoptosis. ► Up-regulation of the IGF-1R-JNK/ERK pathways by UVB induces cell apoptosis. ► Silibinin inhibits IGF-1R pathways to repress caspase-8-mediated apoptosis. -- Abstract: Ultraviolet B (UVB) from sunlight is a major cause of cutaneous lesion. Silibinin, a traditional hepatic protectant, elicits protective effects against UVB-induced cellular damage. In A431 cells, the insulin-like growth factor-1 receptor (IGF-1R) was markedly up-regulated by UVB irradiation. The activation of the IGF-1R signalling pathways contributed to apoptosis of the cells rather than rescuing the cells from death. Up-regulated IGF-1R stimulated downstream mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinases (JNK) and extracellular signal-regulated protein kinases 1/2 (ERK1/2). The subsequent activation of caspase-8 and caspase-3 led to apoptosis. The activation of IGF-1R signalling pathways is the cause of A431 cell death. The pharmacological inhibitors and the small interfering RNA (siRNA) targeting IGF-1R suppressed the downstream activation of JNK/ERK-caspases to help the survival of the UVB-irradiated A431 cells. Indeed, silibinin treatment suppressed the IGF-1R-JNK/ERK pathways and thus protected the cells from UVB-induced apoptosis

  2. Involvement of IGF-1/IGFBP-3 signaling on the conspicuousness of facial pores.

    Science.gov (United States)

    Sugiyama-Nakagiri, Yoriko; Ohuchi, Atsushi; Hachiya, Akira; Kitahara, Takashi

    2010-11-01

    Conspicuous facial pores are one type of serious esthetic defects for many women. We previously reported that the severity of impairment of skin architecture around facial pores correlates well with the appearance of facial pores in several ethnic groups. In our last report, we showed that serum levels of insulin-like growth factor-1 (IGF-1) correlate well with facial pore size and with the severity of impairment of epidermal architecture around facial pores. However, our results could not fully explain the implication between facial pores and IGF signaling. In this study, we conducted a histological analysis of facial skin to determine whether potential changes in IGF-1 availability occur in the skin with or without conspicuous pores. Immunohistochemical observations showed that expression of insulin-like growth factor binding protein-3 (IGFBP-3) is limited to the suprapapillary epidermis around facial pores and to basal cells of rete pegs without tips in epidermis with conspicuous pores. In contrast, in basal cells of skin without conspicuous pores, IGFBP-3 expression is very low. Ki-67 and IGF-1 receptor-positive cells are abundant in basal cells in the tips of the rete pegs in skin with typical epidermal architecture around facial pores. No obvious differences were observed in the expression of filaggrin, involucrin, K1, K6 or K17 in skin with or without conspicuous pores. However, increased expression of K16 was observed in skin with conspicuous pores suggesting hyperproliferation. These results suggest that the IGF-1/IGFBP-3 signaling pathway is involved in the formation of conspicuous facial pores due to the epidermal architecture around facial pores.

  3. Identification of Compounds That Inhibit IGF-I Signaling in Hyperglycemia

    Directory of Open Access Journals (Sweden)

    Laura A. Maile

    2009-01-01

    Full Text Available Increased responsiveness of vascular cells to the growth factor IGF-I has been implicated in complications associated with diabetes. Here we describe the development of an assay and screening of a library of compounds for their ability to accelerate cleavage of the transmembrane protein integrin-associated protein (IAP thereby disrupting the association between IAP and SHPS-1 which we have shown as critical for the enhanced response of vascular cells to IGF-I. The cell-based ELISA utilizes an antibody that specifically detects cleaved, but not intact, IAP. Of the 1040 compounds tested, 14 were considered active by virtue of their ability to stimulate an increase in antibody-binding indicative of IAP cleavage. In experiments with smooth muscle and retinal endothelial cell cultures in hyperglycemic conditions, each active compound was shown to accelerate the cleavage of IAP, and this was associated with a decrease in IAP association with SHPS-1 as determined by coimmunoprecipitation of the proteins from cell lysates. As a consequence of the acceleration in IAP cleavage, the compounds were shown to inhibit IGF-I-stimulated phosphorylation of key signaling molecules including Shc and ERK1/2, and this in turn was associated with a decrease in IGF-I-stimulated cell proliferation. Identification of these compounds that utilize this mechanism has the potential to yield novel therapeutic approaches for the prevention and treatment of vascular complications associated with diabetes.

  4. Serum from Chronic Hepatitis B Patients Promotes Growth and Proliferation via the IGF-II/IGF-IR/MEK/ERK Signaling Pathway in Hepatocellular Carcinoma Cells.

    Science.gov (United States)

    Ji, Yuanyuan; Wang, Zhidong; Chen, Haiyan; Zhang, Lei; Zhuo, Fei; Yang, Qingqing

    2018-05-09

    Chronic hepatitis B virus (HBV) infection (CHB) plays a central role in the etiology of hepatocellular carcinoma (HCC). Emerging evidence implicates insulin-like growth factor (IGF)-II as a major risk factor for the growth and development of HCC. However, the relationship between HBV infection and IGF-II functions remains to be elucidated. Levels of circulating IGF-II and IGF-I receptor (IGF-IR) in healthy donors (HDs) and CHB patients were tested by ELISA. Human HCC cell lines (HepG-2, SMMC-7721, MHCC97-H) were incubated with serum from HDs and CHB patients at various concentrations for 24, 48, and 72 h. MTT and plate colony formation assays, BrdU ELISA, ELISA, small-interfering RNA (siRNA) transfection, quantitative real-time PCR, and western blot were applied to assess the functional and molecular mechanisms in HCC cell lines. Serum levels of IGF-II and IGF-IR were significantly higher in CHB patients than in HDs. Additionally, serum from CHB patients directly induced cell growth, proliferation, IGF-II secretion, and HDGF-related protein-2 (HRP-2) and nuclear protein 1 (NUPR1) mRNA and protein expression in HCC cells. Moreover, serum from CHB patients increased IGF-II-induced cell growth, proliferation, and HRP-2 and NUPR1 mRNA and protein expression in HCC cells. Blockade of IGF-IR clearly inhibited the above effects. Most importantly, interference with IGF-II function markedly repressed the cell proliferation and HRP-2 and NUPR1 mRNA and protein expression induced by serum from CHB patients. Furthermore, serum from CHB patients induced ERK phosphorylation via IGF-IR, with the MEK inhibitor PD98059 significantly decreasing CHB patient serum-induced IGF-II secretion, cell proliferation, and HRP-2 and NUPR1 mRNA and protein expression. Serum from CHB patients increases cell growth and proliferation and enhances HRP-2 and NUPR1 expression in HCC cells via the IGF-II/IGF-IR/MEK/ERK signaling pathway. These findings help to explain the molecular mechanisms

  5. IGF-1 Alleviates High Fat Diet-Induced Myocardial Contractile Dysfunction: Role of Insulin Signaling and Mitochondrial Function

    Science.gov (United States)

    Zhang, Yingmei; Yuan, Ming; Bradley, Katherine M.; Dong, Feng; Anversa, Piero; Ren, Jun

    2012-01-01

    Obesity is often associated with reduced plasma IGF-1 levels, oxidative stress, mitochondrial damage and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high fat diet-induced oxidative, myocardial, geometric and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low (10%) or high fat (45%) diet to induce obesity. High fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin-6, insulin and triglyceride as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end systolic and diastolic diameter, increased wall thickness, and cardiac hypertrophy in high fat-fed FVB mice. High fat diet promoted ROS generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca2+ dysregulation, including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor, post-receptor signaling molecules IRS-1 (tyrosine/serine phosphorylation), Akt, GSK3β, Foxo3a, mTOR, as well as downregulated expression of mitochondrial proteins PPARγ coactivator 1α (PGC1α) and UCP-2. Intriguingly, IGF-1 mitigated high fat diet feeding-induced alterations in ROS, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca2+ handling and insulin signaling, but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly due to preserved cell survival, mitochondrial function and insulin signaling. PMID:22275536

  6. Phosphatidylinositol 3-Kinase (PI3K) Activity Bound to Insulin-like Growth Factor-I (IGF-I) Receptor, which Is Continuously Sustained by IGF-I Stimulation, Is Required for IGF-I-induced Cell Proliferation*

    Science.gov (United States)

    Fukushima, Toshiaki; Nakamura, Yusaku; Yamanaka, Daisuke; Shibano, Takashi; Chida, Kazuhiro; Minami, Shiro; Asano, Tomoichiro; Hakuno, Fumihiko; Takahashi, Shin-Ichiro

    2012-01-01

    Continuous stimulation of cells with insulin-like growth factors (IGFs) in G1 phase is a well established requirement for IGF-induced cell proliferation; however, the molecular components of this prolonged signaling pathway that is essential for cell cycle progression from G1 to S phase are unclear. IGF-I activates IGF-I receptor (IGF-IR) tyrosine kinase, followed by phosphorylation of substrates such as insulin receptor substrates (IRS) leading to binding of signaling molecules containing SH2 domains, including phosphatidylinositol 3-kinase (PI3K) to IRS and activation of the downstream signaling pathways. In this study, we found prolonged (>9 h) association of PI3K with IGF-IR induced by IGF-I stimulation. PI3K activity was present in this complex in thyrocytes and fibroblasts, although tyrosine phosphorylation of IRS was not yet evident after 9 h of IGF-I stimulation. IGF-I withdrawal in mid-G1 phase impaired the association of PI3K with IGF-IR and suppressed DNA synthesis the same as when PI3K inhibitor was added. Furthermore, we demonstrated that Tyr1316-X-X-Met of IGF-IR functioned as a PI3K binding sequence when this tyrosine is phosphorylated. We then analyzed IGF signaling and proliferation of IGF-IR−/− fibroblasts expressing exogenous mutant IGF-IR in which Tyr1316 was substituted with Phe (Y1316F). In these cells, IGF-I stimulation induced tyrosine phosphorylation of IGF-IR and IRS-1/2, but mutated IGF-IR failed to bind PI3K and to induce maximal phosphorylation of GSK3β and cell proliferation in response to IGF-I. Based on these results, we concluded that PI3K activity bound to IGF-IR, which is continuously sustained by IGF-I stimulation, is required for IGF-I-induced cell proliferation. PMID:22767591

  7. CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling.

    Science.gov (United States)

    Manara, Maria Cristina; Terracciano, Mario; Mancarella, Caterina; Sciandra, Marika; Guerzoni, Clara; Pasello, Michela; Grilli, Andrea; Zini, Nicoletta; Picci, Piero; Colombo, Mario P; Morrione, Andrea; Scotlandi, Katia

    2016-11-29

    CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles, whose excessive accumulation provokes methuosis. This process, which is not detected in CD99-expressing normal mesenchymal cells, is inhibited by disruption of the IGF-1R signaling, whereas enhanced by IGF-1 stimulation. Induction of IGF-1R/RAS/Rac1 was also observed in the EWS xenografts that respond to anti-CD99 mAb, further supporting the role of the IGF/RAS/Rac1 axis in the hyperstimulation of macropinocytosis and selective death of EWS cells. Thus, we describe a vulnerability of EWS cells, including those resistant to standard chemotherapy, to a treatment with anti-CD99 mAb, which requires IGF-1R/RAS signaling but bypasses the need for their direct targeting. Overall, we propose CD99 targeting as new opportunity to treat EWS patients resistant to canonical apoptosis-inducing agents.

  8. Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington's Disease human lymphoblasts.

    Science.gov (United States)

    Naia, Luana; Ferreira, I Luísa; Cunha-Oliveira, Teresa; Duarte, Ana I; Ribeiro, Márcio; Rosenstock, Tatiana R; Laço, Mário N; Ribeiro, Maria J; Oliveira, Catarina R; Saudou, Frédéric; Humbert, Sandrine; Rego, A Cristina

    2015-02-01

    Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca(2+) levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca(2+) accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.

  9. Inflammation and linear bone growth: the inhibitory role of SOCS2 on GH/IGF-1 signaling.

    Science.gov (United States)

    Farquharson, Colin; Ahmed, S Faisal

    2013-04-01

    Linear bone growth is widely recognized to be adversely affected in children with chronic kidney disease (CKD) and other chronic inflammatory disorders. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) pathway is anabolic to the skeleton and inflammatory cytokines compromise bone growth through a number of different mechanisms, which include interference with the systemic as well as the tissue-level GH/IGF-1 axis. Despite attempts to promote growth and control disease, there are an increasing number of reports of the persistence of poor growth in a substantial proportion of patients receiving rhGH and/or drugs that block cytokine action. Thus, there is an urgent need to consider better and alternative forms of therapy that are directed specifically at the mechanism of the insult which leads to abnormal bone health. Suppressor of cytokine signaling 2 (SOCS2) expression is increased in inflammatory conditions including CKD, and is a recognized inhibitor of GH signaling. Therefore, in this review, we will focus on the premise that SOCS2 signaling represents a critical pathway in growth plate chondrocytes through which pro-inflammatory cytokines alter both GH/IGF-1 signaling and cellular function.

  10. S-nitrosylation of the IGF-1 receptor disrupts the cell proliferative action of IGF-1.

    Science.gov (United States)

    Okada, Kazushi; Zhu, Bao-Ting

    2017-09-30

    The insulin-like growth factor 1 receptor (IGF-1R) is a disulfide-linked heterotetramer containing two α-subunits and two β-subunits. Earlier studies demonstrate that nitric oxide (NO) can adversely affect IGF-1 action in the central nervous system. It is known that NO can induce S-nitrosylation of the cysteine residues in proteins, thereby partly contributing to the regulation of protein function. In the present study, we sought to determine whether S-nitrosylation of the cysteine residues in IGF-1R is an important post-translational modification that regulates its response to IGF-1. Using cultured SH-SY5Y human neuroblastoma cells as an in vitro model, we found that treatment of cells with S-nitroso-cysteine (SNOC), a NO donor that can nitrosylate the cysteine residues in proteins, induces S-nitrosylation of the β subunit of IGF-1R but not its α-subunit. IGF-1Rβ S-nitrosylation by SNOC is coupled with increased dissociation of the IGF-1R protein complex. In addition, disruption of the IGF-1R function resulting from S-nitrosylation of the IGF-1Rβ subunit is associated with disruption of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. Further, we observed that SNOC-induced IGF-1Rβ S-nitrosylation results in a dose-dependent inhibition of cell proliferation and survival. Together, these results suggest that elevated nitrosative stress may result in dysfunction of cellular IGF-1R signaling through S-nitrosylation of the cysteine residues in the IGF-1Rβ subunit, thereby disrupting the downstream PI3K and MAPK signaling functions and ultimately resulting in inhibition of cell proliferation and survival. Copyright © 2017. Published by Elsevier Inc.

  11. Regulation of dendritic cell function by insulin/IGF-1/PI3K/Akt signaling through klotho expression.

    Science.gov (United States)

    Xuan, Nguyen Thi; Hoang, Nguyen Huy; Nhung, Vu Phuong; Duong, Nguyen Thuy; Ha, Nguyen Hai; Hai, Nong Van

    2017-06-01

    Insulin or insulin-like growth factor 1 (IGF-1) promotes the activation of phosphoinositide 3 kinase (PI3K)/Akt signaling in immune cells including dendritic cells (DCs), the most potent professional antigen-presenting cells for naive T cells. Klotho, an anti-aging protein, participates in the regulation of the PI3K/Akt signaling, thus the Ca 2+ -dependent migration is reduced in klotho-deficient DCs. The present study explored the effects of insulin/IGF-1 on DC function through klotho expression. To this end, the mouse bone marrow cells were isolated and cultured with GM-CSF to attain bone marrow-derived DCs (BMDCs). Cells were treated with insulin or IGF-1 and followed by stimulating with lipopolysaccharides (LPS). Tumor necrosis factor (TNF)-α formation was examined by enzyme-linked immunosorbent assay (ELISA). Phagocytosis was analyzed by FITC-dextran uptake assay. The expression of klotho was determined by quantitative PCR, immunoprecipitation and western blotting. As a result, treatment of the cells with insulin/IGF-1 resulted in reducing the klotho expression as well as LPS-stimulated TNF-α release and increasing the FITC-dextran uptake but unaltering reactive oxygen species (ROS) production in BMDCs. The effects were abolished by using pharmacological inhibition of PI3K/Akt with LY294002 and paralleled by transfecting DCs with klotho siRNA. In conclusion, the regulation of klotho sensitive DC function by IGF-1 or insulin is mediated through PI3K/Akt signaling pathway in BMDCs.

  12. Cerebellar Insulin/IGF-1 signaling in diabetic rats: Effects of exercise training.

    Science.gov (United States)

    Borges, Mariana Eiras; Ribeiro, Alessandra Mussi; Pauli, José Rodrigo; Arantes, Luciana Mendonça; Luciano, Eliete; de Moura, Leandro Pereira; de Almeida Leme, José Alexandre Curiacos; Medeiros, Alessandra; Bertolini, Natália Oliveira; Sibuya, Clarice Yoshiko; Gomes, Ricardo José

    2017-02-03

    The Diabetes Mellitus (DM) is a chronic disease associated with loss of brain regions such as the cerebellum, increasing the risk of developing neurodegenerative diseases such as Parkinson's disease (PD). In the brain of diabetic and PD organisms the insulin/IGF-1 signaling is altered. Exercise training is an effective intervention for the prevention of neurodegerative diseases since it release neurotrophic factors and regulating insulin/IGF-1 signaling in the brain. This study aimed to evaluate the proteins involved in the insulin/IGF-1 pathway in the cerebellum of diabetic rats subjected to exercise training protocol. Wistar rats were distributed in four groups: sedentary control (SC), trained control (TC), sedentary diabetic (SD) and trained diabetic (TD). Diabetes was induced by Alloxan (ALX) (32mg/kgb.w.). The training program consisted in swimming 5days/week, 1h/day, during 6 weeks, supporting an overload corresponding to 90% of the anaerobic threshold. At the end, cerebellum was extracted to determinate the protein expression of GSK-3β, IRβ and IGF-1R and the phosphorylation of β-amyloid, Tau, ERK1+ERK2 by Western Blot analysis. All dependent variables were analyzed by one-way analysis of variance with significance level of 5%. Diabetes causes hyperglycemia in both diabetic groups; however, in TD, there was a reduction in hyperglycemia compared to SD. Diabetes increased Tau and β-amyloid phosphorylation in both SD and TD groups. Furthermore, aerobic exercise increased ERK1+ERK2 expression in TC. The data showed that in cerebellum of diabetic rats induced by alloxan there are some proteins expression like Parkinson cerebellum increased, and the exercise training was not able to modulate the expression of these proteins. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Long-pulse gastric electrical stimulation protects interstitial cells of Cajal in diabetic rats via IGF-1 signaling pathway.

    Science.gov (United States)

    Li, Hai; Chen, Yan; Liu, Shi; Hou, Xiao-Hua

    2016-06-21

    To investigate the effects of different parameters of gastric electrical stimulation (GES) on interstitial cells of Cajal (ICCs) and changes in the insulin-like growth factor 1 (IGF-1) signal pathway in streptozotocin-induced diabetic rats. Male rats were randomized into control, diabetic (DM), diabetic with sham GES (DM + SGES), diabetic with GES1 (5.5 cpm, 100 ms, 4 mA) (DM + GES1), diabetic with GES2 (5.5 cpm, 300 ms, 4 mA) (DM + GES2) and diabetic with GES3 (5.5 cpm, 550 ms, 2 mA) (DM + GES3) groups. The expression levels of c-kit, M-SCF and IGF-1 receptors were evaluated in the gastric antrum using Western blot analysis. The distribution of ICCs was observed using immunolabeling for c-kit, while smooth muscle cells and IGF-1 receptors were identified using α-SMA and IGF-1R antibodies. Serum level of IGF-1 was tested using enzyme-linked immunosorbent assay. Gastric emptying was delayed in the DM group but improved in all GES groups, especially in the GES2 group. The expression levels of c-kit, M-SCF and IGF-1R were decreased in the DM group but increased in all GES groups. More ICCs (c-kit(+)) and smooth muscle cells (α-SMA(+)/IGF-1R(+)) were observed in all GES groups than in the DM group. The average level of IGF-1 in the DM group was markedly decreased, but it was up-regulated in all GES groups, especially in the GES2 group. The results suggest that long-pulse GES promotes the regeneration of ICCs. The IGF-1 signaling pathway might be involved in the mechanism underlying this process, which results in improved gastric emptying.

  14. IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.

    Science.gov (United States)

    Liefers-Visser, J A L; Meijering, R A M; Reyners, A K L; van der Zee, A G J; de Jong, S

    2017-11-01

    The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  15. Activation of IGF-1/IGFBP-3 signaling by berberine improves intestinal mucosal barrier of rats with acute endotoxemia.

    Science.gov (United States)

    He, Yan; Yuan, Xiaoming; Zhou, Guangrong; Feng, Aiwen

    2018-01-01

    Insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) play a role in the maintenance of gut mucosal barrier function. Nevertheless, IGF-I/IGFBP-3 and tight junction protein (TJP) expression in small intestinal mucosa are often impaired during endotoxemia. In this model of acute endotoxemia, the regulatory effect of berberine on IGF-I/IGFBP-3 and TJP expression in ileal mucosa was evaluated. The findings revealed systemic injection of lipopolysaccharide (LPS) suppressed mRNA and protein expression of IGF-I and IGFBP-3, but berberine ameliorated their production. LPS injection inhibited occludin and claudin-1 protein generation, and this inhibitory effect of LPS was abolished by berberine. Inhibition of IGF-I/IGFBP-3 signaling by AG1024 or siRNAs reduced berberine-induced occludin and claudin-1 production. Additionally, GW9662 was found to repress berberine-induced IGF-I/IGFBP-3 expression, indicating of a cross-link between PPARγ and IGF-I/IGFBP-3 axis. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Pachymic acid promotes induction of autophagy related to IGF-1 signaling pathway in WI-38 cells.

    Science.gov (United States)

    Lee, Su-Gyeong; Kim, Moon-Moo

    2017-12-01

    The insulin-like growth factor 1 (IGF-1) signaling pathway has spotlighted as a mechanism to elucidate aging associated with autophagy in recent years. Therefore, we have tried to screen an effective compound capable of inducing autophagy to delay aging process. The aim of this study is to investigate whether pachymic acid, a main compound in Poria cocos, induces autophagy in the aged cells. The aging of young cells was induced by treatment with IGF-1 at 50 ng/ml three times every two days. The effect of pachymic acid on cell viability was evaluated in human lung fibroblasts, WI-38 cells, using MTT assay. The induction of autophagy was detected using autophagy detection kit. The expression of proteins related to autophagy and IGF-1 signaling pathway was examined by western blot analysis and immunofluorescence assay. In this study, pachymic acid showed cytotoxic effect in a dose dependent manner and remarkably induced autophagy at the same time. Moreover, pachymic acid increased the expression of proteins related to autophagy such as LC3-II and Beclin1 and decreased the levels of mTor phosphorylation and p70S6K in the aged cells. In particular, pachymic acid increased the expression of p-PI3K, p-FoxO and Catalase. In addition, pachymic acid remarkably increased the expression of IGFBP-3. Above results suggest that pachymic acid could induce autophagy related to IGF-1 signaling pathway in the aged cells. Copyright © 2017 Elsevier GmbH. All rights reserved.

  17. Cross-talk between Integrin α6β4 and Insulin-like Growth Factor-1 Receptor (IGF1R) through Direct α6β4 Binding to IGF1 and Subsequent α6β4-IGF1-IGF1R Ternary Complex Formation in Anchorage-independent Conditions*

    OpenAIRE

    Fujita, Masaaki; Ieguchi, Katsuaki; Davari, Parastoo; Yamaji, Satoshi; Taniguchi, Yukimasa; Sekiguchi, Kiyotoshi; Takada, Yoko K.; Takada, Yoshikazu

    2012-01-01

    Background: Integrin αvβ3-extracellular matrix interaction and/or αvβ3 binding to insulin-like growth factor-1 (IGF1; and integrin-IGF1-IGF1 receptor ternary complex formation) is critical for IGF signaling.

  18. The IGF-I/JAK2-STAT3/miR-21 signaling pathway may be associated with human renal cell carcinoma cell growth.

    Science.gov (United States)

    Su, Ying; Zhao, An; Cheng, Guoping; Xu, Jingjing; Ji, Enming; Sun, Wenyong

    2017-07-04

    Renal cell carcinoma (RCC) is the highest mortality rate of the genitourinary cancers, and the treatment options are very limited. Thus, identification of molecular mechanisms underlying RCC tumorigenesis, is critical for identifying biomarkers for RCC diagnosis and prognosis. To validate whether the IGF-I/JAK2-STAT3/miR-21 signaling pathway is associated with human RCC cell growth. qRT-PCR and Western blotting were used to detect the mRNA and protein expression levels, respectively. The MTT assay was performed to determine cell survival rate. The Annexin V-FITC/PI apoptosis detection kit was used to detect cell apoptosis. We employed RCC tissues and cell lines (A498; ACHN; Caki-1; Caki-2 and 786-O) in the study. IGF-I, and its inhibitor (NT-157) were administrated to detect the effects of IGF-I on the expression of miR-21 and p-JAK2. JAK2 inhibitor (AG490), and si-STAT3 were used to detect the effects of JAK2/STAT3 signaling pathway on the expression of miR-21. In our study, we firstly showed that the expression levels of IGF-I and miR-21 were up-regulated in RCC tissues and cell lines. After exogenous IGF-I treatment, the expression levels of miR-21, p-IGF-IR and p-JAK2 were significantly increased, whereas NT-157 treatment showed the reversed results. Further study indicated that JAK2 inhibitor or si-STAT3 significantly reversed the IGF-I-induced miR-21 expression level. Finally, we found that IGF-I treatment significantly prompted human RCC cell survival and inhibited cell apoptosis, and NT-157 treatment showed the reversed results. The IGF-I/JAK2-STAT3/miR-21 signaling pathway may be associated with human RCC cell growth.

  19. Antibody-based therapeutics against components of the IGF system

    OpenAIRE

    Feng, Yang; Dimitrov, Dimiter S.

    2012-01-01

    The insulin-like growth factor I (IGF-I) receptor (IGF-1R) is overexpressed in most human neoplasms tested so far. Many tumors in young patients produce high levels of the IGF-1R ligands, IGF-I and IGF-II. Given the complexity of the IGF signaling pathway, its complete inhibition may require combination therapies with antibodies targeting both IGF-1R and IGF-II.

  20. Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells.

    Science.gov (United States)

    Liu, Xunxian; Allen, Jeffrey D; Arnold, Julia T; Blackman, Marc R

    2008-04-01

    Prostate stromal and epithelial cell communication is important in prostate functioning and cancer development. Primary human stromal cells from normal prostate stromal cells (PRSC) maintain a smooth muscle phenotype, whereas those from prostate cancer (6S) display reactive and fibroblastic characteristics. Dihydrotestosterone (DHT) stimulates insulin-like growth factor-I (IGF-I) production by 6S but not PSRC cells. Effects of reactive versus normal stroma on normal human prostate epithelial (NPE or PREC) cells are poorly understood. We co-cultured NPE plus 6S or PRSC cells to compare influences of different stromal cells on normal epithelium. Because NPE and PREC cells lose androgen receptor (AR) expression in culture, DHT effects must be modulated by associated stromal cells. When treated with camptothecin (CM), NPE cells, alone and in stromal co-cultures, displayed a dose-dependent increase in DNA fragmentation. NPE/6S co-cultures exhibited reduced CM-induced cell death with exposure to DHT, whereas NPE/PRSC co-cultures exhibited CM-induced cell death regardless of DHT treatment. DHT blocked CM-induced, IGF-I-mediated, NPE death in co-cultured NPE/6S cells without, but not with, added anti-IGF-I and anti-IGF-R antibodies. Lycopene consumption is inversely related to human prostate cancer risk and inhibits IGF-I and androgen signaling in rat prostate cancer. In this study, lycopene, in dietary concentrations, reversed DHT effects of 6S cells on NPE cell death, decreased 6S cell IGF-I production by reducing AR and beta-catenin nuclear localization and inhibited IGF-I-stimulated NPE and PREC growth, perhaps by attenuating IGF-I's effects on serine phosphorylation of Akt and GSK3beta and tyrosine phosphorylation of GSK3. This study expands the understanding of the preventive mechanisms of lycopene in prostate cancer.

  1. IGF-1: The Jekyll & Hyde of the aging brain.

    Science.gov (United States)

    Gubbi, Sriram; Quipildor, Gabriela Farias; Barzilai, Nir; Huffman, Derek M; Milman, Sofiya

    2018-05-08

    The IGF-1 signaling pathway has emerged as a major regulator of the aging process, from rodents to humans. However, given the pleiotropic actions of IGF-1, its role in the aging brain remains complex and controversial. While IGF-1 is clearly essential for normal development of the central nervous system, conflicting evidence has emerged from preclinical and human studies regarding its relationship to cognitive function, as well as cerebrovascular and neurodegenerative disorders. This review delves into the current state of the evidence examining the role of IGF-1 in the aging brain, encompassing preclinical and clinical studies. A broad examination of the data indicates that IGF-1 may indeed play opposing roles in the aging brain, depending on the underlying pathology and context. Some evidence suggests that in the setting of neurodegenerative diseases that manifest with abnormal protein deposition in the brain, such as Alzheimer's disease, reducing IGF-1 signaling may serve a protective role by slowing disease progression and augmenting clearance of pathologic proteins to maintain cellular homeostasis. In contrast, inducing IGF-1 deficiency has also been implicated in dysregulated function of cognition and the neurovascular system, suggesting that some IGF-1 signaling may be necessary for normal brain function. Furthermore, states of acute neuronal injury, which necessitate growth, repair and survival signals to persevere, typically demonstrate salutary effects of IGF-1 in that context. Appreciating the dual, at times opposing "Dr. Jekyll" and "Mr. Hyde" characteristics of IGF-1 in the aging brain, will bring us closer to understanding its impact and devising more targeted IGF-1-related interventions.

  2. c-kitpos GATA-4 high rat cardiac stem cells foster adult cardiomyocyte survival through IGF-1 paracrine signalling.

    Directory of Open Access Journals (Sweden)

    Nanako Kawaguchi

    2010-12-01

    Full Text Available Resident c-kit positive (c-kitpos cardiac stem cells (CSCs could be considered the most appropriate cell type for myocardial regeneration therapies. However, much is still unknown regarding their biological properties and potential.We produced clones of high and low expressing GATA-4 CSCs from long-term bulk-cultured c-kitpos CSCs isolated from adult rat hearts. When c-kitpos GATA-4 high expressing clonal CSCs (cCSCs were co-cultured with adult rat ventricular cardiomyocytes, we observed increased survival and contractility of the cardiomyocytes, compared to cardiomyocytes cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low expressing cCSCs. When analysed by ELISA, the concentration of IGF-1 was significantly increased in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-cultures and there was a significant correlation between IGF-1 concentration and cardiomyocyte survival. We showed the activation of the IGF-1 receptor and its downstream molecular targets in cardiomyocytes co-cultured with c-kitpos GATA-4 high cCSCs but not in cardiomyocytes that were cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low cCSCs. Addition of a blocking antibody specific to the IGF-1 receptor inhibited the survival of cardiomyocytes and prevented the activation of its signalling in cardiomyocytes in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-culture system. IGF-1 supplementation or IGF-1 high conditioned medium taken from the co-culture of c-kitpos GATA-4 high cCSCs plus cardiomyocytes did extend the survival and contractility of cardiomyocytes cultured alone and cardiomyocytes co-cultured with c-kitpos GATA-4 low cCSCs.c-kitpos GATA-4 high cCSCs exert a paracrine survival effect on cardiomyocytes through induction of the IGF-1R and signalling pathway.

  3. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells

    International Nuclear Information System (INIS)

    Karnevi, Emelie; Said, Katarzyna; Andersson, Roland; Rosendahl, Ann H

    2013-01-01

    Epidemiological studies have shown direct associations between type 2 diabetes and obesity, both conditions associated with hyperglycaemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin. In this study, the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin were investigated. The human pancreatic cancer cell lines AsPC-1, BxPC-3, PANC-1 and MIAPaCa-2 were grown in normal (5 mM) or high (25 mM) glucose conditions, with or without metformin. The influence by metformin on proliferation, apoptosis and the AMPK and IGF-IR signalling pathways were evaluated in vitro. Metformin significantly reduced the proliferation of pancreatic cancer cells under normal glucose conditions. Hyperglycaemia however, protected against the metformin-induced growth inhibition. The anti-proliferative actions of metformin were associated with an activation of AMP-activated protein kinase AMPK Thr172 together with an inhibition of the insulin/insulin-like growth factor-I (IGF-I) receptor activation and downstream signalling mediators IRS-1 and phosphorylated Akt. Furthermore, exposure to metformin during normal glucose conditions led to increased apoptosis as measured by poly(ADP-ribose) polymerase (PARP) cleavage. In contrast, exposure to high glucose levels promoted a more robust IGF-I response and Akt activation which correlated to stimulated AMPK Ser485 phosphorylation and impaired AMPK Thr172 phosphorylation, resulting in reduced anti-proliferative and apoptotic effects by metformin. Our results indicate that metformin has direct anti-tumour activities in pancreatic cancer cells involving AMPK Thr172 activation and suppression of the insulin/IGF signalling pathways

  4. C. elegans VANG-1 modulates life span via insulin/IGF-1-like signaling.

    Directory of Open Access Journals (Sweden)

    Sebastian J Honnen

    Full Text Available The planar cell polarity (PCP pathway is highly conserved from Drosophila to humans and a PCP-like pathway has recently been described in the nematode Caenorhabditis elegans. The developmental function of this pathway is to coordinate the orientation of cells or structures within the plane of an epithelium or to organize cell-cell intercalation required for correct morphogenesis. Here, we describe a novel role of VANG-1, the only C. elegans ortholog of the conserved PCP component Strabismus/Van Gogh. We show that two alleles of vang-1 and depletion of the protein by RNAi cause an increase of mean life span up to 40%. Consistent with the longevity phenotype vang-1 animals also show enhanced resistance to thermal- and oxidative stress and decreased lipofuscin accumulation. In addition, vang-1 mutants show defects like reduced brood size, decreased ovulation rate and prolonged reproductive span, which are also related to gerontogenes. The germline, but not the intestine or neurons, seems to be the primary site of vang-1 function. Life span extension in vang-1 mutants depends on the insulin/IGF-1-like receptor DAF-2 and DAF-16/FoxO transcription factor. RNAi against the phase II detoxification transcription factor SKN-1/Nrf2 also reduced vang-1 life span that might be explained by gradual inhibition of insulin/IGF-1-like signaling in vang-1. This is the first time that a key player of the PCP pathway is shown to be involved in the insulin/IGF-1-like signaling dependent modulation of life span in C. elegans.

  5. Aging, Atherosclerosis, and IGF-1

    Science.gov (United States)

    Higashi, Yusuke; Sukhanov, Sergiy; Anwar, Asif; Shai, Shaw-Yung

    2012-01-01

    Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, and tissue repair. Recent evidence indicates that IGF-1 reduces atherosclerosis burden and improves features of atherosclerotic plaque stability in animal models. Potential mechanisms for this atheroprotective effect include IGF-1–induced reduction in oxidative stress, cell apoptosis, proinflammatory signaling, and endothelial dysfunction. Aging is associated with increased vascular oxidative stress and vascular disease, suggesting that IGF-1 may exert salutary effects on vascular aging processes. In this review, we will provide a comprehensive update on IGF-1's ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging. PMID:22491965

  6. IGF-IR Signaling in Breast Cancer

    National Research Council Canada - National Science Library

    Surmacz, Ewa

    1997-01-01

    Experimental and clinical evidence suggests that the insulin-like growth factor (IGF) system is involved in the growth of breast cancer cells in vitro and may be important in breast cancer etiology and progression...

  7. Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome

    OpenAIRE

    Schmitz Gerd; John Swen; Melnik Bodo C

    2011-01-01

    Abstract The insulin/insulin-like growth factor-1 (IGF-1) pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR) gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS) exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulat...

  8. IGF-1 promotes angiogenesis in endothelial cells/adipose-derived stem cells co-culture system with activation of PI3K/Akt signal pathway.

    Science.gov (United States)

    Lin, Shiyu; Zhang, Qi; Shao, Xiaoru; Zhang, Tao; Xue, Changyue; Shi, Sirong; Zhao, Dan; Lin, Yunfeng

    2017-12-01

    The aim of this study was to investigate the role of insulin-like growth factor-1 (IGF-1) and crosstalk between endothelial cells (ECs) and adipose-derived stem cells (ASCs) in the process of angiogenesis. A three-dimensional collagen gel used to culture mouse ASCs and mouse ECs in vitro was established. The effects of angiogenesis after exposure to IGF-1 were observed by confocal laser scanning microscopy. Western blotting and qPCR were performed to elucidate the underlying mechanisms. IGF-1 treatment promoted the formation of vessel-like structures and the recruitment of ASCs in the three-dimensional collagen gel. The angiogenic genes and proteins in ECs were up-regulated by IGF-1 and in co-culture. Similar changes in the genes and in the proteins were detected in ASCs after exposure to IGF-1 and co-culture. p-Akt expression levels were high in ECs and ASCs after exposure to IGF-1 and co-culture. IGF-1 and co-culture between cells facilitate the process of angiogenesis via the PI3-kinase/Akt signalling pathway. In ECs, IGF-1 stimulates the expression of angiogenesis-related growth factors with the activation of the PI3-kinase/Akt signalling pathway. Co-cultured ECs exposed to excess VEGF-A and other angiogenesis-related growth factors para-secreted from ASCs exhibit high expression of angiogenesis-related genes and proteins. In ASCs, IGF-1 induces the recruitment and function of ASCs by up-regulating the expression of PDGFB, MMPs and α-SMA. Crosstalk with ECs further facilitates changes in ASCs. © 2017 John Wiley & Sons Ltd.

  9. MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells*

    Science.gov (United States)

    Das, Falguni; Dey, Nirmalya; Bera, Amit; Kasinath, Balakuntalam S.; Ghosh-Choudhury, Nandini; Choudhury, Goutam Ghosh

    2016-01-01

    Elevated IGF-1/insulin-like growth factor-1 receptor (IGF-1R) autocrine/paracrine signaling in patients with renal cell carcinoma is associated with poor prognosis of the disease independent of their von Hippel-Lindau (VHL) status. Increased expression of IGF-1R in renal cancer cells correlates with their potency of tumor development and progression. The mechanism by which expression of IGF-1R is increased in renal carcinoma is not known. We report that VHL-deficient and VHL-positive renal cancer cells possess significantly decreased levels of mature, pre-, and pri-miR-214 than normal proximal tubular epithelial cells. We identified an miR-214 recognition element in the 3′UTR of IGF-1R mRNA and confirmed its responsiveness to miR-214. Overexpression of miR-214 decreased the IGF-1R protein levels, resulting in the inhibition of Akt kinase activity in both types of renal cancer cells. IGF-1 provoked phosphorylation and inactivation of PRAS40 in an Akt-dependent manner, leading to the activation of mTORC1 signal transduction to increase phosphorylation of S6 kinase and 4EBP-1. Phosphorylation-deficient mutants of PRAS40 and 4EBP-1 significantly inhibited IGF-1R-driven proliferation of renal cancer cells. Expression of miR-214 suppressed IGF-1R-induced phosphorylation of PRAS40, S6 kinase, and 4EBP-1, indicating inhibition of mTORC1 activity. Finally, miR-214 significantly blocked IGF-1R-forced renal cancer cell proliferation, which was reversed by expression of 3′UTR-less IGF-1R and constitutively active mTORC1. Together, our results identify a reciprocal regulation of IGF-1R levels and miR-214 expression in renal cancer cells independent of VHL status. Our data provide evidence for a novel mechanism for IGF-1R-driven renal cancer cell proliferation involving miR-214 and mTORC1. PMID:27226530

  10. Stress-altered synaptic plasticity and DAMP signaling in the hippocampus-PFC axis; elucidating the significance of IGF-1/IGF-1R/CaMKIIα expression in neural changes associated with a prolonged exposure therapy.

    Science.gov (United States)

    Ogundele, Olalekan M; Ebenezer, Philip J; Lee, Charles C; Francis, Joseph

    2017-06-14

    Traumatic stress patients showed significant improvement in behavior after a prolonged exposure to an unrelated stimulus. This treatment method attempts to promote extinction of the fear memory associated with the initial traumatic experience. However, the subsequent prolonged exposure to such stimulus creates an additional layer of neural stress. Although the mechanism remains unclear, prolonged exposure therapy (PET) likely involves changes in synaptic plasticity, neurotransmitter function and inflammation; especially in parts of the brain concerned with the formation and retrieval of fear memory (Hippocampus and Prefrontal Cortex: PFC). Since certain synaptic proteins are also involved in danger-associated molecular pattern signaling (DAMP), we identified the significance of IGF-1/IGF-1R/CaMKIIα expression as a potential link between the concurrent progression of synaptic and inflammatory changes in stress. Thus, a comparison between IGF-1/IGF-1R/CaMKIIα, synaptic and DAMP proteins in stress and PET may highlight the significance of PET on synaptic morphology and neuronal inflammatory response. In behaviorally characterized Sprague-Dawley rats, there was a significant decline in neural IGF-1 (pIGF-1R expression. These animals showed a significant loss of presynaptic markers (synaptophysin; pIGF-1 (pIGF-1R was recorded in the Stress-PET group (pIGF-1/IGF-1R, an increase in activated hippocampal and cortical microglia was seen in stress (pIGF1/IGF-1R/CaMKIIα. Firstly, we showed a direct relationship between IGF-1/IGF-1R expression, presynaptic function (synaptophysin) and neurotransmitter activity in stress and PET. Secondly, we identified the possible role of CaMKIIα in post-synaptic function and regulation of small ion conductance channels. Lastly, we highlighted some of the possible links between IGF1/IGF-1R/CaMKIIα, the expression of DAMP proteins, Microglia activation, and its implication on synaptic plasticity during stress and PET. Copyright © 2017

  11. IGF-1 induces the epithelial-mesenchymal transition via Stat5 in hepatocellular carcinoma.

    Science.gov (United States)

    Zhao, Chuanzong; Wang, Qian; Wang, Ben; Sun, Qi; He, Zhaobin; Hong, Jianguo; Kuehn, Florian; Liu, Enyu; Zhang, Zongli

    2017-12-19

    It has been reported that the epithelial-mesenchymal transition (EMT) plays an important role in hepatocellular carcinoma (HCC). However, the relationship between the insulin-like growth factor-1 (IGF-1) and EMT of HCC was not fully elucidated. In the present work, we found that the expression of N-cadherin, Vimentin, Snail1, Snail2, and Twist1 was positively associated with IGF-1R expression, while E-cadherin expression was negatively associated with IGF-1 expression in human HCC samples. Furthermore, we observed that IGF-1 up-regulated the expression of N-cadherin, Vimentin, Snail1, Snail2 and Twist1, and down-regulated the expression of E-cadherin. In addition, Stat5 was induced in IGF-1-treated HepG2 and Hep3B cells, and Stat5 inhibition or siRNA significantly affected IGF-1-induced EMT in HepG2 and Hep3B cells. In conclusion, IGF-1 induces EMT of HCC via Stat5 signaling pathway. Thus, IGF-1/Stat5 can be recommended as a potential and novel therapeutic strategy for HCC patients.

  12. Role of IGF-1/IGF-1R in regulation of invasion in DU145 prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Setya Hemani

    2008-07-01

    Full Text Available Abstract Background Prostate cancer progression to androgen independence is the primary cause of mortality by this tumor type. The IGF-1/IGF-1R axis is well known to contribute to prostate cancer initiation, but its contribution to invasiveness and the downstream signalling mechanisms that are involved are unclear at present. Results We examined the invasive response of androgen independent DU145 prostate carcinoma cells to IGF-1 stimulation using Matrigel assays. We then examined the signaling mechanisms and protease activities that are associated with this response. IGF-1 significantly increased the invasive capacity of DU145 cells in vitro, and this increase was inhibited by blocking IGF-1R. We further demonstrated that specific inhibitors of the MAPK and PI3-K pathways decrease IGF-1-mediated invasion. To determine potential molecular mechanisms for this change in invasive capacity, we examined changes in expression and activity of matrix metalloproteinases. We observed that IGF-1 increases the enzymatic activity of MMP-2 and MMP-9 in DU145 cells. These changes in activity are due to differences in expression in the case of MMP-9 but not in the case of MMP-2. This observation is corroborated by the fact that correlated changes of expression in a regulator of MMP-2, TIMP-2, were also seen. Conclusion This work identifies a specific effect of IGF-1 on the invasive capacity of DU145 prostate cancer cells, and furthermore delineates mechanisms that contribute to this effect.

  13. Cell surface GRP78 facilitates hepatoma cells proliferation and migration by activating IGF-IR.

    Science.gov (United States)

    Yin, Yancun; Chen, Chen; Chen, Jinliang; Zhan, Renhui; Zhang, Qiang; Xu, Xiaoyan; Li, Defang; Li, Minjing

    2017-07-01

    The 78kDa glucose regulated protein (GRP78) is a multifunctional chaperone that is involved in a variety of cellular processes. Insulin like growth factor I receptor (IGF-IR) often aberrant expresses in many types of tumor cells. The IGF-IR signaling plays key roles in carcinogenesis and maintenance of the malignant phenotype. The crosstalk between GRP78 and IGF-IR molecules has not well been illuminated. Here, we demonstrated a reciprocal regulation of GRP78 expression and IGF-IR pathway activation. IGF-I induced GRP78 expression in hepatoma cells. IGF-IR knockdown or IGF-IR inhibitor repressed GRP78 expression. Both phosphatidylinositol 3-kianase (PI3K) and mitogen-activated protein kinase (MAPK) pathways involved in IGF-I induction of GRP78 expression. Interestingly, treatment of hepatoma cells with IGF-I re-distributes GRP78 from endoplasmic reticulum (ER) to cell surface and promotes its physical interaction with IGF-IR. Also, GRP78 promotes IGF-IR phosphorylation and activation. Blocked of GRP78 by small interfering RNA or inhibition of GRP78 function by (-)-epigallocatechin gallate (EGCG) blocks IGF-I induced IGF-IR phosphorylation and its downstream signaling. Further, blocked cell surface GRP78 with antibody inhibits IGF-I stimulated cellular proliferation and migration. These data reveal an essential role for the molecular chaperone GRP78 in IGF-IR signaling and implicate the use of GRP78 inhibitors in blocking IGF-IR signaling in hepatoma cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Relative IGF-1 and IGF-2 gene expression in maternal and fetal tissues from diabetic swine

    International Nuclear Information System (INIS)

    Wolverton, C.K.; Leaman, D.W.; White, M.E.; Ramsay, T.G.

    1990-01-01

    Fourteen pregnant, crossbred gilts were utilized in this study. Seven gilts were injected with alloxan (50 mg/kg) at day 75 of gestation to induce diabetes. Gilts underwent caesarean section on day 105 of gestation. Samples were collected from maternal skeletal muscle, adipose tissue, uterus and endometrium; and from fetal skeletal muscle, adipose tissue, placenta, liver, lung, kidney, heart, brain and spleen. Tissues were frozen in liquid nitrogen for later analysis of IGF-1 and IGF-2 gene expression. Samples were pooled and total RNA was isolated using the guanidine isothiocynate method. Total mRNA was analyzed by dot blot hybridization. Blots were probed with 32 P-cDNA for porcine IGF-1 and rat IGF-2. IGF-1 gene expression in maternal tissues was unaffected by diabetes. Maternal diabetes increased IGF-2 mRNA in maternal adipose tissue but exhibited no effect in muscle or uterus. Expression of IGF-2 by maternal endometrium was decreased by diabetes. Maternal diabetes induced an increase in IGF-1 gene expression in muscle and placenta while causing an increase in IGF-2 expression in fetal liver and placenta. IGF-2 mRNA was lower in lung from fetuses of diabetic mothers than in controls. These results suggest that maternal diabetes alters IGF-1 and IGF-2 gene expression in specific tissues and differential regulation of these genes appears to exist in the mother and developing fetus

  15. IGF-1: an endogenous link between traumatic brain injury and Alzheimer disease?

    Science.gov (United States)

    Zheng, Ping; Tong, Wusong

    2017-08-01

    There is a growing body of evidence that the insulin-like growth factor-1 (IGF-1) is dynamically involved in the regulation of body homeostasis and glucose regulation. Traumatic brain injury (TBI) is considered to be a risk factor for Alzheimer's disease (AD). As alterations of IGF-1 have been implicated in both TBI and AD and the IGF-1 signaling also mediates the neuronal excitability and synaptic plasticity in both diseases, we propose that IGF-1 may act as the endogenous connection between TBI and AD. Growing evidence suggests that dysfunction of this pathway contributes to the progressive loss of neurons in Alzheimer's disease (AD), one of the most frequent neurodegenerative disorders. These findings have led to numerous studies in preclinical models of neurodegenerative disorders targeting IGF-1 signaling with currently available antidiabetics. These studies have shown that exogenous administration of IGF-1 reverses signaling abnormalities and has neuroprotective effects. In the first part of this review, we discuss physiological functions of IGF-1 signaling pathway including its distribution within the brain and its relationship with TBI and AD. In the second part, we undertake a comprehensive overview of IGF-1 signaling in TBI and AD, respectively. We then detail targeted IGF-1 in preclinical models of neurodegeneration and the design of clinical trials that have used anti-diabetics for treating AD patients. We close with future considerations that treat relevant issues for successful translation of these encouraging preclinical results into clinical sessions.

  16. Human longevity and variation in GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidant pathway genes: cross sectional and longitudinal studies.

    Science.gov (United States)

    Soerensen, Mette; Dato, Serena; Tan, Qihua; Thinggaard, Mikael; Kleindorp, Rabea; Beekman, Marian; Jacobsen, Rune; Suchiman, H Eka D; de Craen, Anton J M; Westendorp, Rudi G J; Schreiber, Stefan; Stevnsner, Tinna; Bohr, Vilhelm A; Slagboom, P Eline; Nebel, Almut; Vaupel, James W; Christensen, Kaare; McGue, Matt; Christiansen, Lene

    2012-05-01

    Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing these pathways. In a case-control study of 1089 oldest-old (age 92-93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP (rs1002149 (GSR)), 5 GH/IGF-1/INS SNPs (rs1207362 (KL), rs2267723 (GHRHR), rs3842755 (INS), rs572169 (GHSR), rs9456497 (IGF2R)) and 5 DNA repair SNPs (rs11571461 (RAD52), rs13251813 (WRN), rs1805329 (RAD23B), rs2953983 (POLB), rs3211994 (NTLH1)) to be associated with longevity after correction for multiple testing. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes we found 2 pro/antioxidant SNPs (rs10047589 (TNXRD1), rs207444 (XDH)), 1 GH/IGF-1/INS SNP (rs26802 (GHRL)) and 3 DNA repair SNPs (rs13320360 (MLH1), rs2509049 (H2AFX) and rs705649 (XRCC5)) to be associated with mortality in late life after correction for multiple testing. When examining the 11 SNPs from the case-control study in the longitudinal data, rs3842755 (INS), rs13251813 (WRN) and rs3211994 (NTHL1) demonstrated the same directions of effect (ppolymorphisms. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. WISP3 (CCN6 Is a Secreted Tumor-Suppressor Protein that Modulates IGF Signaling in Inflammatory Breast Cancer

    Directory of Open Access Journals (Sweden)

    Celina G. Kleer

    2004-03-01

    Full Text Available Inflammatory breast cancer (IBC is the most lethal form of locally advanced breast cancer. We have found that WISP3 is lost in 80% of human IBC tumors and that it has growth- and angiogenesis-inhibitory functions in breast cancer in vitro and in vivo. WISP3 is a cysteine-rich, putatively secreted protein that belongs to the CCN family. It contains a signal peptide at the N-terminus and four highly conserved motifs. Here, for the first time, we investigate the function of WISP3 protein in relationship to its structural features. We found that WISP3 is secreted into the conditioned media and into the lumens of normal breast ducts. Once secreted, WISP3 was able to decrease, directly or through induction of other molecule(s, the IGF-1-induced activation of the IGF-IR, and two of its main downstream signaling molecules, IRS1 and ERK-1/2, in SUM149 IBC cells. Furthermore, WISP3 containing conditioned media decreased the growth rate of SUM149 cells. This work sheds light into the mechanism of WISP3 function by demonstrating that it is secreted and that, once in the extracellular media, it induces a series of molecular events that leads to modulation of IGF-IR signaling pathways and cellular growth in IBC cells.

  18. Prenatal ethanol exposure increases osteoarthritis susceptibility in female rat offspring by programming a low-functioning IGF-1 signaling pathway

    Science.gov (United States)

    Ni, Qubo; Tan, Yang; Zhang, Xianrong; Luo, Hanwen; Deng, Yu; Magdalou, Jacques; Chen, Liaobin; Wang, Hui

    2015-10-01

    Epidemiological evidence indicates that osteoarthritis (OA) and prenatal ethanol exposure (PEE) are both associated with low birth weight but possible causal interrelationships have not been investigated. To investigate the effects of PEE on the susceptibility to OA in adult rats that experienced intrauterine growth retardation (IUGR), and to explore potential intrauterine mechanisms, we established the rat model of IUGR by PEE and dexamethasone, and the female fetus and 24-week-old adult offspring subjected to strenuous running for 6 weeks were sacrificed. Knee joints were collected from fetuses and adult offspring for histochemistry, immunohistochemistry and qPCR assays. Histological analyses and the Mankin score revealed increased cartilage destruction and accelerated OA progression in adult offspring from the PEE group compared to the control group. Immunohistochemistry showed reduced expression of insulin-like growth factor-1 (IGF-1) signaling pathway components. Furthermore, fetuses in the PEE group experienced IUGR but exhibited a higher postnatal growth rate. The expression of many IGF-1 signaling components was downregulated, which coincided with reduced amounts of type II collagen in the epiphyseal cartilage of fetuses in the PEE group. These results suggest that PEE enhances the susceptibility to OA in female adult rat offspring by down-regulating IGF-1 signaling and retarding articular cartilage development.

  19. Metabolic Fingerprints of Circulating IGF-1 and the IGF-1/IGFBP-3 Ratio

    DEFF Research Database (Denmark)

    Knacke, Henrike; Pietzner, Maik; Do, Kieu Trinh

    2016-01-01

    OBJECTIVE: IGF-1 is known for its various physiological and severe pathophysiological effects on human metabolism; however, underlying molecular mechanisms still remain unsolved. To reveal possible molecular mechanisms mediating these effects, for the first time, we associated serum IGF-1 levels...... with multifluid untargeted metabolomics data. METHODS: Plasma/urine samples of 995 nondiabetic participants of the Study of Health in Pomerania were characterized by mass spectrometry. Sex-specific linear regression analyses were performed to assess the association of IGF-1 and IGF-1/IGF binding protein 3 ratio...... with metabolites. Additionally, the predictive ability of the plasma and urine metabolome for IGF-1 was assessed by orthogonal partial least squares analyses. RESULTS AND CONCLUSIONS: We revealed a multifaceted image of associated metabolites with large sex differences. Confirming previous reports, we detected...

  20. IL-6 and IGF-1 signaling within and between muscle and bone: how important is the mTOR pathway for bone metabolism?

    NARCIS (Netherlands)

    Bakker, A.D.; Jaspers, R.T.

    2015-01-01

    Insulin-like growth factor 1 (IGF-1) and interleukin 6 (IL-6) play an important role in the adaptation of both muscle and bone to mechanical stimuli. Here, we provide an overview of the functions of IL-6 and IGF-1 in bone and muscle metabolism, and the intracellular signaling pathways that are well

  1. IL-6 and IGF-1 Signaling within, and between, Muscle and Bone: How Important is the mTOR Pathway for Bone Metabolism?

    NARCIS (Netherlands)

    Bakker, A.D.; Jaspers, R.T.

    2015-01-01

    Insulin-like growth factor 1 (IGF-1) and interleukin 6 (IL-6) play an important role in the adaptation of both muscle and bone to mechanical stimuli. Here, we provide an overview of the functions of IL-6 and IGF-1 in bone and muscle metabolism, and the intracellular signaling pathways that are well

  2. IGF-1 receptor haploinsufficiency leads to age-dependent development of metabolic syndrome.

    Science.gov (United States)

    Thakur, Sachin; Garg, Neha; Zhang, Ning; Hussey, Sophie E; Musi, Nicolas; Adamo, Martin L

    2017-05-13

    Individuals born small for gestational age (SGA) are at a higher risk of developing the metabolic syndrome later in life. IGF-1 resistance has been reported in placentae from SGA births and mutations in the Igf1 receptor gene have been reported in several cohorts of SGA subjects. We have used the Igf1r heterozygous (Igf1r +/- ) male mouse as a model to investigate the mechanisms by which Igf1r haploinsufficiency leads to insulin resistance. Despite exhibiting IGF-1 resistance, insulin signaling is enhanced in young Igf1r +/- mice but is attenuated in the muscle of old Igf1r +/- mice. Although smaller than WT (wild type) mice, old-aged Igf1r +/- had increased adiposity and exhibit increased lipogenesis. We hypothesize that IGF-1 resistance initially causes a transient increase in insulin signaling thereby promoting a lipogenic phenotype, which subsequently leads to insulin resistance. Copyright © 2017. Published by Elsevier Inc.

  3. Cardiac-specific overexpression of insulin-like growth factor I (IGF-1) rescues lipopolysaccharide-induced cardiac dysfunction and activation of stress signaling in murine cardiomyocytes.

    Science.gov (United States)

    Zhao, Peng; Turdi, Subat; Dong, Feng; Xiao, Xiaoyan; Su, Guohai; Zhu, Xinglei; Scott, Glenda I; Ren, Jun

    2009-07-01

    Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, plays a key role in cardiac dysfunction in sepsis. Low circulating levels of insulin-like growth factor 1 (IGF-1) are found in sepsis, although the influence of IGF-1 on septic cardiac defect is unknown. This study was designed to examine the impact of IGF-1 on LPS-induced cardiac contractile and intracellular Ca2+ dysfunction, activation of stress signal and endoplasmic reticulum (ER) stress. Mechanical and intracellular Ca2+ properties were examined in cardiomyocytes from Fast Violet B and cardiac-specific IGF-1 overexpression mice treated with or without LPS (4 mg kg(-1), 6 h). Reactive oxygen species (ROS), protein carbonyl formation and apoptosis were measured. Activation of mitogen-activated protein kinase pathways (p38, c-jun N-terminal kinase [JNK] and extracellular signal-related kinase [ERK]), ER stress and apoptotic markers were evaluated using Western blot analysis. Our results revealed decreased peak shortening and maximal velocity of shortening/relengthening and prolonged duration of relengthening in LPS-treated Fast Violet B cardiomyocytes associated with reduced intracellular Ca2+ decay. Accumulation of ROS protein carbonyl and apoptosis were elevated after LPS treatment. Western blot analysis revealed activated p38 and JNK, up-regulated Bax, and the ER stress markers GRP78 and Gadd153 in LPS-treated mouse hearts without any change in ERK and Bcl-2. Total protein expression of p38, JNK, and ERK was unaffected by either LPS or IGF-1. Interestingly, these LPS-induced changes in mechanical and intracellular Ca2+ properties, ROS, protein carbonyl, apoptosis, stress signal activation, and ER stress markers were effectively ablated by IGF-1. In vitro LPS exposure (1 microg mL(-1)) produced cardiomyocyte mechanical dysfunction reminiscent of the in vivo setting, which was alleviated by exogenous IGF-1 (50 nM). These data collectively suggested a beneficial of IGF-1 in

  4. The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation.

    Science.gov (United States)

    Warnhoff, Kurt; Murphy, John T; Kumar, Sandeep; Schneider, Daniel L; Peterson, Michelle; Hsu, Simon; Guthrie, James; Robertson, J David; Kornfeld, Kerry

    2014-10-01

    The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance.

  5. IGF-1/IGF-1R/hsa-let-7c axis regulates the committed differentiation of stem cells from apical papilla

    Science.gov (United States)

    Ma, Shu; Liu, Genxia; Jin, Lin; Pang, Xiyao; Wang, Yanqiu; Wang, Zilu; Yu, Yan; Yu, Jinhua

    2016-01-01

    Insulin-like growth factor-1 (IGF-1) and its receptor IGF-1R play a paramount role in tooth/bone formation while hsa-let-7c actively participates in the osteogenic differentiation of mesenchymal stem cells. However, the interaction between IGF-1/IGF-1R and hsa-let-7c on the committed differentiation of stem cells from apical papilla (SCAPs) remains unclear. In this study, human SCAPs were isolated and treated with IGF-1 and hsa-let-7c over/low-expression viruses. The odonto/osteogenic differentiation of these stem cells and the involvement of mitogen-activated protein kinase (MAPK) pathway were subsequently investigated. Alizarin red staining showed that hsa-let-7c low-expression can significantly promote the mineralization of IGF-1 treated SCAPs, while hsa-let-7c over-expression can decrease the calcium deposition of IGF-1 treated SCAPs. Western blot assay and real-time reverse transcription polymerase chain reaction further demonstrated that the expression of odonto/osteogenic markers (ALP, RUNX2/RUNX2, OSX/OSX, OCN/OCN, COL-I/COL-I, DSPP/DSP, and DMP-1/DMP-1) in IGF-1 treated SCAPs were significantly upregulated in Let-7c-low group. On the contrary, hsa-let-7c over-expression could downregulate the expression of these odonto/osteogenic markers. Moreover, western blot assay showed that the JNK and p38 MAPK signaling pathways were activated in Let-7c-low SCAPs but inhibited in Let-7c-over SCAPs. Together, the IGF-1/IGF-1R/hsa-let-7c axis can control the odonto/osteogenic differentiation of IGF-1-treated SCAPs via the regulation of JNK and p38 MAPK signaling pathways. PMID:27833148

  6. Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome

    Directory of Open Access Journals (Sweden)

    Schmitz Gerd

    2011-06-01

    Full Text Available Abstract The insulin/insulin-like growth factor-1 (IGF-1 pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulates IIS. The reduction of IIS in Laron subjects unmasks the potential role of persistent hyperactive IIS mediated by Western diet in the development of diseases of civilization and offers a rational perspective for dietary adjustments with less insulinotropic diets like the Paleolithic diet.

  7. Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome.

    Science.gov (United States)

    Melnik, Bodo C; John, Swen Malte; Schmitz, Gerd

    2011-06-24

    The insulin/insulin-like growth factor-1 (IGF-1) pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR) gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS) exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulates IIS. The reduction of IIS in Laron subjects unmasks the potential role of persistent hyperactive IIS mediated by Western diet in the development of diseases of civilization and offers a rational perspective for dietary adjustments with less insulinotropic diets like the Paleolithic diet.

  8. MiRNA-199a-3p Regulates C2C12 Myoblast Differentiation through IGF-1/AKT/mTOR Signal Pathway

    Directory of Open Access Journals (Sweden)

    Long Jia

    2013-12-01

    Full Text Available MicroRNAs constitute a class of ~22-nucleotide non-coding RNAs. They modulate gene expression by associating with the 3' untranslated regions (3' UTRs of messenger RNAs (mRNAs. Although multiple miRNAs are known to be regulated during myoblast differentiation, their individual roles in muscle development are still not fully understood. In this study, we showed that miR-199a-3p was highly expressed in skeletal muscle and was induced during C2C12 myoblasts differentiation. We also identified and confirmed several genes of the IGF-1/AKT/mTOR signal pathway, including IGF-1, mTOR, and RPS6KA6, as important cellular targets of miR-199a-3p in myoblasts. Overexpression of miR-199a-3p partially blocked C2C12 myoblast differentiation and the activation of AKT/mTOR signal pathway, while interference of miR-199a-3p by antisense oligonucleotides promoted C2C12 differentiation and myotube hypertrophy. Thus, our studies have established miR-199a-3p as a potential regulator of myogenesis through the suppression of IGF-1/AKT/mTOR signal pathway.

  9. Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer.

    Science.gov (United States)

    Mutgan, Ayse Ceren; Besikcioglu, H Erdinc; Wang, Shenghan; Friess, Helmut; Ceyhan, Güralp O; Demir, Ihsan Ekin

    2018-02-23

    Pancreatic ductal adenocarcinoma (PDAC) is unrivalled the deadliest gastrointestinal cancer in the western world. There is substantial evidence implying that insulin and insulin-like growth factor (IGF) signaling axis prompt PDAC into an advanced stage by enhancing tumor growth, metastasis and by driving therapy resistance. Numerous efforts have been made to block Insulin/IGF signaling pathway in cancer therapy. However, therapies that target the IGF1 receptor (IGF-1R) and IGF subtypes (IGF-1 and IGF-2) have been repeatedly unsuccessful. This failure may not only be due to the complexity and homology that is shared by Insulin and IGF receptors, but also due to the complex stroma-cancer interactions in the pancreas. Shedding light on the interactions between the endocrine/exocrine pancreas and the stroma in PDAC is likely to steer us toward the development of novel treatments. In this review, we highlight the stroma-derived IGF signaling and IGF-binding proteins as potential novel therapeutic targets in PDAC.

  10. AKT signaling mediates IGF-I survival actions on otic neural progenitors.

    Directory of Open Access Journals (Sweden)

    Maria R Aburto

    Full Text Available BACKGROUND: Otic neurons and sensory cells derive from common progenitors whose transition into mature cells requires the coordination of cell survival, proliferation and differentiation programmes. Neurotrophic support and survival of post-mitotic otic neurons have been intensively studied, but the bases underlying the regulation of programmed cell death in immature proliferative otic neuroblasts remains poorly understood. The protein kinase AKT acts as a node, playing a critical role in controlling cell survival and cell cycle progression. AKT is activated by trophic factors, including insulin-like growth factor I (IGF-I, through the generation of the lipidic second messenger phosphatidylinositol 3-phosphate by phosphatidylinositol 3-kinase (PI3K. Here we have investigated the role of IGF-dependent activation of the PI3K-AKT pathway in maintenance of otic neuroblasts. METHODOLOGY/PRINCIPAL FINDINGS: By using a combination of organotypic cultures of chicken (Gallus gallus otic vesicles and acoustic-vestibular ganglia, Western blotting, immunohistochemistry and in situ hybridization, we show that IGF-I-activation of AKT protects neural progenitors from programmed cell death. IGF-I maintains otic neuroblasts in an undifferentiated and proliferative state, which is characterised by the upregulation of the forkhead box M1 (FoxM1 transcription factor. By contrast, our results indicate that post-mitotic p27(Kip-positive neurons become IGF-I independent as they extend their neuronal processes. Neurons gradually reduce their expression of the Igf1r, while they increase that of the neurotrophin receptor, TrkC. CONCLUSIONS/SIGNIFICANCE: Proliferative otic neuroblasts are dependent on the activation of the PI3K-AKT pathway by IGF-I for survival during the otic neuronal progenitor phase of early inner ear development.

  11. H2O2 attenuates IGF-1R tyrosine phosphorylation and its survival signaling properties in neuronal cells via NR2B containing NMDA receptor.

    Science.gov (United States)

    Zeng, Zhiwen; Wang, Dejun; Gaur, Uma; Rifang, Liao; Wang, Haitao; Zheng, Wenhua

    2017-09-12

    Impairment of insulin-like growth factor I (IGF-I) signaling plays an important role in the development of neurodegeneration. In the present study, we investigated the effect of H 2 O 2 on the survival signaling of IGF-1 and its underlying mechanisms in human neuronal cells SH-SY5Y. Our results showed that IGF-1 promoted cell survival and stimulated phosphorylation of IGF-1R as well as its downstream targets like AKT and ERK1/2 in these cells. Meanwhile, these effects of IGF-1 were abolished by H 2 O 2 at 200μM concentration which did not cause any significant toxicity to cells itself in our experiments. Moreover, studies using various glutamate receptor subtype antagonists displayed that N-methyl-D -aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) blocked the effects of H 2 O 2 , whereas other glutamate receptor subtype antagonists, such as non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), metabolic glutamate receptor antagonists LY341495 and CPCCOEt, had no effect. Further studies revealed that NR2B-containing NMDARs are responsible for these effects as its effects were blocked by pharmacological inhibitor Ro25-698 or specific siRNA for NR2B, but not NR2A. Finally, our data also showed that Ca 2+ influx contributes to the effects of H 2 O 2 . Similar results were obtained in primary cultured cortical neurons. Taken together, the results from the present study suggested that H 2 O 2 attenuated IGF-1R tyrosine phosphorylation and its survival signaling properties via NR2B containing NMDA receptors and Ca 2+ influx in SH-SY5Y cells. Therefore, NMDAR antagonists, especially NR2B-selective ones, combined with IGF-1 may serve as an alternative therapeutic agent for oxidative stress related neurodegenerative disease.

  12. IGF-1 prevents simvastatin-induced myotoxicity in C2C12 myotubes.

    Science.gov (United States)

    Bonifacio, Annalisa; Sanvee, Gerda M; Brecht, Karin; Kratschmar, Denise V; Odermatt, Alex; Bouitbir, Jamal; Krähenbühl, Stephan

    2017-05-01

    Statins are generally well tolerated, but treatment with these drugs may be associated with myopathy. The mechanisms of statin-associated myopathy are not completely understood. Statins inhibit AKT phosphorylation by an unclear mechanism, whereas insulin-like growth factor (IGF-1) activates the IGF-1/AKT signaling pathway and promotes muscle growth. The aims of the study were to investigate mechanisms of impaired AKT phosphorylation by simvastatin and to assess effects of IGF-1 on simvastatin-induced myotoxicity in C2C12 myotubes. C2C12 mouse myotubes were exposed to 10 μM simvastatin and/or 10 ng/mL IGF-1 for 18 h. Simvastatin inhibited the IGF-1/AKT signaling pathway, resulting in increased breakdown of myofibrillar proteins, impaired protein synthesis and increased apoptosis. Simvastatin inhibited AKT S473 phosphorylation, indicating reduced activity of mTORC2. In addition, simvastatin impaired stimulation of AKT T308 phosphorylation by IGF-1, indicating reduced activation of the IGF-1R/PI3K pathway by IGF-1. Nevertheless, simvastatin-induced myotoxicity could be at least partially prevented by IGF-1. The protective effects of IGF-1 were mediated by activation of the IGF-1R/AKT signaling cascade. Treatment with IGF-1 also suppressed muscle atrophy markers, restored protein synthesis and inhibited apoptosis. These results were confirmed by normalization of myotube morphology and protein content of C2C12 cells exposed to simvastatin and treated with IGF-1. In conclusion, impaired activity of AKT can be explained by reduced function of mTORC2 and of the IGF-1R/PI3K pathway. IGF-1 can prevent simvastatin-associated cytotoxicity and metabolic effects on C2C12 cells. The study gives insight into mechanisms of simvastatin-associated myotoxicity and provides potential targets for therapeutic intervention.

  13. No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone.

    Science.gov (United States)

    Peterse, Elisabeth F P; Cleven, Arjen H G; De Jong, Yvonne; Briaire-de Bruijn, Inge; Fletcher, Jonathan A; Danen, Erik H J; Cleton-Jansen, Anne-Marie; Bovée, Judith V M G

    2016-07-14

    Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study. Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines. Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the

  14. Sex, Sport, IGF-1 and the Community Effect in Height Hypothesis

    Directory of Open Access Journals (Sweden)

    Barry Bogin

    2015-05-01

    Full Text Available We test the hypothesis that differences in social status between groups of people within a population may induce variation in insulin-like growth factor-1(IGF-1 levels and, by extension, growth in height. This is called the community effect in height hypothesis. The relationship between IGF-1, assessed via finger-prick dried blood spot, and elite level sport competition outcomes were analysed for a sample of 116 undergraduate men and women. There was a statistically significant difference between winners and losers of a competition. Winners, as a group, had higher average pre-game and post-game IGF-1 levels than losers. We proposed this type of difference as a proxy for social dominance. We found no evidence that winners increased in IGF-1 levels over losers or that members of the same team were more similar in IGF-1 levels than they were to players from other teams. These findings provide limited support toward the community effect in height hypothesis. The findings are discussed in relation to the action of the growth hormone/IGF-1 axis as a transducer of multiple bio-social influences into a coherent signal which allows the growing human to adjust and adapt to local ecological conditions.

  15. Low Circulating IGF-I Bioactivity in Elderly Men is associated with Increased Mortality

    NARCIS (Netherlands)

    M.P. Brugts (Michael); A.W. van den Beld (Annewieke); L.J. Hofland (Leo); K. van der Wansem (Katy); P.M. van Koetsveld (Peter); J. Frystyk (Jan); S.W.J. Lamberts (Steven); J.A.M.J.L. Janssen (Joseph)

    2008-01-01

    textabstractContext: Low IGF-I signaling activity prolongs lifespan in certain animal models, but the precise role of IGF-I in human survival remains controversial. The IGF-I kinase receptor activation assay (IGF-I KIRA) is a novel method for measuring IGF-I bioactivity in human serum. We

  16. IGF-1-induced MMP-11 expression promotes the proliferation and invasion of gastric cancer cells through the JAK1/STAT3 signaling pathway.

    Science.gov (United States)

    Su, Chao; Wang, Wenchang; Wang, Cunchuan

    2018-05-01

    The present study aimed to investigate the association between insulin-like growth factor-1 (IGF-1) and matrix metalloproteinase-11 (MMP-11) expression in gastric cancer (GC) and the underlying mechanisms in SGC-7901 cells. Reverse transcription-quantitative polymerase chain reaction analysis revealed that the expression of IGF-1 and MMP-11 was significantly upregulated in GC tissues compared with normal gastric tissue. Furthermore, IGF-1 significantly and dose-dependently promoted MMP-11. Western blotting revealed that the addition of IGF-1 to SGC-7901 cells led to an evident enhancement in signal transducer and activator of transcription 3 (STAT3), IGF-1R and Janus kinase 1 (JAK1) phosphorylation at 20 and 40 min. A decrease in the extent of the elevated expression of MMP-11 and the enhanced phosphorylation of STAT3, JAK1 and IGF-1 receptor (IGF-1R) induced by IGF-1 in SGC-7901 cells were observed following treatment with NT157 (an IGF-1R inhibitor). Furthermore, piceatannol (a JAK1 inhibitor) or small interfering RNA against STAT3 reduced the extent of the increased expression of MMP-11 induced by IGF-1 in SGC-7901 cells. Piceatannol treatment induced the dose-dependent decline in the enhancement of STAT3 phosphorylation induced by IGF-1, indicating that the JAK1/STAT3 pathway may be implicated in the elevated expression of MMP-11 induced by IGF-1 in SGC-7901 cells. Finally, IGF-1 treatment significantly promoted the proliferation and invasion of SGC-7901 cells, which was inhibited following NT157, piceatannol or si-STAT3 treatment. The present study therefore demonstrated that IGF-1-induced MMP-11 may have facilitated the proliferation and invasion of SGC-7901 cells via the JAK1/STAT3 pathway.

  17. IGF-1 receptor and IGF binding protein-3 might predict prognosis of patients with resectable pancreatic cancer

    International Nuclear Information System (INIS)

    Hirakawa, Toshiki; Yashiro, Masakazu; Murata, Akihiro; Hirata, Keiichiro; Kimura, Kenjiro; Amano, Ryosuke; Yamada, Nobuya; Nakata, Bunzo; Hirakawa, Kosei

    2013-01-01

    The present study aimed to elucidate the clinicopathologic role of insulin-like growth factor-1 receptor (IGF1R) and IGF binding protein-3 (IGFBP3) in patients with pancreatic cancer. The function of IGFBP3 is controversial, because both inhibition and facilitation of the action of IGF as well as IGF-independent effects have been reported. In this study, IGF1R and IGFBP3 expression was examined, and their potential roles as prognostic markers in patients with pancreatic cancer were evaluated. Clinicopathological features of 122 patients with curatively resected pancreatic cancer were retrospectively reviewed, and expression of IGF1R and IGFBP3 was immunohistochemically analyzed. Expression of IGF1R and IGFBP3 was observed in 50 (41.0%) and 37 (30.3%) patients, respectively. IGF1R expression was significantly associated with histological grade (p = 0.037). IGFBP3 expression had a significant association with tumor location (p = 0.023), and a significant inverse association with venous invasion (p = 0.037). Tumors with IGF1R-positive and IGFBP3-negative expression (n = 32) were significantly frequently Stage II and III (p = 0.011). The prognosis for IGF1R positive patients was significantly poorer than that for IGF1R negative patients (p = 0.0181). IGFBP3 protein expression did not correlate significantly with patient survival. The subset of patients with both positive IGF1R and negative IGFBP3 had worse overall survival (8.8 months versus 12.6 months, respectively, p < 0.001). IGF1R signaling might be associated with tumor aggressiveness, and IGFBP3 might show antiproliferative effects in pancreatic cancer. Both high IGF1R expression and low IGFBP3 expression represent useful prognostic markers for patients with curatively resected pancreatic cancer

  18. IGF-Binding Proteins: Why Do They Exist and Why Are There So Many?

    Directory of Open Access Journals (Sweden)

    John B. Allard

    2018-04-01

    Full Text Available Insulin-like growth factors (IGFs are key growth-promoting peptides that act as both endocrine hormones and autocrine/paracrine growth factors. In the bloodstream and in local tissues, most IGF molecules are bound by one of the members of the IGF-binding protein (IGFBP family, of which six distinct types exist. These proteins bind to IGF with an equal or greater affinity than the IGF1 receptor and are thus in a key position to regulate IGF signaling globally and locally. Binding to an IGFBP increases the half-life of IGF in the circulation and blocks its potential binding to the insulin receptor. In addition to these classical roles, IGFBPs have been shown to modulate IGF signaling locally under various conditions. Although members of the IGFBP family share significant sequence homology, they each have unique structural features and play distinct roles. These IGFBP genes also have different modes of regulation and distinct expression patterns. Some IGFBPs have been found to bind to their own receptors or to translocate into the interior compartments of cells where they may execute IGF-independent actions. In spite of this functional and regulatory diversity, it has been puzzling that loss-of-function studies have yielded relatively little information about the physiological functions of IGFBPs. In this review, we suggest that evolution has tended to retain an array of IGFBPs in order to facilitate fine-tuning of IGF signaling. We explore the emerging explanation that many IGFBP functions have evolved to allow the targeted adjustment of IGF signaling under stressful or irregular conditions, which would likely not be revealed in a standard laboratory setting.

  19. IGF-1 protects cardiac myocytes from hyperosmotic stress-induced apoptosis via CREB

    International Nuclear Information System (INIS)

    Maldonado, Carola; Cea, Paola; Adasme, Tatiana; Collao, Andres; Diaz-Araya, Guillermo; Chiong, Mario; Lavandero, Sergio

    2005-01-01

    Hyperosmotic stress stimulates a rapid and pronounced apoptosis in cardiac myocytes which is attenuated by insulin-like growth factor-1 (IGF-1). Because in these cells IGF-1 induces intracellular Ca 2+ increase, we assessed whether the cyclic AMP response element-binding protein (CREB) is activated by IGF-1 through Ca 2+ -dependent signalling pathways. In cultured cardiac myocytes, IGF-1 induced phosphorylation (6.5 ± 1.0-fold at 5 min), nuclear translocation (30 min post-stimulus) and DNA binding activity of CREB. IGF-1-induced CREB phosphorylation was mediated by MEK1/ERK, PI3-K, p38-MAPK, as well as Ca 2+ /calmodulin kinase and calcineurin. Exposure of cardiac myocytes to hyperosmotic stress (sorbitol 600 mOsm) decreased IGF-1-induced CREB activation Moreover, overexpression of a dominant negative CREB abolished the anti-apoptotic effects of IGF-1. Our results suggest that IGF-1 activates CREB through a complex signalling pathway, and this transcription factor plays an important role in the anti-apoptotic action of IGF-1 in cultured cardiac myocytes

  20. The DAF-16 FOXO transcription factor regulates natc-1 to modulate stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling to protein N-terminal acetylation.

    Directory of Open Access Journals (Sweden)

    Kurt Warnhoff

    2014-10-01

    Full Text Available The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance.

  1. Overexpression of decorin promoted angiogenesis in diabetic cardiomyopathy via IGF1R-AKT-VEGF signaling.

    Science.gov (United States)

    Lai, Jinsheng; Chen, Fuqiong; Chen, Jing; Ruan, Guoran; He, Mengying; Chen, Chen; Tang, Jiarong; Wang, Dao Wen

    2017-03-14

    Microcirculatory dysfunction is believed to play an important role in diabetic cardiomyopathy. The small leucine-rich proteoglycan decorin is generally considered a pro-angiogenic factor. Here, we investigate whether overexpression of decorin ameliorates diabetic cardiomyopathy and its effects on angiogenesis in vivo and in vitro. Diabetes was induced through intraperitoneal injection with streptozotocin combined with a high-fat diet, and decorin was overexpressed via recombinant adeno-associated virus in Wistar rats. Six months later, cardiac function was determined using an echocardiography and cardiac catheter system. The results showed that cardiac function was decreased in diabetic rats and restored by overexpression of decorin. In addition, overexpression of decorin upregulated the expression of VEGF and attenuated the reduction in the cardiac capillary density. In the in vitro study, high glucose induced apoptosis and inhibited the capabilities of tube formation, migration and proliferation, which were all ameliorated by decorin overexpression. Meanwhile, decorin overexpression increased the expression of VEGF and IGF1R, as well as the phosphorylation level of AKT and AP-1. Nonetheless, all of these effects were abolished by pretreatment with the IGF1R antibody or AKT inhibitor. In conclusion, overexpression of decorin ameliorated diabetic cardiomyopathy and promoted angiogenesis through the IGF1R-AKT-VEGF signaling pathway in vivo and in vitro.

  2. No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone

    International Nuclear Information System (INIS)

    Peterse, Elisabeth F. P.; Cleven, Arjen H. G.; De Jong, Yvonne; Briaire-de Bruijn, Inge; Fletcher, Jonathan A.; Danen, Erik H. J.; Cleton-Jansen, Anne-Marie; Bovée, Judith V. M. G.

    2016-01-01

    Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study. Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines. Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the

  3. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Ohshima-Hosoyama, Sachiko; Hosoyama, Tohru; Nelon, Laura D. [Greehey Children' s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Keller, Charles, E-mail: keller@ohsu.edu [Greehey Children' s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229 (United States)

    2010-09-03

    Research highlights: {yields} Igf1r is overexpressed and activated in a Sonic Hedgehog driven model of medulloblastoma. {yields} Picropodophyllin targets and abrogates IGF signaling in medulloblastoma. {yields} Picropodophyllin inhibits medulloblastoma tumor cell growth by induction of apoptosis. -- Abstract: The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.

  4. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

    International Nuclear Information System (INIS)

    Ohshima-Hosoyama, Sachiko; Hosoyama, Tohru; Nelon, Laura D.; Keller, Charles

    2010-01-01

    Research highlights: → Igf1r is overexpressed and activated in a Sonic Hedgehog driven model of medulloblastoma. → Picropodophyllin targets and abrogates IGF signaling in medulloblastoma. → Picropodophyllin inhibits medulloblastoma tumor cell growth by induction of apoptosis. -- Abstract: The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.

  5. Retardation of fetal dendritic development induced by gestational hyperglycemia is associated with brain insulin/IGF-I signals.

    Science.gov (United States)

    Jing, Yu-Hong; Song, Yan-Feng; Yao, Ya-Ming; Yin, Jie; Wang, De-Gui; Gao, Li-Ping

    2014-10-01

    Hyperglycemia is an essential risk factor for mothers and fetuses in gestational diabetes. Clinical observation has indicated that the offspring of mothers with diabetes shows impaired somatosensory function and IQ. However, only a few studies have explored the effects of hyperglycemia on fetal brain development. Neurodevelopment is susceptible to environmental conditions. Thus, this study aims to investigate the effects of maternal hyperglycemia on fetal brain development and to evaluate insulin and insulin-like growth factor-I (IGF-I) signals in fetal brain under hyperglycemia or controlled hyperglycemia. At day 1 of pregnancy, gestational rats were intraperitoneally injected with streptozocin (60 mg/kg). Some of the hyperglycemic gestational rats were injected with insulin (20 IU, two times a day) to control hyperglycemia; the others were injected with saline of equal volume. The gestational rats were sacrificed at days 14, 16, and 18 of embryo development. The dendritic spines of subplate cortex neurons in the fetal brain were detected by Golgi-Cox staining. The mRNA levels of insulin receptors (IRs) and IGF-IR in the fetal brain were measured using qRT-PCR. The protein levels of synaptophysin, IR, and IGF-IR in the fetal brain were detected by western blot. No significant difference in fetal brain formation was observed between the maternal hyperglycemic group and insulin-treated group. By contrast, obvious retardation of dendritic development in the fetus was observed in the maternal hyperglycemic group. Similarly, synaptophysin expression was lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. The mRNA and protein expression levels of IRs in the fetal brain were higher in the hyperglycemic group than in the insulin-treated group. By contrast, the levels of IGF-IR in the brain were lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. These results suggested that

  6. Improved Brain Insulin/IGF Signaling and Reduced Neuroinflammation with T3D-959 in an Experimental Model of Sporadic Alzheimer's Disease.

    Science.gov (United States)

    de la Monte, Suzanne M; Tong, Ming; Schiano, Irio; Didsbury, John

    2017-01-01

    Alzheimer's disease (AD) is associated with progressive impairments in brain insulin, insulin-like growth factor (IGF), and insulin receptor substrate (IRS) signaling through Akt pathways that regulate neuronal growth, survival, metabolism, and plasticity. The intracerebral streptozotocin (i.c. STZ) model replicates the full range of abnormalities in sporadic AD. T3D-959, an orally active PPAR-delta/gamma agonist remediates neurocognitive deficits and AD neuropathology in the i.c. STZ model. This study characterizes the effects of T3D-959 on AD biomarkers, insulin/IGF/IRS signaling through Akt pathways, and neuroinflammation in an i.c. STZ model. Long Evans rats were treated with i.c. STZ or saline, followed by daily oral doses of T3D-959 (1 mg/kg) or saline initiated 1 day (T3D-959-E) or 7 days (T3D-959-L) later through Experimental Day 28. Protein and phospho-protein expression and pro-inflammatory cytokine activation were measured in temporal lobe homogenates by duplex or multiplex bead-based ELISAs. i.c. STZ treatments caused neurodegeneration with increased pTau, AβPP, Aβ42, ubiquitin, and SNAP-25, and reduced levels of synaptophysin, IGF-1 receptor (R), IRS-1, Akt, p70S6K, mTOR, and S9-GSK-3β. i.c. STZ also broadly increased neuroinflammation. T3D-959 abrogated or reduced most of the AD neuropathological and biomarker abnormalities, increased/normalized IGF-1R, IRS-1, Akt, p70S6K, and S9-GSK-3β, and decreased expression of multiple pro-inflammatory cytokines. T3D-959-E or -L effectively restored insulin/IGF signaling, whereas T3D-959-L more broadly resolved neuroinflammation. AD remediating effects of T3D-959 are potentially due to enhanced expression of key insulin/IGF signaling proteins and inhibition of GSK-3β and neuroinflammation. These effects lead to reduced neurodegeneration, cognitive impairment, and AD biomarker levels in the brain.

  7. Evidence for the possible biological significance of the igf-1 gene alternative splicing in prostate cancer

    Directory of Open Access Journals (Sweden)

    Anastassios ePhilippou

    2013-03-01

    Full Text Available Insulin-like growth factor I (IGF-I has been implicated in the pathogenesis of prostate cancer (PCa, since it plays a key role in cell proliferation, differentiation and apoptosis. The IGF-I actions are mediated mainly via its binding to the type I IGF receptor (IGF-IR, however IGF-I signaling via insulin receptor (IR and hybrid IGF-I/IR is also evident. Different IGF-I mRNA splice variants, namely IGF-IEa, IGF-IEb and IGF-IEc, are expressed in human cells and tissues. These transcripts encode several IGF-I precursor proteins which contain the same bioactive product (mature IGF-I, however, they differ by the length of their signal peptides on the amino-terminal end and the structure of the extension peptides (E-peptides on the carboxy-terminal end. There is an increasing interest in the possible different role of the IGF-I transcripts and their respective non-(matureIGF-I products in the regulation of distinct biological activities. Moreover, there is strong evidence of a differential expression profile of the IGF-I splice variants in normal vs. PCa tissues and PCa cells, implying that the expression pattern of the various IGF-I transcripts and their respective protein products may possess different functions in cancer biology. Herein, the evidence that the IGF-IEc transcript regulates PCa growth via Ec-peptide specific and IGF-IR/IR-independent signaling is discussed.

  8. Differential roles of MAPK-Erk1/2 and MAPK-p38 in insulin or insulin-like growth factor-I (IGF-I) signaling pathways for progesterone production in human ovarian cells.

    Science.gov (United States)

    Seto-Young, D; Avtanski, D; Varadinova, M; Park, A; Suwandhi, P; Leiser, A; Parikh, G; Poretsky, L

    2011-06-01

    Insulin and insulin like-growth factor-I (IGF-I) participate in the regulation of ovarian steroidogenesis. In insulin resistant states ovaries remain sensitive to insulin because insulin can activate alternative signaling pathways, such as phosphatidylinositol-3-kinase (PI-3 kinase) and mitogen-activated protein-kinase (MAPK) pathways, as well as insulin receptors and type 1 IGF receptors. We investigated the roles of MAPK-Erk1/2 and MAPK-p38 in insulin and IGF-I signaling pathways for progesterone production in human ovarian cells. Human ovarian cells were cultured in tissue culture medium in the presence of varying concentrations of insulin or IGF-I, with or without PD98059, a specific MAPK-Erk1/2 inhibitor, with or without SB203580, a specific MAPK-p38 inhibitor or with or without a specific PI-3-kinase inhibitor LY294002. Progesterone concentrations were measured using radioimmunoassay. PD98059 alone stimulated progesterone production in a dose-dependent manner by up to 65% (pprogesterone production by 13-18% (pprogesterone production by 17-20% (pprogesterone production by 20-30% (pprogesterone production by 40-60% (pprogesterone synthesis while SB203580 abolished insulin-induced progesterone production. Either PD98059 or SB203580 abolished IGF-I-induced progesterone production. Both MAPK-Erk1/2 and MAPK-p38 participate in IGF-I-induced signaling pathways for progesterone production, while insulin-induced progesterone production requires MAPK-p38, but not MAPK-Erk1/2. These studies provide further evidence for divergence of insulin and IGF-I signaling pathways for human ovarian cell steroidogenesis. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Effect Of IGF-1 On Expression Of Gh Receptor, IGF-1, IGF-1 ...

    African Journals Online (AJOL)

    ... and the skin expression of growth hormone receptor (GHR), insulin-like growth factor1 (IGF-1), insulin-like growth factor receptor (IGF- R), KAP3.2 and KAP6-1 mRNA were measured by RT-PCR. The results indicated that IGF-1 could degrade GHR gene expression, have no effect of IGF-1 and IGF-1R gene expression, ...

  10. Development and clinical evaluation of a novel immunoassay for the binary complex of IGF-I and IGF-binding protein-1 in human serum

    DEFF Research Database (Denmark)

    Frystyk, Jan; Højlund, Kurt; Rasmussen, Kirsten Nyborg

    2002-01-01

    Correlation studies have suggested that IGF-binding protein (IGFBP)-1 is a dynamic regulator of free IGF-I. To further study this, we developed a monoclonal immunofluorometric assay specific for the binary complex of IGF-I and IGFBP-1 in human serum. An IGFBP-1 antibody, which recognizes all...... phospho-forms of IGFBP-1, was used for coating. An europium-labeled IGF-I antibody served as tracer. Assay incubation was performed at conditions approaching those in vivo (i.e. pH 7.4, 37 C). The assay was highly specific: no signal was obtained unless both IGF-I and IGFBP-1 were present and neither...

  11. Muscle atrophy in patients wirh ckd results from fgf23/klotho-mediated supression of insulin/igf-i signaling

    Directory of Open Access Journals (Sweden)

    Shinsuke Kido

    2012-06-01

    Full Text Available Muscle atrophy is a significant consequence of chronic kidney disease (CKD that increases a patient’s risk of mortality and decrease their quality of life. In CKD patients, the circulation levels of FGF23 are significantly increased, but the exact pathological significance of the increase and relationship between FGF23 and muscle atrophy are not clear. Because of Klohto, acts as a co-receptor of FGF23 is detectable in limited tissues including in kidney and brain, but not in skeletal muscles. In contrast, recently reports indicated that the extracellular domain of klohto is cleavage for some reason on the cell surface and detected in the blood in animals. In this study, we attempted to identify the causative factors responsible for the shedding of Klotho, and whether both FGF23 and Klohto induced muscle atrophy via reduction of insulin/IGF-I signaling. We first investigated by treating kidney cells with various factors related in pathological factors in CKD. As a result, we found that advanced glycation endproducts (AGEs, an accumulated in patients with CKD and diabetes mellitus, increases shedding of Klohto in kidney cells. It is common knowledge that insulin/IGF-I signaling is necessary for normal skeletal growth. As a result, we showed that both FGF23 and Klohto inhibited differentiation of cultured skeletal muscle cells through down-regulation of insulin/IGF-I signaling. These observations suggested a divergent role of FGF23 and soluble klohto in the regulation of skeletal muscle differentiation and thereby muscle atrophy under pathological conditioned in CKD patients. Our results further imply that FGF23/Klohto may serve a new therapeutic target for CKD-induced muscle atrophy.

  12. Mechanisms Underlying Testicular Damage and Dysfunction in Mice With Partial IGF-1 Deficiency and the Effectiveness of IGF-1 Replacement Therapy.

    Science.gov (United States)

    Castilla-Cortázar, Inma; Gago, Alberto; Muñoz, Úrsula; Ávila-Gallego, Elena; Guerra-Menéndez, Lucía; Sádaba, María Cruz; García-Magariño, Mariano; Olleros Santos-Ruiz, María; Aguirre, G A; Puche, Juan Enrique

    2015-12-01

    To determine whether insulin-like growth factor (IGF-1) deficiency can cause testicular damage and to examine changes of the testicular morphology and testicular function-related gene expression caused by IGF-1 deficiency. Therefore, this study aims to determine the benefits of low doses of IGF-1 and to explore the mechanisms underlying the IGF-1 replacement therapy. A murine model of IGF-1 deficiency was used to avoid any factor that could contribute to testicular damage. Testicular weight, score of histopathological damage, and gene expressions were studied in 3 experimental groups of mice: controls (wild-type Igf1(+/+)), heterozygous Igf1(+/-) with partial IGF-1 deficiency, and heterozygous Igf1(+/-) treated with IGF-1. Results show that the partial IGF-1 deficiency induced testicular damage and altered expression of genes involved in IGF-1 and growth hormone signaling and regulation, testicular hormonal function, extracellular matrix establishment and its regulation, angiogenesis, fibrogenesis, inflammation, and cytoprotection. In addition, proteins involved in tight junction expression were found to be reduced. However, low doses of IGF-1 restored the testicular damage and most of these parameters. IGF-1 deficiency caused the damage of the blood-testis barrier and testicular structure and induced the abnormal testicular function-related gene expressions. However, low doses of IGF-1 constitute an effective replacement therapy that restores the described testicular damage. Data herein show that (1) cytoprotective activities of IGF-1 seem to be mediated by heat shock proteins and that (2) connective tissue growth factor could play a relevant role together with IGF-1 in the extracellular matrix establishment. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Biochemical characterization of individual human glycosylated pro-insulin-like growth factor (IGF)-II and big-IGF-II isoforms associated with cancer.

    Science.gov (United States)

    Greenall, Sameer A; Bentley, John D; Pearce, Lesley A; Scoble, Judith A; Sparrow, Lindsay G; Bartone, Nicola A; Xiao, Xiaowen; Baxter, Robert C; Cosgrove, Leah J; Adams, Timothy E

    2013-01-04

    Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family, which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint that is lost in many cancers, resulting in up-regulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed "pro" and "big" IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-I receptor and both insulin receptors A and B, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complexes with several IGF-binding proteins (IGFBP-2, IGFBP-3, and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3 or IGFBP-5 and the auxillary protein, acid labile subunit, was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties that may enable them to escape normal sequestration avenues and remain bioavailable in vivo to sustain oncogenic signaling.

  14. Biochemical Characterization of Individual Human Glycosylated pro-Insulin-like Growth Factor (IGF)-II and big-IGF-II Isoforms Associated with Cancer

    Science.gov (United States)

    Greenall, Sameer A.; Bentley, John D.; Pearce, Lesley A.; Scoble, Judith A.; Sparrow, Lindsay G.; Bartone, Nicola A.; Xiao, Xiaowen; Baxter, Robert C.; Cosgrove, Leah J.; Adams, Timothy E.

    2013-01-01

    Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family, which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint that is lost in many cancers, resulting in up-regulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed “pro” and “big” IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-I receptor and both insulin receptors A and B, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complexes with several IGF-binding proteins (IGFBP-2, IGFBP-3, and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3 or IGFBP-5 and the auxillary protein, acid labile subunit, was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties that may enable them to escape normal sequestration avenues and remain bioavailable in vivo to sustain oncogenic signaling. PMID:23166326

  15. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

    Directory of Open Access Journals (Sweden)

    Laurent Kappeler

    2008-10-01

    Full Text Available Mutations that decrease insulin-like growth factor (IGF and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

  16. Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways

    Science.gov (United States)

    Wang, P; Chen, S-H; Hung, W-C; Paul, C; Zhu, F; Guan, P-P; Huso, DL; Kontrogianni-Konstantopoulos, A; Konstantopoulos, K

    2015-01-01

    Interstitial fluid flow in and around the tumor tissue is a physiologically relevant mechanical signal that regulates intracellular signaling pathways throughout the tumor. Yet, the effects of interstitial flow and associated fluid shear stress on the tumor cell function have been largely overlooked. Using in vitro bioengineering models in conjunction with molecular cell biology tools, we found that fluid shear (2 dyn/cm2) markedly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarcoma cells. MMP-12 expression is induced in human chondrocytes during malignant transformation. However, the signaling pathway regulating MMP-12 expression and its potential role in human chondrosarcoma cell invasion and metastasis have yet to be delineated. We discovered that fluid shear stress induces the synthesis of insulin growth factor-2 (IGF-2) and vascular endothelial growth factor (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways. IGF-2-, VEGF-B- or VEGF-D-stimulated chondrosarcoma cells display markedly higher migratory and invasive potentials in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity. Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell invasion in vitro and the lung colonization in vivo. By reconstructing and delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that interfere with chondrosarcoma cell invasion may be identified. PMID:25435370

  17. Nicotine-induced retardation of chondrogenesis through down-regulation of IGF-1 signaling pathway to inhibit matrix synthesis of growth plate chondrocytes in fetal rats

    International Nuclear Information System (INIS)

    Deng, Yu; Cao, Hong; Cu, Fenglong; Xu, Dan; Lei, Youying; Tan, Yang; Magdalou, Jacques; Wang, Hui; Chen, Liaobin

    2013-01-01

    Previous studies have confirmed that maternal tobacco smoking causes intrauterine growth retardation (IUGR) and skeletal growth retardation. Among a multitude of chemicals associated with cigarette smoking, nicotine is one of the leading candidates for causing low birth weights. However, the possible mechanism of delayed chondrogenesis by prenatal nicotine exposure remains unclear. We investigated the effects of nicotine on fetal growth plate chondrocytes in vivo and in vitro. Rats were given 2.0 mg/kg·d of nicotine subcutaneously from gestational days 11 to 20. Prenatal nicotine exposure increased the levels of fetal blood corticosterone and resulted in fetal skeletal growth retardation. Moreover, nicotine exposure induced the inhibition of matrix synthesis and down-regulation of insulin-like growth factor 1 (IGF-1) signaling in fetal growth plates. The effects of nicotine on growth plates were studied in vitro by exposing fetal growth plate chondrocytes to 0, 1, 10, or 100 μM of nicotine for 10 days. Nicotine inhibited matrix synthesis and down-regulated IGF-1 signaling in chondrocytes in a concentration-dependent manner. These results suggest that prenatal nicotine exposure induces delayed chondrogenesis and that the mechanism may involve the down-regulation of IGF-1 signaling and the inhibition of matrix synthesis by growth plate chondrocytes. The present study aids in the characterization of delayed chondrogenesis caused by prenatal nicotine exposure, which might suggest a candidate mechanism for intrauterine origins of osteoporosis and osteoarthritis. - Highlights: ► Prenatal nicotine-exposure could induce delayed chondrogenesis in fetal rats. ► Nicotine inhibits matrix synthesis of fetal growth plate chondrocytes. ► Nicotine inhibits IGF-1 signaling pathway in fetal growth plate chondrocytes

  18. Nicotine-induced retardation of chondrogenesis through down-regulation of IGF-1 signaling pathway to inhibit matrix synthesis of growth plate chondrocytes in fetal rats

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Yu; Cao, Hong; Cu, Fenglong [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Xu, Dan [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China); Lei, Youying [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Tan, Yang [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Magdalou, Jacques [UMR 7561 CNRS-Nancy Université, Faculté de Médicine, Vandoeuvre-lès-Nancy (France); Wang, Hui [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China); Chen, Liaobin, E-mail: lbchen@whu.edu.cn [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China)

    2013-05-15

    Previous studies have confirmed that maternal tobacco smoking causes intrauterine growth retardation (IUGR) and skeletal growth retardation. Among a multitude of chemicals associated with cigarette smoking, nicotine is one of the leading candidates for causing low birth weights. However, the possible mechanism of delayed chondrogenesis by prenatal nicotine exposure remains unclear. We investigated the effects of nicotine on fetal growth plate chondrocytes in vivo and in vitro. Rats were given 2.0 mg/kg·d of nicotine subcutaneously from gestational days 11 to 20. Prenatal nicotine exposure increased the levels of fetal blood corticosterone and resulted in fetal skeletal growth retardation. Moreover, nicotine exposure induced the inhibition of matrix synthesis and down-regulation of insulin-like growth factor 1 (IGF-1) signaling in fetal growth plates. The effects of nicotine on growth plates were studied in vitro by exposing fetal growth plate chondrocytes to 0, 1, 10, or 100 μM of nicotine for 10 days. Nicotine inhibited matrix synthesis and down-regulated IGF-1 signaling in chondrocytes in a concentration-dependent manner. These results suggest that prenatal nicotine exposure induces delayed chondrogenesis and that the mechanism may involve the down-regulation of IGF-1 signaling and the inhibition of matrix synthesis by growth plate chondrocytes. The present study aids in the characterization of delayed chondrogenesis caused by prenatal nicotine exposure, which might suggest a candidate mechanism for intrauterine origins of osteoporosis and osteoarthritis. - Highlights: ► Prenatal nicotine-exposure could induce delayed chondrogenesis in fetal rats. ► Nicotine inhibits matrix synthesis of fetal growth plate chondrocytes. ► Nicotine inhibits IGF-1 signaling pathway in fetal growth plate chondrocytes.

  19. Development and clinical evaluation of a novel immunoassay for the binary complex of IGF-I and IGF-binding protein-1 in human serum

    DEFF Research Database (Denmark)

    Frystyk, Jan; Højlund, Kurt; Rasmussen, Kirsten Nyborg

    2002-01-01

    Correlation studies have suggested that IGF-binding protein (IGFBP)-1 is a dynamic regulator of free IGF-I. To further study this, we developed a monoclonal immunofluorometric assay specific for the binary complex of IGF-I and IGFBP-1 in human serum. An IGFBP-1 antibody, which recognizes all...... phospho-forms of IGFBP-1, was used for coating. An europium-labeled IGF-I antibody served as tracer. Assay incubation was performed at conditions approaching those in vivo (i.e. pH 7.4, 37 C). The assay was highly specific: no signal was obtained unless both IGF-I and IGFBP-1 were present and neither...... IGFBP-2, -3, -4, nor IGF-II caused any cross-reaction. The linear standard curve covered 3 orders of magnitude, and within and in-between assay coefficients of variation were less than 5 and 15%, respectively. To study the dynamic relationship between free IGF-I and binary complex formation, seven...

  20. IGF-1 Has Plaque-Stabilizing Effects in Atherosclerosis by Altering Vascular Smooth Muscle Cell Phenotype

    Science.gov (United States)

    von der Thüsen, Jan H.; Borensztajn, Keren S.; Moimas, Silvia; van Heiningen, Sandra; Teeling, Peter; van Berkel, Theo J.C.; Biessen, Erik A.L.

    2011-01-01

    Insulin-like growth factor-1 (IGF-1) signaling is important for the maintenance of plaque stability in atherosclerosis due to its effects on vascular smooth muscle cell (vSMC) phenotype. To investigate this hypothesis, we studied the effects of the highly inflammatory milieu of the atherosclerotic plaque on IGF-1 signaling and stability-related phenotypic parameters of murine vSMCs in vitro, and the effects of IGF-1 supplementation on plaque phenotype in an atherosclerotic mouse model. M1-polarized, macrophage-conditioned medium inhibited IGF-1 signaling by ablating IGF-1 and increasing IGF-binding protein 3, increased vSMC apoptosis, and decreased proliferation. Expression of α-actin and col3a1 genes was strongly attenuated by macrophage-conditioned medium, whereas expression of matrix-degrading enzymes was increased. Importantly, all of these effects could be corrected by supplementation with IGF-1. In vivo, treatment with the stable IGF-1 analog Long R3 IGF-1 in apolipoprotein E knockout mice reduced stenosis and core size, and doubled cap/core ratio in early atherosclerosis. In advanced plaques, Long R3 IGF-1 increased the vSMC content of the plaque by more than twofold and significantly reduced the rate of intraplaque hemorrhage. We believe that IGF-1 in atherosclerotic plaques may have a role in preventing plaque instability, not only by modulating smooth muscle cell turnover, but also by altering smooth muscle cell phenotype. PMID:21281823

  1. Lysine and Leucine Deficiencies Affect Myocytes Development and IGF Signaling in Gilthead Sea Bream (Sparus aurata.

    Directory of Open Access Journals (Sweden)

    Sheida Azizi

    Full Text Available Optimizing aquaculture production requires better knowledge of growth regulation and improvement in diet formulation. A great effort has been made to replace fish meal for plant protein sources in aquafeeds, making necessary the supplementation of such diets with crystalline amino acids (AA to cover the nutritional requirements of each species. Lysine and Leucine are limiting essential AA in fish, and it has been demonstrated that supplementation with them improves growth in different species. However, the specific effects of AA deficiencies in myogenesis are completely unknown and have only been studied at the level of hepatic metabolism. It is well-known that the TOR pathway integrates the nutritional and hormonal signals to regulate protein synthesis and cell proliferation, to finally control muscle growth, a process also coordinated by the expression of myogenic regulatory factors (MRFs. This study aimed to provide new information on the impact of Lysine and Leucine deficiencies in gilthead sea bream cultured myocytes examining their development and the response of insulin-like growth factors (IGFs, MRFs, as well as key molecules involved in muscle growth regulation like TOR. Leucine deficiency did not cause significant differences in most of the molecules analyzed, whereas Lysine deficiency appeared crucial in IGFs regulation, decreasing significantly IGF-I, IGF-II and IGF-IRb mRNA levels. This treatment also down-regulated the gene expression of different MRFs, including Myf5, Myogenin and MyoD2. These changes were also corroborated by a significant decrease in proliferation and differentiation markers in the Lysine-deficient treatment. Moreover, both Lysine and Leucine limitation induced a significant down-regulation in FOXO3 gene expression, which deserves further investigation. We believe that these results will be relevant for the production of a species as appreciated for human consumption as it is gilthead sea bream and demonstrates

  2. Nutritional regulation of IGF-II, but not IGF-I, is age dependent in sheep.

    Science.gov (United States)

    Oldham, J M; Martyn, J A; Hua, K M; MacDonald, N A; Hodgkinson, S C; Bass, J J

    1999-12-01

    In post-natal animals, plasma concentrations of IGF-I are tightly regulated by nutritional status. The current study reports that plasma levels of IGF-II in sheep are also regulated by nutrition, but whether plasma IGF-II is increased, decreased or remains the same, depends on the age of the animal. Ewe lambs, ranging in age from 2 days to 2 years, were fed or fasted for lengths of time between 24 and 72 h. Blood samples were taken at intervals of 24 h throughout the treatment period and immediately before slaughter. Plasma concentrations of IGF-I increased with advancing age in fed animals (Panimals matured (Pnutrition (Panimals (Panimals (Pnutritional sensitivity of serum IGF-binding proteins (BPs) also changed with age. The 29 kDa BP, which we presume to be BP1, was elevated by fasting in young animals and reduced slightly in older animals. BP2 was increased to a similar magnitude by fasting at all ages. BP3 was depressed by fasting in young animals and showed little change in adults. In contrast, a 24 kDa BP, which is probably BP4, showed little change in young animals and was reduced substantially in older sheep. In conclusion, the response of plasma IGF-II to fasting suggests that this peptide has functions in mediating nutritional stress which depend on the age of the animal, and also that the role of IGF-II may differ from that of IGF-I in adults.

  3. Insulin and insulin-like growth factor-I (IGF-I) receptor phosphorylation in µ-calpain knockout mice

    Science.gov (United States)

    Numerous cellular processes are controlled by insulin and IGF-I signaling pathways. Due to previous work in our laboratories, we hypothesized that insulin (IR) and type 1 IGF-I (IGF-IR) receptor signaling is decreased due to increased protein tyrosine phosphatase 1B (PTP1B) activity. C57BL/6J mice...

  4. IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses

    Science.gov (United States)

    Gazit, Neta; Vertkin, Irena; Shapira, Ilana; Helm, Martin; Slomowitz, Edden; Sheiba, Maayan; Mor, Yael; Rizzoli, Silvio; Slutsky, Inna

    2016-01-01

    Summary The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer’s disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca2+ transients, while promoting spontaneous transmission and resting Ca2+ level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca2+ buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer’s disease. Video Abstract PMID:26804996

  5. Insulin Resistance Negatively Influences the Muscle-Dependent IGF-1-Bone Mass Relationship in Premenarcheal Girls.

    Science.gov (United States)

    Kindler, J M; Pollock, N K; Laing, E M; Jenkins, N T; Oshri, A; Isales, C; Hamrick, M; Lewis, R D

    2016-01-01

    IGF-1 promotes bone growth directly and indirectly through its effects on skeletal muscle. Insulin and IGF-1 share a common cellular signaling process; thus, insulin resistance may influence the IGF-1-muscle-bone relationship. We sought to determine the effect of insulin resistance on the muscle-dependent relationship between IGF-1 and bone mass in premenarcheal girls. This was a cross-sectional study conducted at a university research center involving 147 girls ages 9 to 11 years. Glucose, insulin, and IGF-1 were measured from fasting blood samples. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin. Fat-free soft tissue (FFST) mass and bone mineral content (BMC) were measured by dual-energy x-ray absorptiometry. Our primary outcome was BMC/height. In our path model, IGF-1 predicted FFST mass (b = 0.018; P = .001), which in turn predicted BMC/height (b = 0.960; P IGF-1 predicted BMC/height (b = 0.001; P = .002), but not after accounting for the mediator of this relationship, FFST mass. The HOMA-IR by IGF-1 interaction negatively predicted FFST mass (b = -0.044; P = .034). HOMA-IR had a significant and negative effect on the muscle-dependent relationship between IGF-1 and BMC/height (b = -0.151; P = .047). Lean body mass is an important intermediary factor in the IGF-1-bone relationship. For this reason, bone development may be compromised indirectly via suboptimal IGF-1-dependent muscle development in insulin-resistant children.

  6. IGF-I, IGF-II, and Insulin Stimulate Different Gene Expression Responses through Binding to the IGF-I Receptor

    DEFF Research Database (Denmark)

    Versteyhe, Soetkin; Klaproth, Birgit; Borup, Rehannah

    2013-01-01

    Insulin and the insulin-like growth factors (IGF)-I and -II are closely related peptides important for regulation of metabolism, growth, differentiation, and development. The IGFs exert their main effects through the IGF-I receptor. Although the insulin receptor is the main physiological receptor...... for insulin, this peptide hormone can also bind at higher concentrations to the IGF-I receptor and exert effects through it. We used microarray gene expression profiling to investigate the gene expression regulated by IGF-I, IGF-II, and insulin after stimulation of the IGF-I receptor. Fibroblasts from mice......, knockout for IGF-II and the IGF-II/cation-independent mannose-6-phosphate receptor, and expressing functional IGF-I but no insulin receptors, were stimulated for 4 h with equipotent saturating concentrations of insulin, IGF-I, and IGF-II. Each ligand specifically regulated a group of transcripts...

  7. IGF-II-mediated downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α in myoblast cells involves PI3K/Akt/FoxO1 signaling pathway.

    Science.gov (United States)

    Mu, Xiaoyu; Qi, Weihong; Liu, Yunzhang; Zhou, Jianfeng; Li, Yun; Rong, Xiaozhi; Lu, Ling

    2017-08-01

    Insulin-like growth factor II (IGF-II) can stimulate myogenesis and is critically involved in skeletal muscle differentiation. The presence of negative regulators of this process, however, is not well explored. Here, we showed that in myoblast cells, IGF-II negatively regulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA expression, while constitutive expression of PGC-1α induced myoblast differentiation. These results suggest that the negative regulation of PGC-1α by IGF-II may act as a negative feedback mechanism in IGF-II-induced myogenic differentiation. Reporter assays demonstrated that IGF-II suppresses the basal PGC-1α promoter activity. Blocking the IGF-II signaling pathway increased the endogenous PGC-1α levels. In addition, pharmacological inhibition of PI3 kinase activity prevented the downregulation of PGC-1α but the activation of mTOR was not required for this process. Importantly, further analysis showed that forkhead transcription factor FoxO1 contributes to mediating the effects of IGF-II on PGC-1 promoter activity. These findings indicate that IGF-II reduces PGC-1α expression in skeletal muscle cells through a mechanism involving PI3K-Akt-FoxO1 but not p38 MAPK or Erk1/2 MAPK pathways.

  8. IGF-1 facilitates thrombopoiesis primarily through Akt activation.

    Science.gov (United States)

    Chen, Shilei; Hu, Mengjia; Shen, Mingqiang; Wang, Song; Wang, Cheng; Chen, Fang; Tang, Yong; Wang, Xinmiao; Zeng, Hao; Chen, Mo; Gao, Jining; Wang, Fengchao; Su, Yongping; Xu, Yang; Wang, Junping

    2018-05-25

    It is known that insulin-like growth factor-1 (IGF-1) also functions as a hematopoietic factor, while its direct effect on thrombopoiesis remains unclear. In this study, we show that IGF-1 is able to promote CD34+ cell differentiation toward megakaryocytes (MKs), as well as the facilitation of proplatelet formation (PPF) and platelet production from cultured MKs. The in vivo study demonstrates that IGF-1 administration accelerates platelet recovery in mice after 6.0Gy of irradiation and in mice that received bone marrow transplantation (BMT) following 10.0Gy of lethal irradiation. Subsequent investigations reveal that ERK1/2 and Akt activation mediate the effect of IGF-1 on thrombopoiesis. Notably, Akt activation induced by IGF-1 is more apparent than that of ERK1/2, compared with that of thrombopoietin (TPO) treatment. Moreover, the effect of IGF-1 on thrombopoiesis is independent of TPO signaling, because IGF-1 treatment can also lead to a significant increase of platelet counts in homozygous TPO receptor mutant mice. Further analysis indicates that the activation of Akt triggered by IGF-1 requires the assistance of steroid receptor coactivator-3 (SRC-3). Therefore, our data reveal a distinct role of IGF-1 in regulating thrombopoiesis, providing new insights into TPO-independent regulation of platelet generation. Copyright © 2018 American Society of Hematology.

  9. IGF-1 Prevents Diastolic and Systolic Dysfunction Associated with Cardiomyopathy and Preserves Adrenergic Sensitivity

    Science.gov (United States)

    Roof, Steve R.; Boslett, James; Russell, Duncan; del Rio, Carlos; Alecusan, Joe; Zweier, Jay L.; Ziolo, Mark T.; Hamlin, Robert; Mohler, Peter J.; Curran, Jerry

    2015-01-01

    Aims Insulin-like growth factor 1 (IGF-1)-dependent signaling promotes exercise-induced physiological cardiac hypertrophy. However, the in vivo therapeutic potential of IGF-1 for heart disease is not well established. Here we test the potential therapeutic benefits of IGF-1 on cardiac function using an in vivo model of chronic catecholamine-induced cardiomyopathy. Methods Rats were perfused with isoproterenol via osmotic pump (1 mg/kg/day) and treated with 2 mg/kg IGF-1 (2 mg/kg/day, 6 days a week) for 2 or 4 weeks. Echocardiography, ECG, and blood pressure were assessed. In vivo pressure-volume loop studies were conducted at 4 weeks. Heart sections were analyzed for fibrosis and apoptosis, and relevant biochemical signaling cascades were assessed. Results After 4 weeks, diastolic function (EDPVR, EDP, tau, E/A ratio), systolic function (PRSW, ESPVR, dP/dtmax), and structural remodeling (LV chamber diameter, wall thickness) were all adversely affected in isoproterenol-treated rats. All these detrimental effects were attenuated in rats treated with Iso+IGF-1. Isoproterenol-dependent effects on BP were attenuated by IGF-1 treatment. Adrenergic sensitivity was blunted in isoproterenol-treated rats but was preserved by IGF-1 treatment. Immunoblots indicate that cardioprotective p110α signaling and activated Akt are selectively upregulated in Iso+IGF-1 treated hearts. Expression of iNOS was significantly increased in both the Iso and Iso+IGF-1 groups, however tetrahydrobiopterin (BH4) levels were decreased in the Iso group and maintained by IGF-1 treatment. Conclusion IGF-1 treatment attenuates diastolic and systolic dysfunction associated with chronic catecholamine-induced cardiomyopathy while preserving adrenergic sensitivity and promoting BH4 production. These data support the potential use of IGF-1 therapy for clinical applications for cardiomyopathies. PMID:26399932

  10. R1507, an Anti-Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody, and EWS/FLI-1 siRNA in Ewing's Sarcoma: Convergence at the IGF/IGFR/Akt Axis

    Science.gov (United States)

    Rodon, Jordi; Sun, Michael; Kuenkele, Klaus-Peter; Parsons, Henrique A.; Trent, Jonathan C.; Kurzrock, Razelle

    2011-01-01

    A subset of patients with Ewing's sarcoma responds to anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies. Mechanisms of sensitivity and resistance are unknown. We investigated whether an anti-IGF-1R antibody acts via a pathway that could also be suppressed by small interfering (si) RNA against the EWS/FLI-1 fusion protein, the hallmark of Ewing's sarcoma. The growth of two Ewing's sarcoma cell lines (TC-32 and TC-71) was inhibited by the fully human anti-IGF-1R antibody, R1507 (clonogenic and MTT assays). TC-32 and TC-71 cells express high levels of IGF-2, while RD-ES and A4573 Ewing's cell lines, which were less responsive to R1507 in our assays, express low or undetectable IGF-2, respectively. TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/degradation, an effect which was associated with a decrease in p-IGF-1R, p-IRS-1, and p-Akt. EWS/FLI-1 siRNA also decreased p-Akt, due to its ability to increase IGF-BP3 levels and subsequently decrease IGF-1 and IGF-2 levels, thus inhibiting signaling through p-IGF-1R. This inhibition correlated with growth suppression and apoptosis. The attenuation of Akt activation was confirmed in TC-71 and HEK-293 (human embryonic kidney) cells by transfecting them with IGF-1R siRNA. We conclude that antibodies and siRNA to IGF-1R, as well as siRNA to EWS/FLI-1, act via intersecting IGF/IGF-1R signals that suppress a common point in this pathway, namely the phosphorylation of Akt. PMID:22022506

  11. R1507, an anti-insulin-like growth factor-1 receptor (IGF-1R antibody, and EWS/FLI-1 siRNA in Ewing's sarcoma: convergence at the IGF/IGFR/Akt axis.

    Directory of Open Access Journals (Sweden)

    Helen J Huang

    Full Text Available A subset of patients with Ewing's sarcoma responds to anti-insulin-like growth factor-1 receptor (IGF-1R antibodies. Mechanisms of sensitivity and resistance are unknown. We investigated whether an anti-IGF-1R antibody acts via a pathway that could also be suppressed by small interfering (si RNA against the EWS/FLI-1 fusion protein, the hallmark of Ewing's sarcoma. The growth of two Ewing's sarcoma cell lines (TC-32 and TC-71 was inhibited by the fully human anti-IGF-1R antibody, R1507 (clonogenic and MTT assays. TC-32 and TC-71 cells express high levels of IGF-2, while RD-ES and A4573 Ewing's cell lines, which were less responsive to R1507 in our assays, express low or undetectable IGF-2, respectively. TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/degradation, an effect which was associated with a decrease in p-IGF-1R, p-IRS-1, and p-Akt. EWS/FLI-1 siRNA also decreased p-Akt, due to its ability to increase IGF-BP3 levels and subsequently decrease IGF-1 and IGF-2 levels, thus inhibiting signaling through p-IGF-1R. This inhibition correlated with growth suppression and apoptosis. The attenuation of Akt activation was confirmed in TC-71 and HEK-293 (human embryonic kidney cells by transfecting them with IGF-1R siRNA. We conclude that antibodies and siRNA to IGF-1R, as well as siRNA to EWS/FLI-1, act via intersecting IGF/IGF-1R signals that suppress a common point in this pathway, namely the phosphorylation of Akt.

  12. Zebrafish IGF genes: gene duplication, conservation and divergence, and novel roles in midline and notochord development.

    Directory of Open Access Journals (Sweden)

    Shuming Zou

    Full Text Available Insulin-like growth factors (IGFs are key regulators of development, growth, and longevity. In most vertebrate species including humans, there is one IGF-1 gene and one IGF-2 gene. Here we report the identification and functional characterization of 4 distinct IGF genes (termed as igf-1a, -1b, -2a, and -2b in zebrafish. These genes encode 4 structurally distinct and functional IGF peptides. IGF-1a and IGF-2a mRNAs were detected in multiple tissues in adult fish. IGF-1b mRNA was detected only in the gonad and IGF-2b mRNA only in the liver. Functional analysis showed that all 4 IGFs caused similar developmental defects but with different potencies. Many of these embryos had fully or partially duplicated notochords, suggesting that an excess of IGF signaling causes defects in the midline formation and an expansion of the notochord. IGF-2a, the most potent IGF, was analyzed in depth. IGF-2a expression caused defects in the midline formation and expansion of the notochord but it did not alter the anterior neural patterning. These results not only provide new insights into the functional conservation and divergence of the multiple igf genes but also reveal a novel role of IGF signaling in midline formation and notochord development in a vertebrate model.

  13. Targeting the IGF-1R: The Tale of The Tortoise and The Hare

    Directory of Open Access Journals (Sweden)

    Caitrin eCrudden

    2015-04-01

    Full Text Available The insulin-like growth factor type 1 receptor (IGF-1R plays a key role in the development and maintenance of cancer. Since the first links between growth factor receptors and oncogenes were noted over three decades ago, targeting the IGF-1R has been of great interest. This review follows the progress from inception through intense pharmaceutical development, disappointing clinical trials and recent updates to the signaling paradigm. In light of major developments in signaling understanding and activation complexities, we examine reasons for failure of first line targeting approaches. Recent findings include the fact that the IGF-1R can signal in the absence of the ligand, in the absence of kinase activity and utilizes components of the GPCR system. With recognition of the unappreciated complexities that this first wave of targeting approaches encountered, we advocate recognition of IGF-1R as a valid target for cancer treatment and look to future directions, where both research and pharmaceutical strengths can lend themselves to finally unearthing anti-IGF-1R potential.

  14. Matrix metalloproteinase-1 facilitates MSC migration via cleavage of IGF-2/IGFBP2 complex.

    Science.gov (United States)

    Guan, Shou P; Lam, Alan T L; Newman, Jennifer P; Chua, Kevin L M; Kok, Catherine Y L; Chong, Siao T; Chua, Melvin L K; Lam, Paula Y P

    2018-01-01

    The specific mechanism underlying the tumor tropism of human mesenchymal stem cells (MSCs) for cancer is not well defined. We previously showed that the migration potential of MSCs correlated with the expression and protease activity of matrix metalloproteinase (MMP)-1. Furthermore, highly tumor-tropic MSCs expressed higher levels of MMP-1 and insulin-like growth factor (IGF)-2 than poorly migrating MSCs. In this study, we examined the functional roles of IGF-2 and MMP-1 in mediating the tumor tropism of MSCs. Exogenous addition of either recombinant IGF-2 or MMP-1 could stimulate MSC migration. The correlation between IGF-2, MMP-1 expression, and MSC migration suggests that MMP-1 may play a role in regulating MSC migration via the IGF-2 signaling cascade. High concentrations of IGF binding proteins (IGFBPs) can inhibit IGF-stimulated functions by blocking its binding to its receptors and proteolysis of IGFBP is an important mechanism for the regulation of IGF signaling. We thus hypothesized that MMP-1 acts as an IGFBP2 proteinase, resulting in the cleavage of IGF-2/IGFBP2 complex and extracellular release of free IGF-2. Indeed, our results showed that conditioned media from highly migrating MSCs, which expressed high levels of MMP-1, cleaved the IGF-2/IGFBP2 complex. Taken together, these results showed that the MMP-1 secreted by highly tumor-tropic MSCs cleaved IGF-2/IGFBP2 complex. Free IGF-2 released from the complex may facilitate MSC migration toward tumor.

  15. IGF-I stimulates ERβ and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis.

    Science.gov (United States)

    Zhou, Yan; Zeng, Cheng; Li, Xin; Wu, Pei-Li; Yin, Ling; Yu, Xiao-Lan; Zhou, Ying-Fang; Xue, Qing

    2016-08-01

    Estrogen receptor beta (ERβ, encoded by ESR2 gene) and cytochrome P450 aromatase (encoded by CYP19A1 gene) play critical roles in endometriosis, and the levels of insulin-like growth factor-I (IGF-I) in the peritoneal fluid are significantly higher in patients with endometriosis compared with those in normal women. However, the effects and mechanisms of IGF-I on ERβ and aromatase expression remain to be fully elucidated. In this study, human endometriotic stromal cells (ESCs) and endometrial cells (EMs) derived from ovarian endometriomas and eutopic endometrial tissues. ESCs were cultured with IGF-I, signal pathway inhibitors, and siRNAs. ERβ and aromatase expression were measured by real-time PCR and Western, respectively. The binding of c-Jun and CREB to the ESR2 and CYP19A1 promoters was assessed by chromatin immunoprecipitation assay. Animal experiments were performed in a xenograft mouse model. Levels of IGF-I mRNA in ESCs were markedly higher than those in EMs. IGF-I upregulated ERβ and aromatase expression in ESCs after stimulation of the IGF1R/PI3K/AKT pathway. Following IGF-I treatment, a marked increase in c-Jun and CREB phosphorylation occurred, enhancing binding to the ESR2 and CYP19A1 promoters. An IGF1R inhibitor in vivo reduced IGF-I-induced endometriosis graft growth and ERβ and aromatase expression. In conclusion, this is the first report to describe a mechanistic analysis of ERβ and aromatase expression regulated by IGF-I in ESCs. Moreover, an IGF1R inhibitor impeded ectopic lesion growth in nude mice. These findings suggest that an inhibitor of IGF1R might have therapeutic potential as an antiendometriotic drug. Level of IGF-I mRNA in ESCs is markedly higher than that in EMs. IGF-I up-regulates ERβ and aromatase expression via IGF1R/PI3K/AKT pathway. C-Jun and CREB are recruited to ESR2 or CYP19A1 promoter by IGF-I stimulation. IGF-1R inhibitors in vivo impede the growth of ectopic lesions in nude mice.

  16. Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN

    Science.gov (United States)

    Singh, Karmveer; Maity, Pallab; Krug, Linda; Meyer, Patrick; Treiber, Nicolai; Lucas, Tanja; Basu, Abhijit; Kochanek, Stefan; Wlaschek, Meinhard; Geiger, Hartmut; Scharffetter-Kochanek, Karin

    2015-01-01

    The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions () in mitochondria, either by chemical inhibition of complex I or by genetic silencing of -dismutating mitochondrial Sod2. The -dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of α1(I), α1(III), and α2(I) collagen, the hallmarks of skin ageing. Enhanced led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated -induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with , PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies. PMID:25520316

  17. c-myb stimulates cell growth by regulation of insulin-like growth factor (IGF) and IGF-binding protein-3 in K562 leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Min-Sun; Kim, Sun-Young; Arunachalam, Sankarganesh [Department of Pediatrics, School of Medicine, Chonbuk National University, Jeonju 561-712 (Korea, Republic of); Hwang, Pyoung-Han [Department of Pediatrics, School of Medicine, Chonbuk National University, Jeonju 561-712 (Korea, Republic of); Research Institute of Clinical Medicine, School of Medicine, Chonbuk National University, Jeonju 561-712 (Korea, Republic of); Yi, Ho-Keun [Department of Biochemistry, School of Dentistry, Chonbuk National University, Jeonju 561-712 (Korea, Republic of); Nam, Sang-Yun [Department of Alternative Therapy, School of Alternative Medicine and Health Science, Jeonju University, Jeonju 561-712 (Korea, Republic of); Lee, Dae-Yeol, E-mail: leedy@chonbuk.ac.kr [Department of Pediatrics, School of Medicine, Chonbuk National University, Jeonju 561-712 (Korea, Republic of); Research Institute of Clinical Medicine, School of Medicine, Chonbuk National University, Jeonju 561-712 (Korea, Republic of)

    2009-07-17

    c-myb plays an important role in the regulation of cell growth and differentiation, and is highly expressed in immature hematopoietic cells. The human chronic myelogenous leukemia cell K562, highly expresses IGF-I, IGF-II, IGF-IR, and IGF-induced cellular proliferation is mediated by IGF-IR. To characterize the impact of c-myb on the IGF-IGFBP-3 axis in leukemia cells, we overexpressed c-myb using an adenovirus gene transfer system in K562 cells. The overexpression of c-myb induced cell proliferation, compared to control, and c-myb induced cell growth was inhibited by anti-IGF-IR antibodies. c-myb overexpression resulted in a significant increase in the expression of IGF-I, IGF-II, and IGF-IR, and a decrease in IGFBP-3 expression. By contrast, disruption of c-myb function by DN-myb overexpression resulted in significant reduction of IGF-I, IGF-II, IGF-IR, and elevation of IGFBP-3 expression. In addition, exogenous IGFBP-3 inhibited the proliferation of K562 cells, and c-myb induced cell growth was blocked by IGFBP-3 overexpression in a dose-dependent manner. The growth-promoting effects of c-myb were mediated through two major intracellular signaling pathways, Akt and Erk. Activation of Akt and Erk by c-myb was completely blocked by IGF-IR and IGFBP-3 antibodies. These findings suggest that c-myb stimulates cell growth, in part, by regulating expression of the components of IGF-IGFBP axis in K562 cells. In addition, disruption of c-myb function by DN-myb may provide a useful strategy for treatment of leukemia.

  18. c-myb stimulates cell growth by regulation of insulin-like growth factor (IGF) and IGF-binding protein-3 in K562 leukemia cells

    International Nuclear Information System (INIS)

    Kim, Min-Sun; Kim, Sun-Young; Arunachalam, Sankarganesh; Hwang, Pyoung-Han; Yi, Ho-Keun; Nam, Sang-Yun; Lee, Dae-Yeol

    2009-01-01

    c-myb plays an important role in the regulation of cell growth and differentiation, and is highly expressed in immature hematopoietic cells. The human chronic myelogenous leukemia cell K562, highly expresses IGF-I, IGF-II, IGF-IR, and IGF-induced cellular proliferation is mediated by IGF-IR. To characterize the impact of c-myb on the IGF-IGFBP-3 axis in leukemia cells, we overexpressed c-myb using an adenovirus gene transfer system in K562 cells. The overexpression of c-myb induced cell proliferation, compared to control, and c-myb induced cell growth was inhibited by anti-IGF-IR antibodies. c-myb overexpression resulted in a significant increase in the expression of IGF-I, IGF-II, and IGF-IR, and a decrease in IGFBP-3 expression. By contrast, disruption of c-myb function by DN-myb overexpression resulted in significant reduction of IGF-I, IGF-II, IGF-IR, and elevation of IGFBP-3 expression. In addition, exogenous IGFBP-3 inhibited the proliferation of K562 cells, and c-myb induced cell growth was blocked by IGFBP-3 overexpression in a dose-dependent manner. The growth-promoting effects of c-myb were mediated through two major intracellular signaling pathways, Akt and Erk. Activation of Akt and Erk by c-myb was completely blocked by IGF-IR and IGFBP-3 antibodies. These findings suggest that c-myb stimulates cell growth, in part, by regulating expression of the components of IGF-IGFBP axis in K562 cells. In addition, disruption of c-myb function by DN-myb may provide a useful strategy for treatment of leukemia.

  19. The pro-Forms of Insulin-Like Growth Factor I (IGF-I) Are Predominant in Skeletal Muscle and Alter IGF-I Receptor Activation

    Science.gov (United States)

    Durzyńska, Julia; Philippou, Anastassios; Brisson, Becky K.; Nguyen-McCarty, Michelle

    2013-01-01

    IGF-I is a key regulator of muscle development and growth. The pre-pro-peptide produced by the Igf1gene undergoes several posttranslational processing steps to result in a secreted mature protein, which is thought to be the obligate ligand for the IGF-I receptor (IGF-IR). The goals of this study were to determine what forms of IGF-I exist in skeletal muscle, and whether the mature IGF-I protein was the only form able to activate the IGF-IR. We measured the proportion of IGF-I species in murine skeletal muscle and found that the predominant forms were nonglycosylated pro-IGF-I and glycosylated pro-IGF-I, which retained the C-terminal E peptide extension, instead of mature IGF-I. These forms were validated using samples subjected to viral expression of IGF-I combined with furin and glycosidase digestion. To determine whether the larger molecular weight IGF-I forms were also ligands for the IGF-IR, we generated each specific form through transient transfection of 3T3 cells and used the enriched media to perform kinase receptor activation assays. Compared with mature IGF-I, nonglycosylated pro-IGF-I had similar ability to activate the IGF-IR, whereas glycosylation of pro-IGF-I significantly reduced receptor activation. Thus, it is important to understand not only the quantity, but also the proportion of IGF-I forms produced, to evaluate the true biological activity of this growth factor. PMID:23407451

  20. Role of IGF-1R in ameliorating apoptosis of GNE deficient cells.

    Science.gov (United States)

    Singh, Reema; Chaudhary, Priyanka; Arya, Ranjana

    2018-05-09

    Sialic acids (SAs) are nine carbon acidic amino sugars, found at the outermost termini of glycoconjugates performing various physiological and pathological functions. SA synthesis is regulated by UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) that catalyzes rate limiting steps. Mutations in GNE result in rare genetic disorders, GNE myopathy and Sialuria. Recent studies indicate an alternate role of GNE in cell apoptosis and adhesion, besides SA biosynthesis. In the present study, using a HEK cell-based model for GNE myopathy, the role of Insulin-like Growth Factor Receptor (IGF-1R) as cell survival receptor protein was studied to counter the apoptotic effect of non-functional GNE. In the absence of functional GNE, IGF-1R was hyposialylated and transduced a downstream signal upon IGF-1 (IGF-1R ligand) treatment. IGF-1 induced activation of IGF-1R led to AKT (Protein Kinase B) phosphorylation that may phosphorylate BAD (BCL2 Associated Death Promoter) and its dissociation from BCL2 to prevent apoptosis. However, reduced ERK (Extracellular signal-regulated kinases) phosphorylation in GNE deficient cells after IGF-1 treatment suggests downregulation of the ERK pathway. A balance between the ERK and AKT pathways may determine the cell fate towards survival or apoptosis. Our study suggests that IGF-1R activation may rescue apoptotic cell death of GNE deficient cell lines and has potential as therapeutic target.

  1. Experimental Alcohol-Related Peripheral Neuropathy: Role of Insulin/IGF Resistance

    Directory of Open Access Journals (Sweden)

    James Gilchrist

    2012-08-01

    Full Text Available The mechanisms of alcohol-related peripheral neuropathy (ALPN are poorly understood. We hypothesize that, like alcohol-related liver and brain degeneration, ALPN may be mediated by combined effects of insulin/IGF resistance and oxidative stress. Adult male Long Evans rats were chronically pair-fed with diets containing 0% or 37% ethanol (caloric, and subjected to nerve conduction studies. Chronic ethanol feeding slowed nerve conduction in the tibial (p = 0.0021 motor nerve, and not plantar sensory nerve, but it did not affect amplitude. Histological studies of the sciatic nerve revealed reduced nerve fiber diameters with increased regenerative sprouts, and denervation myopathy in ethanol-fed rats. qRT-PCR analysis demonstrated reduced mRNA levels of insulin, IGF-1, and IGF-2 polypeptides, IGF-1 receptor, and IRS2, and ELISAs revealed reduced immunoreactivity for insulin and IGF-1 receptors, IRS-1, IRS-4, myelin-associated glycoprotein, and tau in sciatic nerves of ethanol-fed rats (all p < 0.05 or better. The findings suggest that ALPN is characterized by (1 slowed conduction velocity with demyelination, and a small component of axonal degeneration; (2 impaired trophic factor signaling due to insulin and IGF resistance; and (3 degeneration of myelin and axonal cytoskeletal proteins. Therefore, ALPN is likely mediated by molecular and signal transduction abnormalities similar to those identified in alcoholic liver and brain degeneration.

  2. Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners.

    Science.gov (United States)

    Sarfstein, Rive; Friedman, Yael; Attias-Geva, Zohar; Fishman, Ami; Bruchim, Ilan; Werner, Haim

    2013-01-01

    Accumulating epidemiological evidence shows that obesity is associated with an increased risk of several types of adult cancers, including endometrial cancer. Chronic hyperinsulinemia, a typical hallmark of diabetes, is one of the leading factors responsible for the obesity-cancer connection. Numerous cellular and circulating factors are involved in the biochemical chain of events leading from hyperinsulinemia and insulin resistance to increased cancer risk and, eventually, tumor development. Metformin is an oral anti-diabetic drug of the biguanide family used for treatment of type 2 diabetes. Recently, metformin was shown to exhibit anti-proliferative effects in ovarian and Type I endometrial cancer, although the mechanisms responsible for this non-classical metformin action remain unclear. The insulin-like growth factors (IGFs) play a prominent role in cancer biology and their mechanisms of action are tightly interconnected with the insulin signaling pathways. Given the cross-talk between the insulin and IGF signaling pathways, the aim of this study was to examine the hypothesis that the anti-proliferative actions of metformin in uterine serous carcinoma (USC) are potentially mediated via suppression of the IGF-I receptor (IGF-IR) pathway. Our results show that metformin interacts with the IGF pathway, and induces apoptosis and inhibition of proliferation and migration of USC cell lines with both wild type and mutant p53. Taken together, our results suggest that metformin therapy could be a novel and attractive therapeutic approach for human USC, a highly aggressive variant of endometrial cancer.

  3. Prenatal stress affects insulin-like growth factor-1 (IGF-1) level and IGF-1 receptor phosphorylation in the brain of adult rats.

    Science.gov (United States)

    Basta-Kaim, Agnieszka; Szczesny, Ewa; Glombik, Katarzyna; Stachowicz, Katarzyna; Slusarczyk, Joanna; Nalepa, Irena; Zelek-Molik, Agnieszka; Rafa-Zablocka, Katarzyna; Budziszewska, Boguslawa; Kubera, Marta; Leskiewicz, Monika; Lason, Wladyslaw

    2014-09-01

    It has been shown that stressful events occurring in early life have a powerful influence on the development of the central nervous system. Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation and survival of both neurons and glial cells and is thought to exert antidepressant-like activity. Thus, it is possible that disturbances in the function of the IGF-1 system may be responsible for disturbances observed over the course of depression. Prenatal stress was used as a valid model of depression. Adult male offspring of control and stressed rat dams were subjected to behavioural testing (forced swim test). The level of IGF-1 in the blood and the expression of IGF-1, IGF-1R, and IRS-1/2 in the hippocampus and frontal cortex using RT-PCR, ELISA and western blotting were measured. In addition the effect of intracerebroventricularly administered IGF-1 and/or the IGF-1R receptor antagonist JB1 in the forced swim test was studied. Prenatally stressed rats showed depressive like behaviour, including increased immobility time as well as decreased mobility and climbing. Intracerebroventricular administration of IGF-1 reversed these effects in stressed animals, whereas concomitant administration of the IGF-1R antagonist JB1 completely blocked the effects. Biochemical analysis of homogenates from the hippocampus and frontal cortex revealed decreases in IGF-1 level and IGF-1R phosphorylation along with disturbances in IRS-1 phosphorylation. These findings reveal that prenatal stress alters IGF-1 signalling, which may contribute to the behavioural changes observed in depression. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  4. A Novel igf3 Gene in Common Carp (Cyprinus carpio): Evidence for Its Role in Regulating Gonadal Development.

    Science.gov (United States)

    Song, Feibiao; Wang, Lanmei; Zhu, Wenbin; Fu, Jianjun; Dong, Juanjuan; Dong, Zaijie

    2016-01-01

    Since the insulin-like growth factor 3 (igf3) gene was recently discovered in fish ovary, its function in the gonads has received much attention. In this study, we isolated two igf3 subtypes from common carp (Cyprinus carpio), which comprised full-length cDNA of 707 and 1153 nucleotides encoding 205 and 198 amino acids (aa), respectively. The Igf3 aa sequence had the highest gene homology of 72% with the corresponding sequence in zebrafish (Danio rerio). Phylogenetic tree construction revealed that the C. carpio igf3 gene was first clustered with D. rerio and then with other teleost species. Igf3 mRNA was widely expressed, with expression being highest in the gonads and blood. In the gonad development stage, igf3a mRNA expression was highest in the maturity and recession stage of the ovary, and decline phase of the testis, while igf3b was highest in the recession and fully mature periods of the ovaries and testes, respectively. Western blotting of testis protein samples showed two bands of approximately 21 kDa and 34 kDa corresponding to the calculated molecular mass of the two Igf3 subtypes; no signal was detected in the ovary. The Igf3 protein was localized in the ovary granulosa cells and testis spermatogonium and spermatids. 17β-Ethinylestradiol treatment increased both ovary and testis igf3 mRNA expression. These findings suggest that Igf3 may play an important role in C. carpio gonadal development.

  5. BRCA1 is expressed in uterine serous carcinoma (USC) and controls insulin-like growth factor I receptor (IGF-IR) gene expression in USC cell lines.

    Science.gov (United States)

    Amichay, Keren; Kidron, Debora; Attias-Geva, Zohar; Schayek, Hagit; Sarfstein, Rive; Fishman, Ami; Werner, Haim; Bruchim, Ilan

    2012-06-01

    The insulin-like growth factor I receptor (IGF-IR) and BRCA1 affect cell growth and apoptosis. Little information is available about BRCA1 activity on the IGF signaling pathway. This study evaluated the effect of BRCA1 on IGF-IR expression. BRCA1 and IGF-IR immunohistochemistry on archival tissues (35 uterine serous carcinomas [USCs] and 17 metastases) were performed. USPC1 and USPC2 cell lines were transiently cotransfected with an IGF-IR promoter construct driving a luciferase reporter gene and a BRCA1 expression plasmid. Endogenous IGF-IR levels were evaluated by Western immunoblotting. We found high BRCA1 and IGF-IR protein expression in primary and metastatic USC tumors. All samples were immunostained for BRCA1-71% strongly stained; and 33/35 (94%) were stained positive for IGF-IR-2 (6%) strongly stained. No difference in BRCA1 and IGF-IR staining intensity was noted between BRCA1/2 mutation carriers and noncarriers. Metastatic tumors stained more intensely for BRCA1 than did the primary tumor site (P = 0.041) and with borderline significance for IGF-IR (P = 0.069). BRCA1 and IGF-IR staining did not correlate to survival. BRCA1 expression led to 35% and 54% reduction in IGF-IR promoter activity in the USPC1 and USCP2 cell lines, respectively. Western immunoblotting showed a decline in phosphorylated IGF-IR and phosphorylated AKT in both transiently and stably transfected cells. BRCA1 and IGF-IR are highly expressed in USC tumors. BRCA1 suppresses IGF-IR gene expression and activity. These findings suggest a possible biological link between the BRCA1 and the IGF-I signaling pathways in USC. The clinical implications of this association need to be explored.

  6. Type 1 IGF receptor translocates to the nucleus of human tumor cells

    OpenAIRE

    Aleksic, Tamara; Chitnis, Meenali M.; Perestenko, Olga V.; Gao, Shan; Thomas, Peter H.; Turner, Gareth D.; Protheroe, Andrew S.; Howarth, Mark; Macaulay, Valentine M.

    2010-01-01

    The type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane glycoprotein comprising two extracellular α subunits and two β subunits with tyrosine kinase activity. The IGF-1R is frequently upregulated in cancers, and signals from the cell surface to promote proliferation and cell survival. Recent attention has focused on the IGF-1R as a target for cancer treatment. Here we report that the nuclei of human tumor cells contain IGF-1R, detectable using multiple antibodies to α- and ...

  7. Compensatory growth assessment by plasma IGF-I hormone ...

    African Journals Online (AJOL)

    USER

    2010-06-21

    Jun 21, 2010 ... feeding diets and regimes will be evaluated in future studies. Key words: Compensatory growth, food coefficient ratio, food intake, IGF-I, rainbow trout, special growth .... Blood was sampled for IGF-I hormone concentration.

  8. Disruption of IGF-1R signaling increases TRAIL-induced apoptosis: A new potential therapy for the treatment of melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Karasic, Thomas B.; Hei, Tom K. [Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States); Ivanov, Vladimir N., E-mail: vni3@columbia.edu [Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States)

    2010-07-15

    Resistance of cancer cells to apoptosis is dependent on a balance of multiple genetic and epigenetic mechanisms, which up-regulate efficacy of the surviving growth factor-receptor signaling pathways and suppress death-receptor signaling pathways. The Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway is highly active in metastatic melanoma cells by mediating downstream activation of PI3K-AKT and MAPK pathways and controlling general cell survival and proliferation. In the present study, we used human melanoma lines with established genotypes that represented different phases of cancer development: radial-growth-phase WM35, vertical-growth-phase WM793, metastatic LU1205 and WM9 [1]. All these lines have normal NRAS. WM35, WM793, LU1205 and WM9 cells have mutated BRAF (V600E). WM35 and WM9 cells express normal PTEN, while in WM793 cells PTEN expression is down-regulated; finally, in LU1205 cells PTEN is inactivated by mutation. Cyclolignan picropodophyllin (PPP), a specific inhibitor of IGF-1R kinase activity, strongly down-regulated the basal levels of AKT activity in WM9 and in WM793 cells, modestly does so in LU1205, but has no effect on AKT activity in the early stage WM35 cells that are deficient in IGF-1R. In addition, PPP partially down-regulated the basal levels of active ERK1/2 in all lines used, highlighting the role of an alternative, non-BRAF pathway in MAPK activation. The final result of PPP treatment was an induction of apoptosis in WM793, WM9 and LU1205 melanoma cells. On the other hand, dose-dependent inhibition of IGF-1R kinase activity by PPP at a relatively narrow dose range (near 500 nM) has different effects on melanoma cells versus normal cells, inducing apoptosis in cancer cells and G2/M arrest of fibroblasts. To further enhance the pro-apoptotic effects of PPP on melanoma cells, we used a combined treatment of TNF-Related Apoptosis-Inducing Ligand (TRAIL) and PPP. This combination substantially increased death by apoptosis for

  9. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, S.M.; Vertregt, Maarten

    2011-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital

  10. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, S.M.; Vertregt, Maarten

    2010-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital

  11. Role of heterotrimeric G protein and calcium in cardiomyocyte hypertrophy induced by IGF-1.

    Science.gov (United States)

    Carrasco, Loreto; Cea, Paola; Rocco, Paola; Peña-Oyarzún, Daniel; Rivera-Mejias, Pablo; Sotomayor-Flores, Cristian; Quiroga, Clara; Criollo, Alfredo; Ibarra, Cristian; Chiong, Mario; Lavandero, Sergio

    2014-04-01

    In the heart, insulin-like growth factor-1 (IGF-1) is a peptide with pro-hypertrophic and anti-apoptotic actions. The pro-hypertrophic properties of IGF-1 have been attributed to the extracellular regulated kinase (ERK) pathway. Recently, we reported that IGF-1 also increases intracellular Ca(2+) levels through a pertussis toxin (PTX)-sensitive G protein. Here we investigate whether this Ca(2+) signal is involved in IGF-1-induced cardiomyocyte hypertrophy. Our results show that the IGF-1-induced increase in Ca(2+) level is abolished by the IGF-1 receptor tyrosine kinase inhibitor AG538, PTX and the peptide inhibitor of Gβγ signaling, βARKct. Increases in the activities of Ca(2+) -dependent enzymes calcineurin, calmodulin kinase II (CaMKII), and protein kinase Cα (PKCα) were observed at 5 min after IGF-1 exposure. AG538, PTX, βARKct, and the dominant negative PKCα prevented the IGF-1-dependent phosphorylation of ERK1/2. Participation of calcineurin and CaMKII in ERK phosphorylation was discounted. IGF-1-induced cardiomyocyte hypertrophy, determined by cell size and β-myosin heavy chain (β-MHC), was prevented by AG538, PTX, βARKct, dominant negative PKCα, and the MEK1/2 inhibitor PD98059. Inhibition of calcineurin with CAIN did not abolish IGF-1-induced cardiac hypertrophy. We conclude that IGF-1 induces hypertrophy in cultured cardiomyocytes by activation of the receptor tyrosine kinase activity/βγ-subunits of a PTX-sensitive G protein/Ca(2+) /PKCα/ERK pathway without the participation of calcineurin. © 2013 Wiley Periodicals, Inc.

  12. Disposition of radiolabelled insulin-like growth factor I (IGF-I), IGF-II and their N-terminal truncated variants in rats

    International Nuclear Information System (INIS)

    Yamamoto, Hiroyuki; Kato, Yuzuru; Murphy, L.J.

    1996-01-01

    Serum half life, tissue uptake and urinary excretion of N-terminal truncated IGF variants and their intact precursors were compared to see whether the variants regulate the bioavailability of those growth factors. IGF-I, des(1-3) IGF-I, IGF-II and des(1-6) IGF-II were labeled with 125 I and intravenously administered to SD rats. Blood from femoral artery and urine from implanted bladder catheter were collected at appropriate intervals until sacrifice of animals at 2 hr after administration. Tissues were dissected out and all of these samples were measured for their radioactivity with a gamma counter. The half lives of des(1-3) IGF-I, IGF-I, des(1-6) IGF-II and IGF-II were 20.5, 228.3, 21.3 and 181.7 min, respectively. Maximal accumulation of all peptides was found in the kidney. 125 I-IGF-I and -II showed the following distribution pattern; levels were higher in the kidney>pancreas>small intestine>liver>duodenum>stomach>lung>spleen>heart>large intestine>testis>brain>skeletal muscle. Skeletal muscle, kidney and testis showed a preferential uptake of the variants. Urinary excretion of the variants were much greater. Thus the variants were more rapidly cleared from circulation. The physiological significance of tissue distribution of 4 peptides remains to be further investigated. (K.H.)

  13. Function of Matrix IGF-1 in Coupling Bone Resorption and Formation

    Science.gov (United States)

    Crane, Janet L.; Cao, Xu

    2013-01-01

    Balancing bone resorption and formation is the quintessential component for the prevention of osteoporosis. Signals that determine the recruitment, replication, differentiation, function, and apoptosis of osteoblasts and osteoclasts direct bone remodeling and determine whether bone tissue is gained, lost, or balanced. Therefore understanding the signaling pathways involved in the coupling process will help develop further targets for osteoporosis therapy, by blocking bone resorption or enhancing bone formation in a space and time dependent manner. Insulin-like growth factor type 1 (IGF-1) has long been known to play a role in bone strength. It is one of the most abundant substances in the bone matrix, circulates systemically and is secreted locally, and has a direct relationship with bone mineral density. Recent data has helped further our understanding of the direct role of IGF-1 signaling in coupling bone remodeling which will be discussed in this review. The bone marrow microenvironment plays a critical role in the fate of MSCs and HSCs and thus how IGF-1 interacts with other factors in the microenvironment are equally important. While previous clinical trials with IGF-1 administration have been unsuccessful at enhancing bone formation, advances in basic science studies have provided insight into further mechanisms that should be considered for future trials. Additional basic science studies dissecting the regulation and the function of matrix IGF-1 in modeling and remodeling will continue to provide further insight for future directions for anabolic therapies for osteoporosis. PMID:24068256

  14. Function of matrix IGF-1 in coupling bone resorption and formation.

    Science.gov (United States)

    Crane, Janet L; Cao, Xu

    2014-02-01

    Balancing bone resorption and formation is the quintessential component for the prevention of osteoporosis. Signals that determine the recruitment, replication, differentiation, function, and apoptosis of osteoblasts and osteoclasts direct bone remodeling and determine whether bone tissue is gained, lost, or balanced. Therefore, understanding the signaling pathways involved in the coupling process will help develop further targets for osteoporosis therapy, by blocking bone resorption or enhancing bone formation in a space- and time-dependent manner. Insulin-like growth factor type 1 (IGF-1) has long been known to play a role in bone strength. It is one of the most abundant substances in the bone matrix, circulates systemically and is secreted locally, and has a direct relationship with bone mineral density. Recent data has helped further our understanding of the direct role of IGF-1 signaling in coupling bone remodeling which will be discussed in this review. The bone marrow microenvironment plays a critical role in the fate of mesenchymal stem cells and hematopoietic stem cells and thus how IGF-1 interacts with other factors in the microenvironment are equally important. While previous clinical trials with IGF-1 administration have been unsuccessful at enhancing bone formation, advances in basic science studies have provided insight into further mechanisms that should be considered for future trials. Additional basic science studies dissecting the regulation and the function of matrix IGF-1 in modeling and remodeling will continue to provide further insight for future directions for anabolic therapies for osteoporosis.

  15. DNA Methylation Changes in the IGF1R Gene in Birth Weight Discordant Adult Monozygotic Twins

    DEFF Research Database (Denmark)

    Tsai, Pei-Chien; Van Dongen, Jenny; Tan, Qihua

    2015-01-01

    persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg...... were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect...... was particularly pronounced in older twins (random-effects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent...

  16. [The role of alterations in the brain signaling systems regulated by insulin, IGF-1 and leptin in the transition of impaired glucose tolerance to overt type 2 diabetes mellitus].

    Science.gov (United States)

    Shpakov, A O

    2014-01-01

    One of the crucial factors leading to the development of pre-diabetes and type 2 diabetes mellitus (DM2) are the disturbances in the brain hormonal signaling systems regulated by insulin, insulin-like growth factor-1 (IGF-1) and leptin. The causes of these disturbances are the changes in the redox balance and lipid metabolism leading to lipotoxicity and endoplasmic reticulum stress in neuronal cells, as well as the dysfunctions in neurotransmitter systems of the brain that are functionally associated with insulin, IGF-1 and leptin signaling systems. The identification of molecular disturbances in insulin, IGF-1 and leptin systems of the brain in pre-diabetes and DM2 can be used for early diagnostics of these diseases, and to develop new strategies for preventive treatment of DM2 at the pre-diabetic stage. In the review, the literature data and the results of own investigations concerning the changes in the insulin, IGF-1 and leptin systems of the brain in pre-diabetes and DM2 and their role in the etiology and pathogenesis of DM2 are analyzed, and the approaches to restore the functional activity of these systems are discussed.

  17. IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway.

    Science.gov (United States)

    Wang, Yongmei; Cheng, Zhiqiang; Elalieh, Hashem Z; Nakamura, Eiichiro; Nguyen, Minh-Thanh; Mackem, Susan; Clemens, Thomas L; Bikle, Daniel D; Chang, Wenhan

    2011-07-01

    Systemic derangements and perinatal death of generalized insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) knockout mice preclude definitive assessment of IGF-1R actions in growth-plate (GP) chondrocytes. We generated cartilage-specific Igf1r knockout ((Cart) Igf1r(-/-)) mice to investigate local control of chondrocyte differentiation in the GP by this receptor. These mice died shortly after birth and showed disorganized chondrocyte columns, delayed ossification and vascular invasion, decreased cell proliferation, increased apoptosis, and increased expression of parathyroid hormone-related protein (Pthrp) RNA and protein in their GPs. The increased Pthrp expression in the knockout GPs likely was due to an increase in gene transcription, as determined by the increased activity of a LacZ reporter that was inserted downstream of the endogenous PTHrP promoter and bred into the knockout mice. To circumvent the early death of (Cart) Igf1r(-/-) mice and investigate the role of IGF-1R during postnatal growth, we made tamoxifen (Tam)-inducible, cartilage-specific Igf1r knockout ((TamCart) Igf1r(-/-)) mice. At 2 weeks of age and 7 to 8 days after Tam injection, the (TamCart) Igf1r(-/-) mice showed growth retardation with a disorganized GP, reduced chondrocyte proliferation, decreased type 2 collagen and Indian Hedgehog (Ihh) expression, but increased expression of PTHrP. Consistent with in vivo observations, in vitro knockout of the Igf1r gene by adenoviral expression of Cre recombinase suppressed cell proliferation, promoted apoptosis, and increased Pthrp expression. Our data indicate that the IGF-1R in chondrocytes controls cell growth, survival, and differentiation in embryonic and postnatal GPs in part by suppression of Pthrp expression. Copyright © 2011 American Society for Bone and Mineral Research.

  18. IGF-I Stimulates Cooperative Interaction between the IGF-I Receptor and CSK Homologous Kinase that Regulates SHPS-1 Phosphorylation in Vascular Smooth Muscle Cells

    Science.gov (United States)

    Radhakrishnan, Yashwanth; Shen, Xinchun; Maile, Laura A.; Xi, Gang

    2011-01-01

    IGF-I plays an important role in smooth muscle cell proliferation and migration. In vascular smooth muscle cells cultured in 25 mm glucose, IGF-I stimulated a significant increase in Src homology 2 domain containing protein tyrosine phosphatase substrate-1 (SHPS-1) phosphorylation compared with 5 mm glucose and this increase was required for smooth muscle cell proliferation. A proteome-wide screen revealed that carboxyl-terminal SRC kinase homologous kinase (CTK) bound directly to phosphotyrosines in the SHPS-1 cytoplasmic domain. Because the kinase(s) that phosphorylates these tyrosines in response to IGF-I is unknown, we determined the roles of IGF-I receptor (IGF-IR) and CTK in mediating SHPS-1 phosphorylation. After IGF-I stimulation, CTK was recruited to IGF-IR and subsequently to phospho-SHPS-1. Expression of an IGF-IR mutant that eliminated CTK binding reduced CTK transfer to SHPS-1, SHPS-1 phosphorylation, and cell proliferation. IGF-IR phosphorylated SHPS-1, which provided a binding site for CTK. CTK recruitment to SHPS-1 resulted in a further enhancement of SHPS-1 phosphorylation. CTK knockdown also impaired IGF-I-stimulated SHPS-1 phosphorylation and downstream signaling. Analysis of specific tyrosines showed that mutation of tyrosines 428/452 in SHPS-1 to phenylalanine reduced SHPS-1 phosphorylation but allowed CTK binding. In contrast, the mutation of tyrosines 469/495 inhibited IGF-IR-mediated the phosphorylation of SHPS-1 and CTK binding, suggesting that IGF-IR phosphorylated Y469/495, allowing CTK binding, and that CTK subsequently phosphorylated Y428/452. Based on the above findings, we conclude that after IGF-I stimulation, CTK is recruited to IGF-IR and its recruitment facilitates CTK's subsequent association with phospho-SHPS-1. This results in the enhanced CTK transfer to SHPS-1, and the two kinases then fully phosphorylate SHPS-1, which is necessary for IGF-I stimulated cellular proliferation. PMID:21799000

  19. High fat-diet and saturated fatty acid palmitate inhibits IGF-1 function in chondrocytes.

    Science.gov (United States)

    Nazli, S A; Loeser, R F; Chubinskaya, S; Willey, J S; Yammani, R R

    2017-09-01

    Insulin-like growth factor-1 (IGF-1) promotes matrix synthesis and cell survival in cartilage. Chondrocytes from aged and osteoarthritic cartilage have a reduced response to IGF-1. The purpose of this study was to determine the effect of free fatty acids (FFA) present in a high-fat diet on IGF-1 function in cartilage and the role of endoplasmic reticulum (ER) stress. C57BL/6 male mice were maintained on either a high-fat (60% kcal from fat) or a low-fat (10% kcal from fat) diet for 4 months. Mice were then sacrificed; femoral head cartilage caps were collected and treated with IGF-1 to measure proteoglycan (PG) synthesis. Cultured human chondrocytes were treated with 500 μM FFA palmitate or oleate, followed by stimulation with (100 ng/ml) IGF-1 overnight to measure CHOP (a protein marker for ER stress) and PG synthesis. Human chondrocytes were pre-treated with palmitate or 1 mM 4-phenyl butyric acid (PBA) or 1 μM C-Jun N terminal Kinase (JNK) inhibitor, and IGF-1 function (PG synthesis and signaling) was measured. Cartilage explants from mice on the high fat-diet showed reduced IGF-1 mediated PG synthesis compared to a low-fat group. Treatment of human chondrocytes with palmitate induced expression of CHOP, activated JNK and inhibited IGF-1 function. PBA, a small molecule chemical chaperone that alleviates ER stress rescued IGF-1 function and a JNK inhibitor rescued IGF-1 signaling. Palmitate-induced ER stress inhibited IGF-1 function in chondrocytes/cartilage via activating the mitogen-activated protein (MAP) kinase JNK. This is the first study to demonstrate that ER stress is metabolic factor that regulates IGF-1 function in chondrocytes. Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  20. IGF-1 attenuates LPS induced pro-inflammatory cytokines expression in buffalo (Bubalus bubalis) granulosa cells.

    Science.gov (United States)

    Onnureddy, K; Ravinder; Onteru, Suneel Kumar; Singh, Dheer

    2015-03-01

    Interaction between immune and endocrine system is a diverse process influencing cellular function and homeostasis in animals. Negative energy balance (NEB) during postpartum period in dairy animals usually suppresses these systems resulting in reproductive tract infection and infertility. These negative effects could be due to competition among endocrine and immune signaling pathways for common signaling molecules. The present work studied the effect of IGF-1 (50 ng/ml) on LPS (1 μg/ml) mediated pro-inflammatory cytokine expression (IL-1β, TNF-α, IL-6) and aromatase (CYP19A1) genes' expressions as well as proliferation of buffalo granulosa cells. The crosstalk between LPS and IGF-1 was also demonstrated through studying the activities of downstream signaling molecules (ERK1/2, Akt, NF-κB) by western blot and immunostaining. Gene expression analysis showed that IGF-1 significantly reduced the LPS induced expression of IL-1β, TNF-α and IL-6. LPS alone inhibited the CYP19A1 expression. However, co-treatment with IGF-1 reversed the inhibitory effect of LPS on CYP19A1 expression. LPS alone did not affect granulosa cell proliferation, but co-treatment with IGF-1, and IGF-1 alone enhanced the proliferation. Western blot results demonstrated that LPS caused the nuclear translocation of the NF-κB and increased the phosphorylation of ERK1/2 and Akt maximum at 15 min and 60 min, respectively. Nonetheless, co-treatment with IGF-1 delayed LPS induced phosphorylation of ERK1/2 (peak at 120 min), while promoting early Akt phosphorylation (peak at 5 min) with no effect on NF-κB translocation. Overall, IGF-1 delayed and reversed the effects of LPS, suggesting that high IGF-1 levels may combat infection during critical periods like NEB in postpartum dairy animals. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Insulin-like growth factor-I (IGF-1), IGF-binding protein-3 (IGFBP-3) and mammographic features.

    Science.gov (United States)

    Izzo, L; Meggiorini, M L; Nofroni, I; Pala, A; De Felice, C; Meloni, P; Simari, T; Izzo, S; Pugliese, F; Impara, L; Merlini, G; Di Cello, P; Cipolla, V; Forcione, A R; Paliotta, A; Domenici, L; Bolognese, A

    2012-05-01

    The IGF system has recently been shown to play an important role in the regulation of breast tumor cell proliferation. However, also breast density is currently considered as the strongest breast cancer risk factor. It is not yet clear whether these factors are interrelated and if and how they are influenced by menopausal status. The purpose of this study was to examine the possible effects of IGF-1 and IGFBP-3 and IGF-1/IGFBP-3 molar ratio on mammographic density stratified by menopausal status. A group of 341 Italian women were interviewed to collect the following data: family history of breast cancer, reproductive and menstrual factors, breast biopsies, previous administration of hormonal contraceptive therapy, hormone replacement therapy (HRT) in menopause and lifestyle information. A blood sample was drawn for determination of IGF-1, IGFBP-3 levels. IGF-1/ IGFBP-3 molar ratio was then calculated. On the basis of recent mammograms the women were divided into two groups: dense breast (DB) and non-dense breast (NDB). Student's t-test was employed to assess the association between breast density and plasma level of IGF-1, IGFBP-3 and molar ratio. To assess if this relationship was similar in subgroups of pre- and postmenopausal women, the study population was stratified by menopausal status and Student's t-test was performed. Finally, multivariate analysis was employed to evaluate if there were confounding factors that might influence the relationship between growth factors and breast density. The analysis of the relationship between mammographic density and plasma level of IGF-1, IGFBP-3 and IGF-1/ IGFBP-3 molar ratio showed that IGF-1 levels and molar ratio varied in the two groups resulting in higher mean values in the DB group (IGF-1: 109.6 versus 96.6 ng/ml; p= 0.001 and molar ratio 29.4 versus 25.5 ng/ml; p= 0.001) whereas IGFBP-3 showed similar values in both groups (DB and NDB). Analysis of plasma level of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio

  2. Phenothiourea sensitizes zebrafish cranial neural crest and extraocular muscle development to changes in retinoic acid and IGF signaling.

    Directory of Open Access Journals (Sweden)

    Brenda L Bohnsack

    Full Text Available 1-Phenyl 2-thiourea (PTU is a tyrosinase inhibitor commonly used to block pigmentation and aid visualization of zebrafish development. At the standard concentration of 0.003% (200 µM, PTU inhibits melanogenesis and reportedly has minimal other effects on zebrafish embryogenesis. We found that 0.003% PTU altered retinoic acid and insulin-like growth factor (IGF regulation of neural crest and mesodermal components of craniofacial development. Reduction of retinoic acid synthesis by the pan-aldehyde dehydrogenase inhibitor diethylbenzaldehyde, only when combined with 0.003% PTU, resulted in extraocular muscle disorganization. PTU also decreased retinoic acid-induced teratogenic effects on pharyngeal arch and jaw cartilage despite morphologically normal appearing PTU-treated controls. Furthermore, 0.003% PTU in combination with inhibition of IGF signaling through either morpholino knockdown or pharmacologic inhibition of tyrosine kinase receptor phosphorylation, disrupted jaw development and extraocular muscle organization. PTU in and of itself inhibited neural crest development at higher concentrations (0.03% and had the greatest inhibitory effect when added prior to 22 hours post fertilization (hpf. Addition of 0.003% PTU between 4 and 20 hpf decreased thyroxine (T4 in thyroid follicles in the nasopharynx of 96 hpf embryos. Treatment with exogenous triiodothyronine (T3 and T4 improved, but did not completely rescue, PTU-induced neural crest defects. Thus, PTU should be used with caution when studying zebrafish embryogenesis as it alters the threshold of different signaling pathways important during craniofacial development. The effects of PTU on neural crest development are partially caused by thyroid hormone signaling.

  3. Effect of microRNA-135a on Cell Proliferation, Migration, Invasion, Apoptosis and Tumor Angiogenesis Through the IGF-1/PI3K/Akt Signaling Pathway in Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Zhou, Yufei; Li, Shaoxia; Li, Jiangtao; Wang, Dongfeng; Li, Quanxing

    2017-01-01

    This study explored the ability of microRNA-135a (miR-135a) to influence cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer (NSCLC). NSCLC tissues and adjacent normal tissues were collected from 138 NSCLC patients. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of miR-135a and IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 mRNA; western blotting was used to determine the expression levels of IGF-1, PI3K and Akt protein; and enzyme-linked immunosorbent assay (ELISA) was used to analyze the expression levels of VEGF, bFGF and IL-8 protein. Human NSCLC cell lines (A549, H460, and H1299) and the human bronchial epithelial cell line (HBE) were selected. A549 cells were assigned to blank, negative control (NC), miR-135a mimics, miR-135a inhibitors, IGF-1 siRNA and miR-135a inhibitors + IGF-1 siRNA groups. The following were performed: an MTT assay to assess cell proliferation, a scratch test to detect cell migration, a Transwell assay to measure cell invasion, and a flow cytometry to analyze cell apoptosis. The expression level of miR-135a was lower while those of IGF-1, PI3K and Akt mRNA were higher in NSCLC tissues than in the adjacent normal tissues. Dual-luciferase reporter assay indicated IGF-1 as a target of miR-135a. The in vitro results showed that compared with the blank group, cell proliferation, migration and invasion were suppressed, mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 were reduced, and cell apoptosis was enhanced in the miR-135a mimics and IGF-1 siRNA groups. Compared with the IGF-1 siRNA group, cells in the miR-135a inhibitors + IGF-1 siRNA group demonstrated increased cell proliferation, migration and invasion, elevated mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 and reduced cell apoptosis. These findings indicated that miR-135a promotes cell apoptosis and inhibits

  4. Autocrine IGF-1 Action in Adipocytes Controls Systemic IGF-1 Concentrations and Growth

    OpenAIRE

    Kl?ting, Nora; Koch, Linda; Wunderlich, Thomas; Kern, Matthias; Ruschke, Karen; Krone, Wilhelm; Br?ning, Jens C.; Bl?her, Matthias

    2008-01-01

    OBJECTIVE?IGF-1 and the IGF-1 receptor (IGF-1R) have been implicated in the regulation of adipocyte differentiation and lipid accumulation in vitro. RESEARCH DESIGN AND METHODS?To investigate the role of IGF-1 receptor in vivo, we have inactivated the Igf-1r gene in adipose tissue (IGF-1RaP2Cre mice) using conditional gene targeting strategies. RESULTS?Conditional IGF-1R inactivation resulted in increased adipose tissue mass with a predominantly increased lipid accumulation in epigonadal fat ...

  5. Expression of IGF-I, IGF-I receptor and IGF binding proteins-1, -2, -3, -4 and -5 in human atherectomy specimens.

    Science.gov (United States)

    Grant, M B; Wargovich, T J; Ellis, E A; Tarnuzzer, R; Caballero, S; Estes, K; Rossing, M; Spoerri, P E; Pepine, C

    1996-12-17

    The molecular and cellular processes that induce rapid atherosclerotic plaque progression in patients with unstable angina and initiate restenosis following coronary interventional procedures are uncertain. We examined primary (de novo) and restenotic lesions retrieved at the time of directional coronary atherectomy for expression of insulin-like-growth factor-I (IGF-I). IGF-I receptor, and five IGF binding proteins (IGFBPs), IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 in smooth muscle cells (SMCs) using colloidal gold immunocytochemistry. IGF-1, its receptor and binding proteins were not detected in SMCs of normal coronary arteries. IGF-I localized primarily in synthetic smooth muscle cells (sSMCs) in both de novo and restenotic plaques. IGF-I receptor localized on sSMCs and their processes and colocalized with IGF-I. Although morphometric analysis of IGF-I and IGF-I receptor immunoreactivity in sSMCs of de novo and restenotic lesions showed comparable levels of IGF-I (3.2 +/- 1.0 and 2.9 +/- 0.9, respectively). IGF-I receptor was significantly higher in de novo lesions as compared to restenotic lesions (10.7 +/- 2.5 and 4.2 +/- 1.3, P system.

  6. The fetal programming effect of prenatal smoking on Igf1r and Igf1 methylation is organ- and sex-specific.

    Science.gov (United States)

    Meyer, Karolin F; Verkaik-Schakel, Rikst Nynke; Timens, Wim; Kobzik, Lester; Plösch, Torsten; Hylkema, Machteld N

    2017-01-01

    The impact of prenatal smoke exposure (PSE) on DNA methylation has been demonstrated in blood samples from children of smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. As the identified differentially methylated genes can be associated with developmental processes, and insulin-like growth factors (IGFs) play a critical role in prenatal tissue growth, we hypothesized that PSE induces fetal programming of Igf1r and Igf1. Using a mouse model of smoking during pregnancy, we show that PSE alters promoter methylation of Igf1r and Igf1 and deregulates their gene expression in lung and liver of fetal (E17.5) and neonatal (D3) mouse offspring. By further comparing female versus male, lung versus liver, or fetal versus neonatal time point, our results demonstrate that CpG site-specific aberrant methylation patterns sex-dependently vary per organ and time point. Moreover, PSE reduces gene expression of Igf1r and Igf1, dependent on organ, sex, and offspring's age. Our results indicate that PSE may be a source of organ-specific rather than general systemic fetal programming. This is exemplified here by gene promoter methylation and mRNA levels of Igf1r and Igf1, together with a sex- and organ-specific naturally established correlation of both parameters that is affected by prenatal smoke exposure. Moreover, the comparison of fetuses with neonates suggests a CpG site-dependent reversibility/persistence of PSE-induced differential methylation patterns.

  7. Reversal of muscle atrophy by Zhimu and Huangbai herb pair via activation of IGF-1/Akt and autophagy signal in cancer cachexia.

    Science.gov (United States)

    Zhuang, Pengwei; Zhang, Jinbao; Wang, Yan; Zhang, Mixia; Song, Lili; Lu, Zhiqiang; Zhang, Lu; Zhang, Fengqi; Wang, Jing; Zhang, Yanjun; Wei, Hongjun; Li, Hongyan

    2016-03-01

    Muscle atrophy is the prominent clinical feature of cancer-induced cachexia. Zhimu and Huangbai herb pair (ZBHP) has been used since ancient China times and have been phytochemically investigated for constituents that might cause anti-cancer, diabetes, and their complication. In this study, the effects and mechanisms of ZBHP on reversal of muscle atrophy were explored. C57BL/6 mice implanted with colon-26 adenocarcinoma were chosen to develop cancer cachexia for evaluating the effects of ZBHP on reversal of muscle atrophy. The body weight, survival time, inflammatory cytokines, and pathological changes of muscle were monitored. In addition, IGF-1/Akt and autophagy pathway members were analyzed to interpret the mechanism of drug response. The function and morphology of skeletal muscle in cachexia model were significantly disturbed, and the survival time was shortened. Consistently, inflammatory cytokines and muscle atrophy-related atrogin-1, MuRF1, and FOXO3 were significantly increased, and IGF-1/Akt and autophagy signal pathways were depressed. Treatment with ZBHP significantly alleviated tumor-free body weight reduction and cachexia-induced changes in cytokines and prolonged survival. ZBHP treatment not only inhibited the muscle atrophy-related genes but also activated the IGF-1/Akt and autophagy signal pathways to facilitate the protein synthesis. The results revealed that ZBHP treatment could inhibit the muscle atrophy induced by cancer cachexia and prolong the survival time, and ZBHP may be of value as a pharmacological alternative in treatment of cancer cachexia.

  8. The trajectory of IGF-1 across age and duration of type 1 diabetes.

    Science.gov (United States)

    Palta, Mari; LeCaire, Tamara J; Sadek-Badawi, Mona; Herrera, Victor M; Danielson, Kirstie K

    2014-11-01

    Individuals with type 1 diabetes may have low IGF-1, related to insulinopenia and insulin resistance. There are few longitudinal studies of IGF-1 levels to establish its pattern in type 1 diabetes with duration and age, and to examine whether IGF-1 tracks within individuals over time. We examine age and duration trends, and the relationship of IGF-1 to gender, glycaemic control, insulin level and other factors. Participants in the Wisconsin Diabetes Registry Study, an incident cohort study of type 1 diabetes diagnosed May 1987-April 1992, were followed for up to 18 years with IGF-1 samples up to age 45 for women and age 37 for men. IGF-1 is lower with type 1 diabetes than in normative samples. Although, the pattern across age resembles that in normative samples with a peak in adolescence and slow decline after age 20, the adolescent peak is delayed for women with type 1 diabetes. There was low to moderate tracking of IGF-1 within an individual. Higher insulin dose was associated with higher IGF-1 as was puberty, and female gender. Adjusted for these factors, IGF-1 declined rapidly across early diabetes duration. Lower HbA1c was most strongly related to higher IGF-1 at Tanner stages 1 and 2. IGF-1 is low in type 1 diabetes, with a delayed adolescent peak in women and is especially influenced by glycaemic control in early and pre-adolescence. High variability within an individual is likely a challenge in investigating associations between IGF-1 and long-term outcomes, and may explain contradictory findings. Copyright © 2014 John Wiley & Sons, Ltd.

  9. IGF binding proteins.

    Science.gov (United States)

    Bach, Leon A

    2017-12-18

    Insulin-like growth factor binding proteins (IGFBPs) 1-6 bind IGFs but not insulin with high affinity. They were initially identified as serum carriers and passive inhibitors of IGF actions. However, subsequent studies showed that, although IGFBPs inhibit IGF actions in many circumstances, they may also potentiate these actions. IGFBPs are widely expressed in most tissues, and they are flexible endocrine and autocrine/paracrine regulators of IGF activity, which is essential for this important physiological system. More recently, individual IGFBPs have been shown to have IGF-independent actions. Mechanisms underlying these actions include (i) interaction with non-IGF proteins in compartments including the extracellular space and matrix, the cell surface and intracellularly; (ii) interaction with and modulation of other growth factor pathways including EGF, TGF- and VEGF; and (iii) direct or indirect transcriptional effects following nuclear entry of IGFBPs. Through these IGF-dependent and IGF-independent actions, IGFBPs modulate essential cellular processes including proliferation, survival, migration, senescence, autophagy and angiogenesis. They have been implicated in a range of disorders including malignant, metabolic, neurological and immune diseases. A more complete understanding of their cellular roles may lead to the development of novel IGFBP-based therapeutic opportunities.

  10. IGF-II receptors and IGF-II-stimulated glucose transport in human fat cells

    International Nuclear Information System (INIS)

    Sinha, M.K.; Buchanan, C.; Raineri-Maldonado, C.; Khazanie, P.; Atkinson, S.; DiMarchi, R.; Caro, J.F.

    1990-01-01

    Insulin-like growth factor II (IGF-II) receptors have been described in rat but not in human adipocytes. In both species, IGF-II has been reported to stimulate glucose transport by interacting with the insulin receptor. In this study, we have unequivocally demonstrated the presence of IGF-II receptors in human adipocytes. 125I-labeled IGF-II specifically binds to intact adipocytes, membranes, and lectin-purified detergent solubilized extracts. Through the use of 0.5 mM disuccinimidyl suberate, 125I-IGF-II is cross-linked to a 260-kDa protein that is identified as the IGF-II receptor by displacement experiments with unlabeled IGF-II, IGF-I, and insulin and either by immunoprecipitation or by Western blot analysis with mannose 6-phosphate receptor antibodies. The concentrations of IGF-II required for half-maximal and maximal stimulation of glucose transport in human adipocytes are 35 and 100 times more than that of insulin. The possibility of IGF-II stimulating glucose transport by interacting predominantly with the insulin receptor is suggested by the following: (1) the concentration of IGF-II that inhibits half of insulin binding is only 20 times more than that of insulin; (2) the lack of an additive effect of IGF-II and insulin for maximal stimulation of glucose transport; (3) the ability of monoclonal insulin receptor antibodies to decrease glucose transport stimulated by submaximal concentrations of both IGF-II and insulin; and (4) the ability of IGF-II to stimulate insulin receptor autophosphorylation albeit at a reduced potency when compared with insulin

  11. Differences in IGF-axis protein expression and survival among multiethnic breast cancer patients

    International Nuclear Information System (INIS)

    Hernandez, Brenda Y; Wilkens, Lynne R; Le Marchand, Loïc; Horio, David; Chong, Clayton D; Loo, Lenora W M

    2015-01-01

    There is limited knowledge about the biological basis of racial/ethnic disparities in breast cancer outcomes. Aberrations in IGF signaling induced by obesity and other factors may contribute to these disparities. This study examines the expression profiles of the insulin-like growth factor (IGF)-axis proteins and the association with breast cancer survival across a multiethnic population. We examined the expression profiles of the IGF1, IGF1R, IGFBP2 (IGF-binding proteins), and IGFBP3 proteins in breast tumor tissue and their relationships with all-cause and breast cancer-specific survival up to 17 years postdiagnosis in a multiethnic series of 358 patients in Hawaii, USA. Native Hawaiians, Caucasians, and Japanese were compared. Covariates included demographic and clinical factors and ER/PR/HER2 (estrogen receptor/progesterone receptor/human epidermal growth factor receptor-2) status. In Native Hawaiian patients, IGFBP2 and IGFBP3 expression were each independently associated with overall and breast cancer mortality (IGFB2: HR mort = 10.96, 95% CI: 2.18–55.19 and HR mort = 35.75, 95% CI: 3.64–350.95, respectively; IGFBP3: HR mort = 5.16, 95% CI: 1.27–20.94 and HR mort = 8.60, 95% CI: 1.84–40.15, respectively). IGF1R expression was also positively associated with all-cause mortality in Native Hawaiians. No association of IGF-axis protein expression and survival was observed in Japanese or Caucasian patients. The interaction of race/ethnicity and IGFBP3 expression on mortality risk was significant. IGF-axis proteins may have variable influence on breast cancer progression across different racial/ethnic groups. Expression of binding proteins and receptors in breast tumors may influence survival in breast cancer patients by inducing aberrations in IGF signaling and/or through IGF-independent mechanisms. Additional studies to evaluate the role of the IGF-axis in breast cancer are critical to improve targeted breast cancer treatment strategies

  12. SP600125 Induces Src and Type I IGF Receptor Phosphorylation Independent of JNK

    Directory of Open Access Journals (Sweden)

    Qingbin Kong

    2014-09-01

    Full Text Available c-Jun N-terminal kinases (JNK are members of the mitogen-activated protein kinase (MAPK family that have important roles in signal transduction. The small molecule SP600125 is widely used in biochemical studies as a JNK inhibitor. However, recent studies indicate that SP600125 may also act independent of JNK. Here, we report that SP600125 can induce Src, type I insulin-like growth factor receptor (IGF-IR, Akt and Erk1/2 phosphorylation. Notably, these effects are independent of its inhibition of JNK. Inhibition of Src abrogates the stimulation of IGF-IR, Akt and Erk1/2 phosphorylation. IGF-IR knockdown blunts the induction of both Akt and Erk1/2 phosphorylation by SP600125. Moreover, combination of SP600125 and the Src inhibitor saracatinib synergistically inhibits cell proliferation. We conclude that SP600125 can activate Src-IGF-IR-Akt/Erk1/2 signaling pathways independent of JNK.

  13. Hsp90α forms a stable complex at the cilium neck for the interaction of signalling molecules in IGF-1 receptor signalling.

    Science.gov (United States)

    Wang, Hongzhong; Zou, Xinle; Wei, Zhuang; Wu, Yuan; Li, Rongxia; Zeng, Rong; Chen, Zhengjun; Liao, Kan

    2015-01-01

    The primary cilium is composed of an axoneme that protrudes from the cell surface, a basal body beneath the membrane and a transition neck in between. It is a sensory organelle on the plasma membrane, involved in mediating extracellular signals. In the transition neck region of the cilium, the microtubules change from triplet to doublet microtubules. This region also contains the transition fibres that crosslink the axoneme with the membrane and the necklace proteins that regulate molecules being transported into and out of the cilium. In this protein-enriched, complex area it is important to maintain the correct assembly of all of these proteins. Here, through immunofluorescent staining and protein isolation, we identify the molecular chaperone Hsp90α clustered at the periciliary base. At the transition neck region, phosphorylated Hsp90α forms a stable ring around the axoneme. Heat shock treatment causes Hsp90α to dissipate and induces resorption of cilia. We further identify that Hsp90α at the transition neck region represents a signalling platform on which IRS-1 interacts with intracellular downstream signalling molecules involved in IGF-1 receptor signalling. © 2015. Published by The Company of Biologists Ltd.

  14. Evidence That Graves' Ophthalmopathy Immunoglobulins Do Not Directly Activate IGF-1 Receptors.

    Science.gov (United States)

    Marcus-Samuels, Bernice; Krieger, Christine C; Boutin, Alisa; Kahaly, George J; Neumann, Susanne; Gershengorn, Marvin C

    2018-05-01

    Graves' ophthalmopathy (GO) pathogenesis involves thyrotropin (TSH) receptor (TSHR)-stimulating autoantibodies. Whether there are autoantibodies that directly stimulate insulin-like growth factor 1 receptors (IGF-1Rs), stimulating insulin-like growth factor receptor antibodies (IGFRAbs), remains controversial. This study attempted to determine whether there are stimulating IGFRAbs in patients with GO. Immunoglobulins (Igs) were purified from normal volunteers (NV-Igs) and patients with GO (GO-Igs). The effects of TSH, IGF-1, NV-Igs, and GO-Igs on pAKT and pERK1/2, members of pathways used by IGF-1R and TSHR, were compared in orbital fibroblasts from GO patients (GOFs) and U2OS-TSHR cells overexpressing TSHRs, and U2OS cells that express TSHRs at very low endogenous levels. U2OS-TSHR and U2OS cells were used because GOFs are not easily manipulated using molecular techniques such as transfection, and U2OS cells because they express TSHRs at levels that do not measurably stimulate signaling. Thus, comparing U2OS-TSHR and U2OS cells permits specifically distinguishing signaling mediated by the TSHR and IGF-1R. In GOFs, all GO-Igs stimulated pERK1/2 formation and 69% stimulated pAKT. In U2OS-TSHR cells, 15% of NV-IGs and 83% of GO-Igs stimulated increases in pERK1/2, whereas all NV-Igs and GO-Igs stimulated increases in pAKT. In U2OS cells, 70% of GO-Igs stimulated small increases in pAKT. Knockdown of IGF-1R caused a 65 ± 6.3% decrease in IGF-1-stimulated pAKT but had no effect on GO-Igs stimulation of pAKT. Thus, GO-Igs contain factor(s) that stimulate pAKT formation. However, this factor(s) does not directly activate IGF-1R. Based on the findings analyzing these two signaling pathways, it is concluded there is no evidence of stimulating IGFRAbs in GO patients.

  15. IGF-1 induces SOCS-2 but not SOCS-1 and SOCS-3 transcription in juvenile Nile tilapia (Oreochromis niloticus).

    Science.gov (United States)

    Liu, Cai-Zhi; Luo, Yuan; Limbu, Samwel Mchele; Chen, Li-Qiao; Du, Zhen-Yu

    2018-05-20

    Insulin-like growth factor-1 (IGF-1) plays a crucial role in regulating growth in vertebrates whereas suppressors of cytokine signaling (SOCS) act as feedback inhibitors of the GH/IGF-1 axis. Although SOCS-2 binds the IGF-1 receptor and inhibits IGF-1-induced STAT3 activation, presently there is no clear evidence as to whether IGF-1 could induce SOCS gene expression. The current study aimed to determine whether IGF-1 could induce the transcription of SOCS in juvenile Nile tilapia ( Oreochromis niloticus ). We show that there is a common positive relationship between the mRNA expression of IGF-I and SOCS-2 under different nutritional statuses and stimulants, but not the mRNA expression of SOCS-1 and SOCS-3 Furthermore, rhIGF-1 treatment and transcriptional activity assay confirmed the hypothesis that IGF-1 could induce SOCS-2 expression, whereas it had no effect or even decreased the expression of SOCS-1 and SOCS-3 Overall, we obtained evidence that the transcription of SOCS-2, but not SOCS-1 or SOCS-3, could be induced by IGF signaling, suggesting that SOCS-2 serves as a feedback suppressor of the IGF-1 axis in juvenile Nile tilapia. © 2018. Published by The Company of Biologists Ltd.

  16. Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605

    International Nuclear Information System (INIS)

    Pappano, William N; Sheppard, George S; Donawho, Cherrie; Buchanan, Fritz G; Davidsen, Steven K; Bell, Randy L; Wang, Jieyi; Jung, Paul M; Meulbroek, Jonathan A; Wang, Yi-Chun; Hubbard, Robert D; Zhang, Qian; Grudzien, Meagan M; Soni, Niru B; Johnson, Eric F

    2009-01-01

    The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics. We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers. A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models. These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation

  17. Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer.

    Science.gov (United States)

    Buck, Elizabeth; Gokhale, Prafulla C; Koujak, Susan; Brown, Eric; Eyzaguirre, Alexandra; Tao, Nianjun; Rosenfeld-Franklin, Maryland; Lerner, Lorena; Chiu, M Isabel; Wild, Robert; Epstein, David; Pachter, Jonathan A; Miglarese, Mark R

    2010-10-01

    Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and critical activator of the phosphatidylinositol 3-kinase-AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis. These observations have spurred anticancer drug discovery and development efforts for both biological and small-molecule IGF-1R inhibitors. The ability for one RTK to compensate for another to maintain tumor cell viability is emerging as a common resistance mechanism to antitumor agents targeting individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), we asked whether IR is tumorigenic and whether IR-AKT signaling contributes to resistance to IGF-1R inhibition. Both IGF-1R and IR(A) are tumorigenic in a mouse mammary tumor model. In human tumor cells coexpressing IGF-1R and IR, bidirectional cross talk was observed following either knockdown of IR expression or treatment with a selective anti-IGF-1R antibody, MAB391. MAB391 treatment resulted in a compensatory increase in phospho-IR, which was associated with resistance to inhibition of IRS1 and AKT. In contrast, treatment with OSI-906, a small-molecule dual inhibitor of IGF-1R/IR, resulted in enhanced reduction in phospho-IRS1/phospho-AKT relative to MAB391. Insulin or IGF-2 activated the IR-AKT pathway and decreased sensitivity to MAB391 but not to OSI-906. In tumor cells with an autocrine IGF-2 loop, both OSI-906 and an anti-IGF-2 antibody reduced phospho-IR/phospho-AKT, whereas MAB391 was ineffective. Finally, OSI-906 showed superior efficacy compared with MAB391 in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. Collectively, these data indicate that cotargeting IGF-1R and IR may provide superior antitumor efficacy compared with targeting IGF-1R alone.

  18. Serial analysis of resected prostate cancer suggests up-regulation of type 1 IGF receptor with disease progression.

    Science.gov (United States)

    Turney, Benjamin W; Turner, Gareth D H; Brewster, Simon F; Macaulay, Valentine M

    2011-05-01

    • To compare immunostaining protocols using different antibodies for the type 1 insulin-like growth factor receptor (IGF-1R) in channel transurethal resection of the prostate (chTURP) chips, and to investigate how IGF-1R expression varies with time in serial prostate cancer specimens from individual patients. • We studied IGF-1R expression in 44 prostate cancer specimens from 18 patients who had undergone serial chTURP at least 3 months apart. • Retrospective analysis of the hospital notes was undertaken to obtain clinical information, including age, Gleason score, prostate-specific antigen (PSA) level, hormone treatment and metastatic disease status at the time of each operation. • After an optimization process using three commercially-available IGF-1R antibodies, we used two antibodies for semiquantititve immunostaining of serial chTURP chips. • Santa Cruz antibody sc713 gave positive staining in IGF-1R null R- cells, and was not used further. Antibodies from Cell Signaling Technology (Beverly, MA, USA) (CS) and NeoMarkers Inc. (Fremont, CA, USA) (NM) did not stain R- cells and, in prostate tissue, showed staining of the glandular epithelium, with negligible stromal staining. All 44 chTURP samples contained identifiable malignant tissue and, of these, 73% and 64% scored moderately or strongly (score 3 or 4) with the CS and NM antibodies respectively. • There was significant correlation of IGF-1R scores of malignant tissue between the two antibodies (P < 0.001). By contrast, staining of benign glands showed poor correlation between antibodies: CS gave significantly weaker staining than malignant epithelium in the same sections (P < 0.001), whereas NM showed poor discrimination between malignant and benign glands. IGF-1R staining scores generated by the CS antibody were used to analyze the clinical data. • Most patients (six of seven) with falling IGF-1R staining scores were responding to androgen deprivation therapy (confirmed by PSA response

  19. Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: A review.

    Science.gov (United States)

    Frater, Julanne; Lie, David; Bartlett, Perry; McGrath, John J

    2018-03-01

    Insulin-like Growth Factor 1 (IGF-1) and its signaling pathway play a primary role in normal growth and ageing, however serum IGF-1 is known to reduce with advancing age. Recent findings suggest IGF-1 is essential for neurogenesis in the adult brain, and this reduction of IGF-1 with ageing may contribute to age-related cognitive decline. Experimental studies have shown manipulation of the GH/GF-1 axis can slow rates of cognitive decline in animals, making IGF-1 a potential biomarker of cognition, and/or its signaling pathway a possible therapeutic target to prevent or slow age-related cognitive decline. A systematic literature review and qualitative narrative summary of current evidence for IGF-1 as a biomarker of cognitive decline in the ageing brain was undertaken. Results indicate IGF-1 concentrations do not confer additional diagnostic information for those with cognitive decline, and routine clinical measurement of IGF-1 is not currently justified. In cases of established cognitive impairment, it remains unclear whether increasing circulating or brain IGF-1 may reverse or slow down the rate of further decline. Advances in neuroimaging, genetics, neuroscience and the availability of large well characterized biobanks will facilitate research exploring the role of IGF-1 in both normal ageing and age-related cognitive decline. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline.

    Science.gov (United States)

    Huffman, Derek M; Farias Quipildor, Gabriela; Mao, Kai; Zhang, Xueying; Wan, Junxiang; Apontes, Pasha; Cohen, Pinchas; Barzilai, Nir

    2016-02-01

    Low insulin-like growth factor-1 (IGF-1) signaling is associated with improved longevity, but is paradoxically linked with several age-related diseases in humans. Insulin-like growth factor-1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF-1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole-body insulin action in aging. Utilizing hyperinsulinemic-euglycemic clamps, we show that old insulin-resistant rats with age-related declines in IGF-1 level demonstrate markedly improved whole-body insulin action, when treated with central IGF-1, as compared to central vehicle or insulin (P IGF-1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P IGF-1 action in the brain and periphery provides a 'balance' between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at 'tipping the balance' of IGF-1 action centrally are the optimal approach to achieve healthy aging and longevity in humans. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  1. Changes in circulating level of IGF-I and IGF-binding protein-1 from the first to second trimester as predictors of preeclampsia

    DEFF Research Database (Denmark)

    Vatten, Lars J; Nilsen, Tom I L; Juul, Anders

    2008-01-01

    OBJECTIVE: To assess whether circulating IGF-I and IGF-binding protein-1 (IGFBP-1) in the first and second trimester are associated with subsequent risk of preterm and term preeclampsia. METHODS: Nested case-control study within a cohort of 29 948 pregnant women. Cases were women, who later...... developed preeclampsia, and controls were randomly selected women, who did not develop preeclampsia. IGF-I and IGFBP-1 were measured with ELISA in maternal blood samples that were collected in the first and second trimesters. We assessed associations of IGF-I and IGFBP-1 concentrations with later...... development of preterm (before the 37th week of gestation) and term preeclampsia. RESULTS: An increase in IGF-I from the first to second trimester was associated with higher risk of preterm preeclampsia; the odds ratio (OR) for the highest compared with lowest quartile of increase was 4.9 (95% confidence...

  2. The IGF2 Locus

    Science.gov (United States)

    Insulin-like growth factor 2 (IGF2) is a peptide hormone regulating various cellular processes such as proliferation and apoptosis. IGF2 is vital to embryo development. The IGF2 locus covers approximately 150-kb genomic region on human chromosome 11, containing two imprinted genes, IGF2 and H19, sha...

  3. Gastric cancer: the role of insulin-like growth factor 2 (IGF 2) and its receptors (IGF 1R and M6-P/IGF 2R).

    Science.gov (United States)

    Pavelić, Kresimir; Kolak, Toni; Kapitanović, Sanja; Radosević, Senka; Spaventi, Sime; Kruslin, Bozo; Pavelić, Jasminka

    2003-11-01

    Insulin-like growth factor 2 (IGF 2) appears to be involved in the progression of many tumours. It binds to at least two different types of receptor: IGF type 1 (IGF 1R) and mannose 6-phosphate/IGF type 2 (M6-P/IGF 2R). Ligand binding to IGF 1R provokes mitogenic and anti-apoptotic effects. M6-P/IGF 2R has a tumour suppressor function--it mediates IGF 2 degradation. Mutation of M6-P/IGF 2R causes both diminished growth suppression and augmented growth stimulation. The aim of this study was to investigate the role of IGF 2 and its receptors (IGF 1R and IGF 2R) in human gastric cancer. The expression of IGF 2 and its receptors was measured in order to analyse the possible correlation between the activity of these genes and cell proliferation in two different gastric tumour types: diffuse and intestinal. The effect of IGF 1 receptor blockage on cell proliferation and anchorage-independent cell growth was also examined. Increased expression of IGF 2 and IGF 1R genes (at the mRNA and protein level) was found in gastric cancer when compared with non-tumour tissue. Furthermore, there was a significant difference between IGF 2 expression in the more aggressive diffuse type and that in the intestinal type of gastric cancer. Moreover, the IGF 2 peptide level in the culture media obtained from the diffuse type of cancer cells was significantly higher when compared with the intestinal type. The level of IGF 2 peptide in the conditioned media strongly correlated with [3H]thymidine incorporation and cell proliferation. On the contrary, IGF 2R mRNA expression was much higher in the intestinal type of cancer than in the diffuse type. In addition, IGF 2R protein expression was substantially lower with progression of the diffuse cancer type to a higher stage. The alphaIR3 monoclonal antibody strongly inhibited [3H]thymidine incorporation and decreased the number of colonies in soft agar of cells overexpressing IGF 2. These findings suggest that members of the IGF family are involved

  4. IGF-I and branchial IGF receptor expression and localization during salinity acclimation in striped bass

    DEFF Research Database (Denmark)

    Tipsmark, Christian Kølbaek; Luckenbach, John Adam; Madsen, Steffen

    2007-01-01

    The initial response of the IGF-I system and the expression and cellular localization of IGF type-I receptor (IGF-IR) were studied in the gill of a euryhaline teleost during salinity acclimation. Exposure of striped bass (Morone saxatilis) to hyperosmotic and hypoosmotic challenges induced small...... in either plasma IGF-I, liver, or gill IGF-I mRNA, or gill IGF-IR mRNA levels. In a separate experiment, FW-acclimated fish were injected with saline or IGF-I prior to a 24-h SW challenge. Rapid regain of osmotic balance following SW transfer was hindered by IGF-I. Immunohistochemistry revealed...

  5. Maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3 and the hypertensive disorders of pregnancy.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2012-02-01

    OBJECTIVE: To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational hypertension and pre-eclampsia (PET). METHODS: Prospective cohort study of 1650 low-risk Caucasian women in a University teaching hospital in London. Statistical analysis was performed using commercial software (SPSS for Windows, version 6.1, SPSS, Chicago, IL), with P < 0.05 as significant. Maternal IGF 1, IGF 2 and IGF BP-3 were assessed on maternal blood at booking. Blood pressure was checked at each visit in conjunction with urine analysis. The Davey & MacGillivray 1988 classification system was used in making the diagnosis of PET. RESULTS: There was no significant correlation between maternal IGF-1 or IGFBP-3 levels and gestational hypertension or PET. However, a significant positive correlation does exist between maternal IGF-2 levels and PET. CONCLUSIONS: Maternal IGF-2 has a significant positive correlation with PET.

  6. Role of IGF1R in breast cancer subtypes, stemness, and lineage differentiation

    Directory of Open Access Journals (Sweden)

    Susan M Farabaugh

    2015-04-01

    Full Text Available Insulin-like growth factor (IGF signaling is fundamental for growth and survival. A large body of evidence (laboratory, epidemiological, and clinical implicates the exploitation of this pathway in cancer. Up to 50% of breast tumors express the activated form of the IGF1 receptor (IGF1R. Breast cancers are categorized into subtypes based upon hormone and ERRB2 receptor expression and/or gene expression profiling. Even though IGF1R influences tumorigenic phenotypes and drug resistance across all breast cancer subtypes, it has specific expression and function in each. In some subtypes, IGF1R levels correlate with a favorable prognosis, while in others it is associated with recurrence and poor prognosis, suggesting different actions based upon cellular and molecular contexts. In this review, we examine IGF1R expression and function as it relates to breast cancer subtype and therapy-acquired resistance. Additionally, we discuss the role of IGF1R in stem cell maintenance and lineage differentiation and how these cell fate influences may alter the differentiation potential and cellular composition of breast tumors.

  7. Insulin and IGF1 Receptors Are Essential for XX and XY Gonadal Differentiation and Adrenal Development in Mice

    Science.gov (United States)

    Romero, Yannick; Conne, Béatrice; Truong, Vy; Papaioannou, Marilena D.; Schaad, Olivier; Docquier, Mylène; Herrera, Pedro Luis; Wilhelm, Dagmar; Nef, Serge

    2013-01-01

    Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. These findings indicate that prior to sex determination somatic progenitors in Insr;Igf1r mutant gonads are not lineage primed and thus incapable of upregulating/repressing the male and female genetic programs required for cell fate restriction. In consequence, embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that Insr;Igf1r mutant gonads, irrespective of genetic sex, remained in an extended undifferentiated state, before the ovarian differentiation program ultimately is initiated at around E16.5. PMID:23300479

  8. IGF-IR internalizes with Caveolin-1 and PTRF/Cavin in HaCat cells.

    Directory of Open Access Journals (Sweden)

    Barbara Salani

    Full Text Available BACKGROUND: Insulin-like growth factor-I receptor (IGF-IR is a tyrosine kinase receptor (RTK associated with caveolae, invaginations of the plasma membrane that regulate vesicular transport, endocytosis and intracellular signaling. IGF-IR internalization represents a key mechanism of down-modulation of receptors number on plasma membrane. IGF-IR interacts directly with Caveolin-1 (Cav-1, the most relevant protein of caveolae. Recently it has been demonstrated that the Polymerase I and Transcript Release Factor I (PTRF/Cavin is required for caveolae biogenesis and function. The role of Cav-1 and PTRF/Cavin in IGF-IR internalization is still to be clarified. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the interaction of IGF-IR with Cav-1 and PTRF/Cavin in the presence of IGF1in human Hacat cells. We show that IGF-IR internalization triggers Cav-1 and PTRF/Cavin translocation from plasma membrane to cytosol and increases IGF-IR interaction with these proteins. In fact, Cav-1 and PTRF/Cavin co-immunoprecipitate with IGF-IR during receptor internalization. We found a different time course of co-immunoprecipitation between IGF-IR and Cav-1 compared to IGF-IR and PTRF/Cavin. Cav-1 and PTRF/Cavin silencing by siRNA differently affect surface IGF-IR levels following IGF1 treatment: Cav-1 and PTRF/Cavin silencing significantly affect IGF-IR rate of internalization, while PTRF/Cavin silencing also decreases IGF-IR plasma membrane recovery. Since Cav-1 phosphorylation could have a role in IGF-IR internalization, the mutant Cav-1Y14F lacking Tyr14 was transfected. Cav-1Y14F transfected cells showed a reduced internalization of IGF-IR compared with cells expressing wild type Cav-1. Receptor internalization was not impaired by Clathrin silencing. These findings support a critical role of caveolae in IGF-IR intracellular traveling. CONCLUSIONS/SIGNIFICANCE: These data indicate that Caveolae play a role in IGF-IR internalization. Based on these findings

  9. Hepatic JAK2 protects against atherosclerosis through circulating IGF-1.

    Science.gov (United States)

    Sivasubramaniyam, Tharini; Schroer, Stephanie A; Li, Angela; Luk, Cynthia T; Shi, Sally Yu; Besla, Rickvinder; Dodington, David W; Metherel, Adam H; Kitson, Alex P; Brunt, Jara J; Lopes, Joshua; Wagner, Kay-Uwe; Bazinet, Richard P; Bendeck, Michelle P; Robbins, Clinton S; Woo, Minna

    2017-07-20

    Atherosclerosis is considered both a metabolic and inflammatory disease; however, the specific tissue and signaling molecules that instigate and propagate this disease remain unclear. The liver is a central site of inflammation and lipid metabolism that is critical for atherosclerosis, and JAK2 is a key mediator of inflammation and, more recently, of hepatic lipid metabolism. However, precise effects of hepatic Jak2 on atherosclerosis remain unknown. We show here that hepatic Jak2 deficiency in atherosclerosis-prone mouse models exhibited accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content. JAK2's essential role in growth hormone signalling in liver that resulted in reduced IGF-1 with hepatic Jak2 deficiency played a causal role in exacerbating atherosclerosis. As such, restoring IGF-1 either pharmacologically or genetically attenuated atherosclerotic burden. Together, our data show hepatic Jak2 to play a protective role in atherogenesis through actions mediated by circulating IGF-1 and, to our knowledge, provide a novel liver-centric mechanism in atheroprotection.

  10. Binding of IGF I and IGF I-stimulated phosphorylation in canine renal basolateral membranes

    International Nuclear Information System (INIS)

    Hammerman, M.R.; Gavin, J.R. III.

    1986-01-01

    To characterize the interaction of the renal proximal tubular cell with insulin like growth factor I (IGF I), we measured binding of 125 I-IGF I to proximal tubular basolateral membranes from dog kidney and induced IGF I-stimulated phosphorylation of basolateral membranes. Specific binding of 125 I-IGF I to basolateral membranes was observed that was half-maximal at between 10(-9) and 10(-8) M IGF I. 125 I-IGF I was affinity cross-linked to a 135,000 Mr protein in basolateral membranes that was distinct from the alpha-subunit of the insulin receptor and from the IGF II receptor. IGF I-stimulated phosphorylation of a 92,000 Mr protein was effected in detergent-solubilized membranes incubated with 100 microM [gamma- 32 P]ATP. The 32 P-labeled protein was distinct from the beta-subunit of the insulin receptor, the 32 P phosphorylation of which was stimulated by insulin. We conclude that specific receptors for IGF I are present in the basolateral membrane of the renal proximal tubular cell. Physiological actions of IGF I at this nephron site may occur through the binding of this peptide circulating in plasma, to specific basolateral membrane receptors, followed by IGF I stimulated phosphorylation

  11. Targeted mass spectrometry analysis of the proteins IGF1, IGF2, IBP2, IBP3 and A2GL by blood protein precipitation

    DEFF Research Database (Denmark)

    Such-Sanmartín, Gerard; Bache, Nicolai; Callesen, Anne K

    2015-01-01

    aggravated when using fast high-throughput methods, which are necessary for analysis of hundreds and thousands of samples in clinical laboratories. The blood proteins IGF1, IGF2, IBP2, IBP3 and A2GL have been proposed as indirect biomarkers for detection of GH administration and as putative biomarkers...

  12. The cAMP Response Element Binding protein (CREB) is activated by Insulin-like Growth Factor-1 (IGF-1) and regulates myostatin gene expression in skeletal myoblast

    International Nuclear Information System (INIS)

    Zuloaga, R.; Fuentes, E.N.; Molina, A.; Valdés, J.A.

    2013-01-01

    Highlights: •IGF-1 induces the activation of CREB via IGF-1R/PI3K/PLC signaling pathway. •Calcium dependent signaling pathways regulate myostatin gene expression. •IGF-1 regulates myostatin gene expression via CREB transcription in skeletal myoblast. -- Abstract: Myostatin, a member of the Transforming Growth Factor beta (TGF-β) superfamily, plays an important role as a negative regulator of skeletal muscle growth and differentiation. We have previously reported that IGF-1 induces a transient myostatin mRNA expression, through the activation of the Nuclear Factor of Activated T cells (NFAT) in an IP 3 /calcium-dependent manner. Here we examined the activation of CREB transcription factor as downstream targets of IGF-1 during myoblast differentiation and its role as a regulator of myostatin gene expression. In cultured skeletal myoblast, IGF-1 induced the phosphorylation and transcriptional activation of CREB via IGF-1 Receptor/Phosphatidylinositol 3-Kinase (PI3K)/Phospholipase C gamma (PLC γ), signaling pathways. Also, IGF-1 induced calcium-dependent molecules such as Calmodulin Kinase II (CaMK II), Extracellular signal-regulated Kinases (ERK), Protein Kinase C (PKC). Additionally, we examined myostatin mRNA levels and myostatin promoter activity in differentiated myoblasts stimulated with IGF-1. We found a significant increase in mRNA contents of myostatin and its reporter activity after treatment with IGF-1. The expression of myostatin in differentiated myoblast was downregulated by the transfection of siRNA–CREB and by pharmacological inhibitors of the signaling pathways involved in CREB activation. By using pharmacological and genetic approaches together these data demonstrate that IGF-1 regulates the myostatin gene expression via CREB transcription factor during muscle cell differentiation

  13. The cAMP Response Element Binding protein (CREB) is activated by Insulin-like Growth Factor-1 (IGF-1) and regulates myostatin gene expression in skeletal myoblast

    Energy Technology Data Exchange (ETDEWEB)

    Zuloaga, R. [Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago (Chile); Fuentes, E.N.; Molina, A. [Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), Víctor Lamas 1290, PO Box 160-C, Concepción (Chile); Valdés, J.A., E-mail: jvaldes@unab.cl [Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), Víctor Lamas 1290, PO Box 160-C, Concepción (Chile)

    2013-10-18

    Highlights: •IGF-1 induces the activation of CREB via IGF-1R/PI3K/PLC signaling pathway. •Calcium dependent signaling pathways regulate myostatin gene expression. •IGF-1 regulates myostatin gene expression via CREB transcription in skeletal myoblast. -- Abstract: Myostatin, a member of the Transforming Growth Factor beta (TGF-β) superfamily, plays an important role as a negative regulator of skeletal muscle growth and differentiation. We have previously reported that IGF-1 induces a transient myostatin mRNA expression, through the activation of the Nuclear Factor of Activated T cells (NFAT) in an IP{sub 3}/calcium-dependent manner. Here we examined the activation of CREB transcription factor as downstream targets of IGF-1 during myoblast differentiation and its role as a regulator of myostatin gene expression. In cultured skeletal myoblast, IGF-1 induced the phosphorylation and transcriptional activation of CREB via IGF-1 Receptor/Phosphatidylinositol 3-Kinase (PI3K)/Phospholipase C gamma (PLC γ), signaling pathways. Also, IGF-1 induced calcium-dependent molecules such as Calmodulin Kinase II (CaMK II), Extracellular signal-regulated Kinases (ERK), Protein Kinase C (PKC). Additionally, we examined myostatin mRNA levels and myostatin promoter activity in differentiated myoblasts stimulated with IGF-1. We found a significant increase in mRNA contents of myostatin and its reporter activity after treatment with IGF-1. The expression of myostatin in differentiated myoblast was downregulated by the transfection of siRNA–CREB and by pharmacological inhibitors of the signaling pathways involved in CREB activation. By using pharmacological and genetic approaches together these data demonstrate that IGF-1 regulates the myostatin gene expression via CREB transcription factor during muscle cell differentiation.

  14. Insulin-like growth factor binding protein-3 induces angiogenesis through IGF-I- and SphK1-dependent mechanisms.

    Science.gov (United States)

    Granata, R; Trovato, L; Lupia, E; Sala, G; Settanni, F; Camussi, G; Ghidoni, R; Ghigo, E

    2007-04-01

    Angiogenesis is critical for development and repair, and is a prominent feature of many pathological conditions. Based on evidence that insulin-like growth factor binding protein (IGFBP)-3 enhances cell motility and activates sphingosine kinase (SphK) in human endothelial cells, we have investigated whether IGFBP-3 plays a role in promoting angiogenesis. IGFBP-3 potently induced network formation by human endothelial cells on Matrigel. Moreover, it up-regulated proangiogenic genes, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)-2 and -9. IGFBP-3 even induced membrane-type 1 MMP (MT1-MMP), which regulates MMP-2 activation. Decreasing SphK1 expression by small interfering RNA (siRNA), blocked IGFBP-3-induced network formation and inhibited VEGF, MT1-MMP but not IGF-I up-regulation. IGF-I activated SphK, leading to sphingosine-1-phosphate (S1P) formation. The IGF-I effect on SphK activity was blocked by specific inhibitors of IGF-IR, PI3K/Akt and ERK1/2 phosphorylation. The disruption of IGF-I signaling prevented the IGFBP-3 effect on tube formation, SphK activity and VEGF release. Blocking ERK1/2 signaling caused the loss of SphK activation and VEGF and IGF-I up-regulation. Finally, IGFBP-3 dose-dependently stimulated neovessel formation into subcutaneous implants of Matrigel in vivo. Thus, IGFBP-3 positively regulates angiogenesis through involvement of IGF-IR signaling and subsequent SphK/S1P activation.

  15. Crosstalk between adiponectin and IGF-IR in breast cancer

    Directory of Open Access Journals (Sweden)

    Loredana eMauro

    2015-07-01

    Full Text Available Obesity is a chronic and multifactorial disorder that is reaching epidemic proportions. It is characterized by an enlarged mass of adipose tissue caused by a combination of size increase of preexisting adipocytes (hypertrophy and de novo adipocyte differentiation (hyperplasia. Obesity is related to many metabolic disorders like hypertension, type 2 diabetes, metabolic syndrome, cardiovascular disease, and it is associated with an increased risk of cancer development in different tissues including breast. Adipose tissue is now regarded as not just a storage reservoir for excess energy, but rather as an endocrine organ, secreting a large number of bioactive molecules called adipokines. Among these, adiponectin represents the most abundant adipose tissue-excreted protein, which exhibits insulin-sensitizing, anti-inflammatory and antiatherogenic properties. The serum concentrations of adiponectin are inversely correlated with body mass index. Recently, low levels of plasma adiponectin have been associated with an increased risk for obesity-related cancers and development of more aggressive phenotype, concomitantly with alterations in the bioavailability of Insulin-like Growth Factor-I (IGF-I and IGF-I Receptor (IGF-IR signaling pathways. In this review we discuss the cross-talk between adiponectin/AdipoR1 and IGF-I/IGF-IR in breast cancer.

  16. Involvement of Igf1r in Bronchiolar Epithelial Regeneration: Role during Repair Kinetics after Selective Club Cell Ablation.

    Directory of Open Access Journals (Sweden)

    Icíar P López

    Full Text Available Regeneration of lung epithelium is vital for maintaining airway function and integrity. An imbalance between epithelial damage and repair is at the basis of numerous chronic lung diseases such as asthma, COPD, pulmonary fibrosis and lung cancer. IGF (Insulin-like Growth Factors signaling has been associated with most of these respiratory pathologies, although their mechanisms of action in this tissue remain poorly understood. Expression profiles analyses of IGF system genes performed in mouse lung support their functional implication in pulmonary ontogeny. Immuno-localization revealed high expression levels of Igf1r (Insulin-like Growth Factor 1 Receptor in lung epithelial cells, alveolar macrophages and smooth muscle. To further understand the role of Igf1r in pulmonary homeostasis, two distinct lung epithelial-specific Igf1r mutant mice were generated and studied. The lack of Igf1r disturbed airway epithelial differentiation in adult mice, and revealed enhanced proliferation and altered morphology in distal airway club cells. During recovery after naphthalene-induced club cell injury, the kinetics of terminal bronchiolar epithelium regeneration was hindered in Igf1r mutants, revealing increased proliferation and delayed differentiation of club and ciliated cells. Amid airway restoration, lungs of Igf1r deficient mice showed increased levels of Igf1, Insr, Igfbp3 and epithelial precursor markers, reduced amounts of Scgb1a1 protein, and alterations in IGF signaling mediators. These results support the role of Igf1r in controlling the kinetics of cell proliferation and differentiation during pulmonary airway epithelial regeneration after injury.

  17. Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF-1.

    Science.gov (United States)

    Dobie, Ross; Ahmed, Syed F; Staines, Katherine A; Pass, Chloe; Jasim, Seema; MacRae, Vicky E; Farquharson, Colin

    2015-11-01

    Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like-growth factor-1 (IGF-1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling-2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF-1 levels. Wild-type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (P growth over a 12 day period. Despite this increase, IGF-1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF-1 levels were unchanged in GH-challenged postnatal Socs2(-/-) conditioned medium despite metatarsals showing enhanced linear growth. Growth-plate Igf1 mRNA levels were not elevated in juvenile Socs2(-/-) mice. GH did however elevate IGF-binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2(-/-) metatarsals. GH did not enhance the growth of Socs2(-/-) metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF-2 may be responsible as IGF-2 promoted metatarsal growth and Igf2 expression was elevated in Socs2(-/-) (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2(-/-) mice, promoting growth via a mechanism that is independent of IGF-1. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

  18. HSF1 phosphorylation by ERK/GSK3 suppresses RNF126 to sustain IGF-IIR expression for hypertension-induced cardiomyocyte hypertrophy.

    Science.gov (United States)

    Huang, Chih-Yang; Lee, Fa-Lun; Peng, Shu-Fen; Lin, Kuan-Ho; Chen, Ray-Jade; Ho, Tsung-Jung; Tsai, Fu-Jen; Padma, Vijaya V; Kuo, Wei-Wen; Huang, Chih-Yang

    2018-02-01

    Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure (HF). Inhibition of extracellular signal-regulated kinases (ERK) efficaciously suppressed angiotensin II (ANG II)-induced cardiomyocyte hypertrophy and apoptosis by blocking insulin-like growth factor II receptor (IGF-IIR) signaling. However, the detailed mechanism by which ANG II induces ERK-mediated IGF-IIR signaling remains elusive. Here, we found that ANG II activated ERK to upregulate IGF-IIR expression via the angiotensin II type I receptor (AT 1 R). ERK activation subsequently phosphorylates HSF1 at serine 307, leading to a secondary phosphorylation by glycogen synthase kinase III (GSK3) at serine 303. Moreover, we found that ANG II mediated ERK/GSK3-induced IGF-IIR protein stability by downregulating the E3 ubiquitin ligase of IGF-IIR RING finger protein CXXVI (RNF126). The expression of RNF126 decreased following ANG II-induced HSF1 S303 phosphorylation, resulting in IGF-IIR protein stability and increased cardiomyocyte injury. Inhibition of GSK3 significantly alleviated ANG II-induced cardiac hypertrophy in vivo and in vitro. Taken together, these results suggest that HSF1 phosphorylation stabilizes IGF-IIR protein stability by downregulating RNF126 during cardiac hypertrophy. ANG II activates ERK/GSK3 to phosphorylate HSF1, resulting in RNF126 degradation, which stabilizes IGF-IIR protein expression and eventually results in cardiac hypertrophy. HSF1 could be a valuable therapeutic target for cardiac diseases among hypertensive patients. © 2017 Wiley Periodicals, Inc.

  19. IGF-I abuse in sport.

    Science.gov (United States)

    Guha, Nishan; Dashwood, Alexander; Thomas, Nicholas J; Skingle, Alexander J; Sönksen, Peter H; Holt, Richard I G

    2009-09-01

    It is widely believed that growth hormone (GH) is abused by athletes for its anabolic and lipolytic effects. Many of the physiological effects of GH are mediated by the production of insulin-like growth factor-I (IGF-I). Both GH and IGF-I appear on the World Anti-Doping Agency list of prohibited substances. Little is known, however, about the prevalence of abuse with exogenous IGF-I. IGF-I has effects on carbohydrate, lipid and protein metabolism and some of these actions could prove beneficial to competitive athletes. No studies have demonstrated a positive effect of IGF-I on physical performance in healthy individuals but this has not yet been studied in appropriately designed trials. Two pharmaceutical preparations of IGF-I have recently become available for the treatment of growth disorders in children. This availability is likely to increase the prevalence of IGF-I abuse. Combining IGF-I with its binding protein IGFBP-3 in one preparation has the potential to reduce the side-effect profile but the adverse effects of long term IGF-I abuse are currently unknown. Detection of abuse with IGF-I is a major challenge for anti-doping authorities. It is extremely difficult to distinguish the exogenous recombinant form of the hormone from endogenously-produced IGF-I. One approach currently being investigated is based on measuring markers of GH and IGF-I action. This has already proved successful in the fight against GH abuse and, it is hoped, will subsequently lead to a similar test for detection of IGF-I abuse.

  20. IGF1 as predictor of all cause mortality and cardiovascular disease in an elderly population

    DEFF Research Database (Denmark)

    Andreassen, Mikkel; Raymond, Ilan; Kistorp, Caroline

    2009-01-01

    BACKGROUND: IGF1 is believed to influence ageing and development of cardiovascular disease (CVD) through complex mechanisms. Reduced IGF1 levels might be causally associated with conditions accompanying ageing including development of CVD. However, in animal models reduced GH-IGF1 signalling...... increases lifespan. Reduced IGF1 activity might also be associated with longevity in humans. OBJECTIVE: The objective was to investigate if plasma IGF1 levels were associated with all cause mortality, and the development of chronic heart failure (CHF) and a major CV event. PATIENTS AND DESIGN: A population...... systolic function and without prevalent CVD. Outcomes were ascertained after 5 years using hospital discharge diagnoses. RESULTS: Adjustment for risk factors IGF1 values in the fourth quartile versus values below the fourth quartile was associated with increased mortality (n=103), hazard ratio (HR) 1...

  1. Insulin-Like Growth Factor (IGF Binding Protein-2, Independently of IGF-1, Induces GLUT-4 Translocation and Glucose Uptake in 3T3-L1 Adipocytes

    Directory of Open Access Journals (Sweden)

    Biruhalem Assefa

    2017-01-01

    Full Text Available Insulin-like growth factor binding protein-2 (IGFBP-2 is the predominant IGF binding protein produced during adipogenesis and is known to increase the insulin-stimulated glucose uptake (GU in myotubes. We investigated the IGFBP-2-induced changes in basal and insulin-stimulated GU in adipocytes and the underlying mechanisms. We further determined the role of insulin and IGF-1 receptors in mediating the IGFBP-2 and the impact of IGFBP-2 on the IGF-1-induced GU. Fully differentiated 3T3-L1 adipocytes were treated with IGFBP-2 in the presence and absence of insulin and IGF-1. Insulin, IGF-1, and IGFBP-2 induced a dose-dependent increase in GU. IGFBP-2 increased the insulin-induced GU after long-term incubation. The IGFBP-2-induced impact on GU was neither affected by insulin or IGF-1 receptor blockage nor by insulin receptor knockdown. IGFBP-2 significantly increased the phosphorylation of PI3K, Akt, AMPK, TBC1D1, and PKCζ/λ and induced GLUT-4 translocation. Moreover, inhibition of PI3K and AMPK significantly reduced IGFBP-2-stimulated GU. In conclusion, IGFBP-2 stimulates GU in 3T3-L1 adipocytes through activation of PI3K/Akt, AMPK/TBC1D1, and PI3K/PKCζ/λ/GLUT-4 signaling. The stimulatory effect of IGFBP-2 on GU is independent of its binding to IGF-1 and is possibly not mediated through the insulin or IGF-1 receptor. This study highlights the potential role of IGFBP-2 in glucose metabolism.

  2. Insulin-like growth factor (IGF-I and IGF binding proteins axis in diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Min Sun Kim

    2015-06-01

    Full Text Available Increasing evidence suggests an important role of the insulin-like growth factor (IGF-IGF binding protein (IGFBP axis in the maintenance of normal glucose and lipid metabolism. Significant changes occur in the local IGF-I-IGFBPs environment in response to the diabetic milieu. A significant reduction of serum IGF-I levels was observed in patients with type 1 diabetes mellitus (T1DM. Inversely, considerably increased serum levels of IGF-I and IGFBP-3 levels were detected in individuals with glucose intolerance including T2DM. Recently, several prospective studies indicated that baseline levels of IGF-I and IGFBPs are associated with the development of diabetes. These findings suggest that disturbances in insulin and IGF-I-IGFBP axis can affect the development of glucose intolerance including diabetes.

  3. The Role of Insulin/IGF-1/PI3K/Akt/GSK3β Signaling in Parkinson's Disease Dementia

    Directory of Open Access Journals (Sweden)

    Liying Yang

    2018-02-01

    Full Text Available Dementia, a condition that frequently afflicts patients in advanced stages of Parkinson's disease (PD, results in decreased quality of life and survival time. Nevertheless, the pathological mechanisms underlying Parkinson's disease dementia (PDD are not completely understood. The symptoms characteristic of PDD may be the result of functional and structural deficiencies. The present study implicates the accumulation of Lewy bodies in the cortex and limbic system as a potent trigger in the development of PDD. In addition, significant Alzheimer-type pathologies, including amyloid-β (Aβ plaques and NFTs, are observed in almost half of PDD patients. Interestingly, links between PDD pathogenesis and the mechanisms underlying the development of insulin resistance have begun to emerge. Furthermore, previous studies have demonstrated that insulin treatment reduces amyloid plaques in Alzheimer's disease (AD, and normalizes the production and functionality of dopamine and ameliorates motor impairments in 6-OHDA-induced rat PD models. GSK3β, a downstream substrate of PI3K/Akt signaling following induction by insulin and IGF-1, exerts an influence on AD and PD physiopathology. The genetic overexpression of GSK3β in cortex and hippocampus results in signs of neurodegeneration and spatial learning deficits in in vivo models (Lucas et al., 2001, whereas its inhibition results in improvements in cognitive impairment in these rodents, including AD and PD. Accordingly, insulin- or IGF-1-activated PI3K/Akt/GSK3β signaling may be involved in PDD pathogenesis, at least in the pathology of PD-type + AD-type.

  4. Dietary protein-induced hepatic IGF-1 secretion mediated by PPARγ activation.

    Science.gov (United States)

    Wan, Xiaojuan; Wang, Songbo; Xu, Jingren; Zhuang, Lu; Xing, Kongping; Zhang, Mengyuan; Zhu, Xiaotong; Wang, Lina; Gao, Ping; Xi, Qianyun; Sun, Jiajie; Zhang, Yongliang; Li, Tiejun; Shu, Gang; Jiang, Qingyan

    2017-01-01

    Dietary protein or amino acid (AA) is a crucial nutritional factor to regulate hepatic insulin-like growth factor-1 (IGF-1) expression and secretion. However, the underlying intracellular mechanism by which dietary protein or AA induces IGF-1 expression remains unknown. We compared the IGF-1 gene expression and plasma IGF-1 level of pigs fed with normal crude protein (CP, 20%) and low-protein levels (LP, 14%). RNA sequencing (RNA-seq) was performed to detect transcript expression in the liver in response to dietary protein. The results showed that serum concentrations and mRNA levels of IGF-1 in the liver were higher in the CP group than in the LP group. RNA-seq analysis identified a total of 1319 differentially expressed transcripts (667 upregulated and 652 downregulated), among which the terms "oxidative phosphorylation", "ribosome", "gap junction", "PPAR signaling pathway", and "focal adhesion" were enriched. In addition, the porcine primary hepatocyte and HepG2 cell models also demonstrated that the mRNA and protein levels of IGF-1 and PPARγ increased with the increasing AA concentration in the culture. The PPARγ activator troglitazone increased IGF-1 gene expression and secretion in a dose dependent manner. Furthermore, inhibition of PPARγ effectively reversed the effects of the high AA concentration on the mRNA expression of IGF-1 and IGFBP-1 in HepG2 cells. Moreover, the protein levels of IGF-1 and PPARγ, as well as the phosphorylation of mTOR, significantly increased in HepG2 cells under high AA concentrations. mTOR phosphorylation can be decreased by the mTOR antagonist, rapamycin. The immunoprecipitation results also showed that high AA concentrations significantly increased the interaction of mTOR and PPARγ. In summary, PPARγ plays an important role in the regulation of IGF-1 secretion and gene expression in response to dietary protein.

  5. The impact of the IGF-1 system of cancer cells on radiation response - An in vitro study.

    Science.gov (United States)

    Venkatachalam, Senthiladipan; Mettler, Esther; Fottner, Christian; Miederer, Matthias; Kaina, Bernd; Weber, Matthias M

    2017-12-01

    Overexpression of the insulin-like growth factor-1 receptor (IGF-1R) is associated with increased cell proliferation, differentiation, transformation, and tumorigenicity. Additionally, signaling involved in the resistance of cancer cells to radiotherapy originates from IGF-1R. The purpose of this study was to investigate the role of the IGF-1 system in the radiation response and further evaluate its effect on the expression of DNA repair pathway genes. To inhibit the IGF-1 system, we stably transfected the Caco-2 cell line to express a kinase-deficient IGF-1R mutant. We then studied the effects of this mutation on cell growth, the response to radiation, and clonogenic survival, as well as using a cell viability assay to examine DNA damage and repair. Finally, we performed immunofluorescence for γ-H2AX to examine double-strand DNA breaks and evaluated the expression of 84 key genes involved in DNA repair with a real-time PCR array. Mutant IGF-1R cells exhibited significantly blunted cell growth and viability, compared to wild-type cells, as well as reduced clonogenic survival after γ-irradiation. However, mutant IGF-1R cells did not show any significant delays in the repair of radiation-induced DNA double-strand breaks. Furthermore, expression of mutant IGF-1R significantly down-regulated the mRNA levels of BRCA2, a major protein involved in homologous recombination DNA repair. These results indicate that blocking the IGF-1R-mediated signaling cascade, through the expression of a kinase-deficient IGF-1R mutant, reduces cell growth and sensitizes cancer cells to ionizing radiation. Therefore, the IGF-1R system could be a potential target to enhance radio-sensitivity and the efficacy of cancer treatments.

  6. Inhibition of EGFR or IGF-1R signaling enhances radiation response in head and neck cancer models but concurrent inhibition has no added benefit

    International Nuclear Information System (INIS)

    Raju, Uma; Molkentine, David P; Valdecanas, David R; Deorukhkar, Amit; Mason, Kathryn A; Buchholz, Thomas A; Meyn, Raymond E; Ang, Kie-Kian; Skinner, Heath

    2015-01-01

    Interaction between the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGF-1R) has been well established in many cancer types. We investigated the effects of cetuximab (EGFR antibody) and IMC-A12 (IGF-1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to radiation therapy (RT). The effects of cetuximab and IMC-A12 on cell viability and radiosensitivity were determined by clonogenic cell survival assay. Formation of nuclear γ-H2AX and 53BP1 foci was monitored by immunofluorescence. Alterations in target signaling were analyzed by Western blots. In vivo tumor growth delay assay was performed to determine the efficacy of triple therapy with IMC-A12, cetuximab, and RT. In vitro data showed that cetuximab differentially affected the survival and the radiosensitivity of HNSCC cells. Cetuximab suppressed DNA repair that was evident by the prolonged presence of nuclear γ-H2AX and 53BP1 foci. IMC-A12 did not have any effect on the cell survival. However, it increased the radiosensitivity of one of the cell lines. EGFR inhibition increased IGF-1R expression levels and also the association between EGFR and IGF-1R. Addition of IMC-A12 to cetuximab did not increase the radiosensitivity of these cells. Tumor xenografts exhibited enhanced response to RT in the presence of either cetuximab or IMC-A12. Concurrent treatment regimen failed to further enhance the tumor response to cetuximab and/or RT. Taken together our data suggest that concomitant inhibition of both EGFR and IGF-1R pathways did not yield additional therapeutic benefit in overcoming resistance to RT

  7. Structural analysis of the interaction of IGF I with the IGF types 1 and 2 and insulin receptors

    International Nuclear Information System (INIS)

    Cascieri, M.A.; Chicchi, G.G.; Hayes, N.S.; Green, B.G.; Applebaum, J.A.; Bayne, M.L.

    1987-01-01

    A synthetic gene for human IGF I has been synthesized which directs the synthesis and secretion of fully active human IGF I (rIGF I) from yeast. rIGF I inhibits binding of 125 I-IGF I to type 1 IGF receptors from human placenta (IGF-R1, IC50 = 4 nM), binding of 125 I-insulin to insulin receptors (IR, IC50 = 881 nM), binding of 125 I-MSA to type 2 IGF receptors from rat liver (IGF-R2, IC50 = 80 nM), and binding of 125 I-IGF I to crude human serum binding protein (hBP, IC50 = 0.42 nM). rIGF I is equipotent to human IGF I in stimulating glucose transport in murine BC3H1 cells and in stimulating DNA synthesis in rat A10 cells. Site directed mutagenesis of the synthetic gene is being used to characterize the structural requirements for binding to these receptors. IGF I (FFY) B(23-25) is equipotent to rIGF I at the IGF-R1 (6.9 nM), the IGF-R2 (36 nM), and the IR (841 nM) and is less potent at the hBP (1.7 nM). In contrast, IGF I(SFY) B(23-25) is 20-fold less potent than rIGF I at the IGF-R1 and is 10-fold less potent than rIGF I at hBP. This peptide is greater than 10-fold less active at the IGF-R2 and the IR. This peptide is a full agonist in the cell assays but 20-50 fold less potent than rIGF I. These data are consistent with the hypothesis that the F to S change destabilizes the tertiary structure of IGF I

  8. Novel functional polymorphism in IGF-1 gene associated with multiple sclerosis: A new insight to MS.

    Science.gov (United States)

    Shahbazi, Majid; Abdolmohammadi, Reza; Ebadi, Hamid; Farazmandfar, Touraj

    2017-04-01

    Interactions between several genes and environment may play a role in susceptibility to multiple sclerosis (MS). The IGF-1 plays a key role in proliferation, maintenance and survival of nerve cells. Therefore, we hypothesized that IGF-1 may be a target for prediction and control MS. We aimed to analysis IGF-1 gene promoter sequence, to investigate the effect of the single nucleotide variants on IGF-1 expression and its association with MS. We enrolled 339 MS patients and 431 healthy controls. A specific region in IGF-1 gene promoter was investigated by SSCP analysis. All samples were genotyped by SSP-PCR. In-vitro and in-vivo IGF-1 production was measured by ELISA assay. IGF-1 expression in PBMCs was measured using real-time PCR. We identified a T to C single nucleotide substitution at position -1089 and a C to T at position -383 from transcription start site in the IGF-1 gene promoter. There was a significant association between MS and genotypes IGF-1(-383) C/T (p=0.001) and IGF-1(-383) C/C (pMS (p=0.001). In-vitro and in-vivo IGF-1 level showed that IGF-1 production in samples with genotype IGF-1(-383) C/C significantly was less than T/T (p=0.004) but not T/C (p=0.220). According to IGF-1 roles in CNS and our results, this study suggests that low IGF-1 level may be associated with susceptibility to MS. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression.

    Science.gov (United States)

    Cheng, Chia-Wei; Adams, Gregor B; Perin, Laura; Wei, Min; Zhou, Xiaoying; Lam, Ben S; Da Sacco, Stefano; Mirisola, Mario; Quinn, David I; Dorff, Tanya B; Kopchick, John J; Longo, Valter D

    2014-06-05

    Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. The adaptor protein CrkII regulates IGF-1-induced biological behaviors of pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Liu, Rui; Wang, Qing; Xu, Guangying; Li, Kexin; Zhou, Lingli; Xu, Baofeng

    2016-01-01

    Recently, the adaptor protein CrkII has been proved to function in initiating signals for proliferation and invasion in some malignancies. However, the specific mechanisms underlying insulin-like growth factor 1 (IGF-1)-CrkII signaling-induced proliferation of pancreatic ductal adenocarcinoma (PDAC) were not unraveled. In this work, PDAC tissues and cell lines were subjected to in vitro and in vivo assays. Our findings showed that CrkII was abundantly expressed in PDAC tissues and closely correlated with tumor-node-metastasis (TNM) stage and invasion. When cells were subjected to si-CrkII, si-CrkII inhibited IGF-1-mediated PDAC cell growth. In vitro, we demonstrated the upregulation of CrkII, p-Erk1/2, and p-Akt occurring in IGF-1-treated PDAC cells. Conversely, si-CrkII affected upregulation of CrkII, p-Erk1/2, and p-Akt. In addition, cell cycle and in vivo assay identified that knockdown of CrkII inhibited the entry of G1 into S phase and the increase of PDAC tumor weight. In conclusion, CrkII mediates IGF-1 signaling and further balanced PDAC biological behaviors via Erk1/2 and Akt pathway, which indicates that CrkII gene and protein may act as an effective target for the treatment of PDAC.

  11. The Effects of IGF-1 on TNF-α-Treated DRG Neurons by Modulating ATF3 and GAP-43 Expression via PI3K/Akt/S6K Signaling Pathway.

    Science.gov (United States)

    Zhang, Lei; Yue, Yaping; Ouyang, Meishuo; Liu, Huaxiang; Li, Zhenzhong

    2017-05-01

    imply that IGF-1 counteracts the toxic effect of higher concentration of TNF-α, while potentiates the growth-promoting effect of lower concentration of TNF-α, with the node for TNF-α and IGF-1 interaction being the PI3K/Akt/S6K signaling pathway. This study is helpful for interpretation of the association of IGF-1 with TNF-α and the neurobiological effects elicited by interaction of IGF-1 and TNF-α in neurological disorders.

  12. Impact of IGF-1, IGF-1R, and IGFBP-3 promoter methylation on the risk and prognosis of esophageal carcinoma.

    Science.gov (United States)

    Ye, Peng; Qu, Chang-Fa; Hu, Xue-Lin

    2016-05-01

    The aim of this study is to investigate IGF-1, IGF-1R, and IGFBP-3 methylations in esophageal carcinoma (EC) patients and their relationship with the development and prognosis of EC. This study population consisted of 264 patients (case group) whom EC radical resection was performed and 283 healthy individuals (control group). Methylation-specific PCR (MSP) detected the methylation status of IGF-1, IGF-1R, and IGFBP-3 in the peripheral blood in both groups. The expressions of IGF-1, IGF-1R, and IGFBP-3 in EC and adjacent normal tissues were detected by immunohistochemistry (IHC). The methylation rates of IGF-1, IGF-1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 in the case group were higher than those in the control group (all P IGF-1, IGF-1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 IGF-1 among patients of different clinicopathological features (all P IGF-1 and IGF-1R in EC were significantly higher than those in adjacent normal tissues (both P IGF-1 and IGF1R gene promoter methylation was positively correlated with the positive expressions of IGF-1 (r = 0.139, P = 0.024) and IGF-1R (r = 0.135, P = 0.028), while the IGFBP3 methylation was negatively correlated with the positive expression of IGFBP3 (r = -0.133, P = 0.031). The positive expressions of IGF-1, IGF-1R, and IGFBP-3 were related to different clinicopathological features (all P IGF-1, IGF-1R, and IGF-1 + IGF1R + IGFBP3 ; expressions of IGF-1 and IGF-1R protein; infiltration depth; and lymph node metastasis (LNM) were independent factors of EC prognosis. Our study demonstrated that methylation of IGF-1, IGF1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 was closely linked with the occurrence of EC and patients' clinicopathological features. Besides, the methylation status of the target genes and the expressions of IGF-1 and IGF-1R protein were independent factors of EC prognosis, which could provide a direction for the prognosis and treatment of EC.

  13. IGF-1-dependent subunit communication of the IGF-1 holoreceptor: Interactions between αβ heterodimeric receptor halves

    International Nuclear Information System (INIS)

    Wilden, P.A.; Treadway, J.L.; Morrison, B.D.; Pessin, J.E.

    1989-01-01

    Examination of 125 I-IGF-1 affinity cross-linking and β-subunit autophosphorylation has indicated that IGF-1 induces a covalent association of isolated αβ heterodimeric IGF-1 receptors into an α 2 β 2 heterotetrameric state, in a similar manner to that observed for the insulin receptor. The formation of the α 2 β 2 heterotetrameric IGF-1 receptor complex from the partially purified αβ heterodimers was time dependent with half-maximal formation in approximately 30 min at saturating IGF-1 concentrations. The IGF-1-dependent association of the partially purified αβ heterodimers into an α 2 β 2 heterotetrameric state was specific for the IGF-1 receptors since IGF-1 was unable to stimulate the protein kinase activity of the purified αβ heterodimeric insulin receptor complex. Incubation of the α 2 β 2 heterotetrameric IGF-1 holoreceptor with the specific sulfhydryl agent iodoacetamide (IAN) did not alter 125 I-IGF-1 binding or IGF-1 stimulation of protein kinase activity. However, IAN treatment of the αβ heterodimeric IGF-1 receptors inhibited the IGF-1 dependent covalent formation of the disulfide-linked α 2 β 2 heterotetrameric complex. These data indicate that IGF-1 induces the covalent association of isolated αβ heterodimeric IGF-1 receptor complexes into a disulfide-linked α 2 β 2 heterotetrameric state whereas Mn/MgATP induces a noncovalent association. Therefore, unlike the insulin receptor in which noncovalent association is sufficient for kinase activation, only the covalent assembly of the IGF-1 receptor αβ heterodimers into the α 2 β 2 heterotetrameric holoreceptor complex is associated with ligand-stimulated protein kinase activation

  14. IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Handayaningsih, Anastasia-Evi; Takahashi, Michiko; Fukuoka, Hidenori; Iguchi, Genzo; Nishizawa, Hitoshi; Yamamoto, Masaaki; Suda, Kentaro [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Takahashi, Yutaka, E-mail: takahash@med.kobe-u.ac.jp [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Cellular senescence plays an important role in tumorigenesis and aging process. Black-Right-Pointing-Pointer We demonstrated IGF-I enhanced cellular senescence in primary confluent cells. Black-Right-Pointing-Pointer IGF-I enhanced cellular senescence in the ROS and p53-dependent manner. Black-Right-Pointing-Pointer These results may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging. -- Abstract: Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated {beta}-galactosidase (SA-{beta}-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, {gamma}H2AX, the increased levels of p53 and p21 proteins, and activated SA-{beta}-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-{beta}-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging.

  15. IGF-I enhances cellular senescence via the reactive oxygen species–p53 pathway

    International Nuclear Information System (INIS)

    Handayaningsih, Anastasia-Evi; Takahashi, Michiko; Fukuoka, Hidenori; Iguchi, Genzo; Nishizawa, Hitoshi; Yamamoto, Masaaki; Suda, Kentaro; Takahashi, Yutaka

    2012-01-01

    Highlights: ► Cellular senescence plays an important role in tumorigenesis and aging process. ► We demonstrated IGF-I enhanced cellular senescence in primary confluent cells. ► IGF-I enhanced cellular senescence in the ROS and p53-dependent manner. ► These results may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging. -- Abstract: Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated β-galactosidase (SA-β-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, γH2AX, the increased levels of p53 and p21 proteins, and activated SA-β-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-β-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging.

  16. The Regulatory Mechanism of MLT/MT1 Signaling on the Growth of Antler Mesenchymal Cells

    Directory of Open Access Journals (Sweden)

    Feifei Yang

    2017-10-01

    Full Text Available Melatonin (MLT plays an important role in regulating the physiological cycle of seasonal breeding animals. Melatonin receptor I (MT1 is effectively expressed in the cambium layer of deer antler. However, the function and metabolic mechanism of MLT/MT1 signaling in the mesenchymal cells of sika deer remain to be further elucidated. In this work, we detected the effects of MLT/MT1 signaling on mesenchymal cells proliferation and the interaction between MLT/MT1 and IGF1/IGF1-R signaling. The results show that (1 deer antler mesenchymal cells actually express MT1; (2 exogenous melatonin significantly promotes mesenchymal cells proliferation, while MT1 knock-down significantly impairs the positive effects of melatonin; and (3 melatonin significantly enhanced IGF1/IGF1-R signaling, as both the expression of IGF1 and IGF-1R increased, while MT1 knock-down significantly decreased IGF1-R expression and IGF1 synthesis. In summary, these data verified that MLT/MT1 signaling plays a crucial role in antler mesenchymal proliferation, which may be mediated by IGF1/IGF1-R.

  17. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1

    Science.gov (United States)

    Guan, Jian; Gluckman, Peter; Yang, Panzao; Krissansen, Geoff; Sun, Xueying; Zhou, Yongzhi; Wen, Jingyuan; Phillips, Gemma; Shorten, Paul R.; McMahon, Chris D.; Wake, Graeme C.; Chan, Wendy H. K.; Thomas, Mark F.; Ren, April; Moon, Steve; Liu, Dong-Xu

    2014-03-01

    The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation in cell culture suggested that cGP promoted the activity of IGF-1 when it was insufficient, but inhibited the activity of IGF-1 when it was excessive. Mathematical modelling revealed that the efficacy of cGP was a modulated IGF-1 effect via changing the binding of IGF-1 to its binding proteins, which dynamically regulates the balance between bioavailable and non-bioavailable IGF-1. Our data reveal a novel mechanism of auto-regulation of IGF-1, which has physiological and pathophysiological consequences and potential pharmacological utility.

  18. Blood Brain Barrier and Neuroinflammation Are Critical Targets of IGF-1-Mediated Neuroprotection in Stroke for Middle-Aged Female Rats

    Science.gov (United States)

    Bake, Shameena; Selvamani, Amutha; Cherry, Jessica; Sohrabji, Farida

    2014-01-01

    Ischemia-induced cerebral infarction is more severe in older animals as compared to younger animals, and is associated with reduced availability of insulin-like growth factor (IGF)-1. This study determined the effect of post-stroke IGF-1 treatment, and used microRNA profiling to identify mechanisms underlying IGF-1’s neuroprotective actions. Post-stroke ICV administration of IGF-1 to middle-aged female rats reduced infarct volume by 39% when measured 24h later. MicroRNA analyses of ischemic tissue collected at the early post-stroke phase (4h) indicated that 8 out of 168 disease-related miRNA were significantly downregulated by IGF-1. KEGG pathway analysis implicated these miRNA in PI3K-Akt signaling, cell adhesion/ECM receptor pathways and T-and B-cell signaling. Specific components of these pathways were subsequently analyzed in vehicle and IGF-1 treated middle-aged females. Phospho-Akt was reduced by ischemia at 4h, but elevated by IGF-1 treatment at 24h. IGF-1 induced Akt activation was preceded by a reduction of blood brain barrier permeability at 4h post-stroke and global suppression of cytokines including IL-6, IL-10 and TNF-α. A subset of these cytokines including IL-6 was also suppressed by IGF-1 at 24h post-stroke. These data are the first to show that the temporal and mechanistic components of post-stroke IGF-1 treatment in older animals, and that cellular components of the blood brain barrier may serve as critical targets of IGF-1 in the aging brain. PMID:24618563

  19. Systemic analysis of different colorectal cancer cell lines and TCGA datasets identified IGF-1R/EGFR-PPAR-CASPASE axis as important indicator for radiotherapy sensitivity.

    Science.gov (United States)

    Chen, Lin; Zhu, Zhe; Gao, Wei; Jiang, Qixin; Yu, Jiangming; Fu, Chuangang

    2017-09-05

    Insulin-like growth factor 1 receptor (IGF-1R) is proved to contribute the development of many types of cancers. But, little is known about its roles in radio-resistance of colorectal cancer (CRC). Here, we demonstrated that low IGF-1R expression value was associated with the better radiotherapy sensitivity of CRC. Besides, through Quantitative Real-time PCR (qRT-PCR), the elevated expression value of epidermal growth factor receptor (EGFR) was observed in CRC cell lines (HT29, RKO) with high radio-sensitivity compared with those with low sensitivity (SW480, LOVO). The irradiation induced apoptosis rates of wild type and EGFR agonist (EGF) or IGF-1R inhibitor (NVP-ADW742) treated HT29 and SW480 cells were quantified by flow cytometry. As a result, the apoptosis rate of EGF and NVP-ADW742 treated HT29 cells was significantly higher than that of those wild type ones, which indicated that high EGFR and low IGF-1R expression level in CRC was associated with the high sensitivity to radiotherapy. We next conducted systemic bioinformatics analysis of genome-wide expression profiles of CRC samples from the Cancer Genome Atlas (TCGA). Differential expression analysis between IGF-1R and EGFR abnormal CRC samples, i.e. CRC samples with higher IGF-1R and lower EGFR expression levels based on their median expression values, and the rest of CRC samples identified potential genes contribute to radiotherapy sensitivity. Functional enrichment of analysis of those differential expression genes (DEGs) in the Database for Annotation, Visualization and Integrated Discovery (DAVID) indicated PPAR signaling pathway as an important pathway for the radio-resistance of CRC. Our study identified the potential biomarkers for the rational selection of radiotherapy for CRC patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Extraocular muscle regeneration in zebrafish requires late signals from Insulin-like growth factors.

    Science.gov (United States)

    Saera-Vila, Alfonso; Louie, Ke'ale W; Sha, Cuilee; Kelly, Ryan M; Kish, Phillip E; Kahana, Alon

    2018-01-01

    Insulin-like growth factors (Igfs) are key regulators of key biological processes such as embryonic development, growth, and tissue repair and regeneration. The role of Igf in myogenesis is well documented and, in zebrafish, promotes fin and heart regeneration. However, the mechanism of action of Igf in muscle repair and regeneration is not well understood. Using adult zebrafish extraocular muscle (EOM) regeneration as an experimental model, we show that Igf1 receptor blockage using either chemical inhibitors (BMS754807 and NVP-AEW541) or translation-blocking morpholino oligonucleotides (MOs) reduced EOM regeneration. Zebrafish EOMs regeneration depends on myocyte dedifferentiation, which is driven by early epigenetic reprogramming and requires autophagy activation and cell cycle reentry. Inhibition of Igf signaling had no effect on either autophagy activation or cell proliferation, indicating that Igf signaling was not involved in the early reprogramming steps of regeneration. Instead, blocking Igf signaling produced hypercellularity of regenerating EOMs and diminished myosin expression, resulting in lack of mature differentiated muscle fibers even many days after injury, indicating that Igf was involved in late re-differentiation steps. Although it is considered the main mediator of myogenic Igf actions, Akt activation decreased in regenerating EOMs, suggesting that alternative signaling pathways mediate Igf activity in muscle regeneration. In conclusion, Igf signaling is critical for re-differentiation of reprogrammed myoblasts during late steps of zebrafish EOM regeneration, suggesting a regulatory mechanism for determining regenerated muscle size and timing of differentiation, and a potential target for regenerative therapy.

  1. Insulin-like growth factor-1 signaling in renal cell carcinoma

    International Nuclear Information System (INIS)

    Tracz, Adam F.; Szczylik, Cezary; Porta, Camillo; Czarnecka, Anna M.

    2016-01-01

    Renal cell carcinoma (RCC) incidence is highest in highly developed countries and it is the seventh most common neoplasm diagnosed. RCC management include nephrectomy and targeted therapies. Type 1 insulin-like growth factor (IGF-1) pathway plays an important role in cell proliferation and apoptosis resistance. IGF-1 and insulin share overlapping downstream signaling pathways in normal and cancer cells. IGF-1 receptor (IGF1R) stimulation may promote malignant transformation promoting cell proliferation, dedifferentiation and inhibiting apoptosis. Clear cell renal cell carcinoma (ccRCC) patients with IGF1R overexpression have 70 % increased risk of death compared to patients who had tumors without IGF1R expression. IGF1R signaling deregulation may results in p53, WT, BRCA1, VHL loss of function. RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression. Silencing of IGF1R increase the chemosensitivity of ccRCC cells and the effect is greater in VHL mutated cells. Understanding the role of IGF-1 signaling pathway in RCC may result in development of new targeted therapeutic interventions. First preclinical attempts with anti-IGF-1R monoclonal antibodies or fragment antigen-binding (Fab) fragments alone or in combination with an mTOR inhibitor were shown to inhibit in vitro growth and reduced the number of colonies formed by of RCC cells

  2. Possible effects of insulin-like growth factor-I, IGF-binding protein-3 and IGF-1/IGFBP-3 molar ratio on mammographic density: a cross-sectional study.

    Science.gov (United States)

    Meggiorini, M L; Cipolla, V; Borgoni, G; Nofroni, I; Pala, A; de Felice, C

    2012-01-01

    The purpose of this study was to examine the possible effects of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio on mammographic density and assess whether this relationship was similar in subgroups of pre- and postmenopausal women. A group of 341 Italian women of childbearing age or naturally postmenopausal who had performed mammographic examination at the section of radiology of our department a maximum three months prior to recruitment were enrolled. A blood sample was drawn for determination of IGF-1, IGFBP-3 levels and IGF-1/IGFBP-3 molar ratio was calculated. On the basis of recent mammograms the women were divided into two groups: dense breast (DB) and non-dense breast (NDB). To assess the association between mammographic density and IGF-1, IGFBP-3 and Molar ratio Student's t-test was employed before and after stratified by menopausal status. The analysis of the relationship between mammographic density and plasma levels of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio showed that IGF-1 levels and molar ratio varied in the two groups resulting in higher mean values in the DB group whereas IGFBP-3 showed similar values in both groups (DB and NDB). After stratification of the study population by menopausal status, no association was found. Our study provides strong evidence of a crude association between breast density, and plasma levels of IGF-1 and molar ratio. IGF-1 and molar ratio might increase mammographic density and thus the risk of developing breast cancer.

  3. Salivary and serum insulin-like growth factor (IGF-1) assays in anorexic patients.

    Science.gov (United States)

    Paszynska, Elzbieta; Dmitrzak-Weglarz, Monika; Slopien, Agnieszka; Tyszkiewicz-Nwafor, Marta; Rajewski, Andrzej

    2016-12-01

    The purpose of this study was to measure the salivary and serum free IGF-1 concentration of patients with anorexia nervosa (AN) in comparison to an average population. A controlled clinical trial was designed for an age- and gender-matched group of 121 AN patients and 77 healthy individuals. A clinical examination was made and blood and salivary samples were taken during the acute stage of AN (BMI measuring free IGF-1 was used. Anorexic patients had significant reductions in salivary unstimulated flow rate (UFR), pH and free IGF-1 levels in their saliva and serum. Significant correlations between serum IGF-1 and BMI; salivary IGF-1 and UFR and pH were detected. Salivary and serum IGF-1 analyses appear to be a reliable biochemical indicator of malnutrition in AN patients. Measurement of salivary IGF-1 levels would allow new perspectives in monitoring AN in its early stages.

  4. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    International Nuclear Information System (INIS)

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A.; Gallardo-Escarate, C.; Molina, A.; Valdés, J.A.

    2015-01-01

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast

  5. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Gallardo-Escarate, C. [Laboratory of Biotechnology and Aquatic Genomics, Universidad de Concepción, Concepción (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Molina, A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Valdés, J.A., E-mail: jvaldes@unab.cl [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile)

    2015-08-21

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast.

  6. Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models.

    Science.gov (United States)

    Berryman, Darlene E; Christiansen, Jens Sandahl; Johannsson, Gudmundur; Thorner, Michael O; Kopchick, John J

    2008-12-01

    Animal models are fundamentally important in our quest to understand the genetic, epigenetic, and environmental factors that contribute to human aging. In comparison to humans, relatively short-lived mammals are useful models as they allow for rapid assessment of both genetic manipulation and environmental intervention as related to longevity. These models also allow for the study of clinically relevant pathologies as a function of aging. Data associated with more distant species offers additional insight and critical consideration of the basic physiological processes and molecular mechanisms that influence lifespan. Consistently, two interventions, caloric restriction and repression of the growth hormone (GH)/insulin-like growth factor-1/insulin axis, have been shown to increase lifespan in both invertebrates and vertebrate animal model systems. Caloric restriction (CR) is a nutrition intervention that robustly extends lifespan whether it is started early or later in life. Likewise, genes involved in the GH/IGF-1 signaling pathways can lengthen lifespan in vertebrates and invertebrates, implying evolutionary conservation of the molecular mechanisms. Specifically, insulin and insulin-like growth factor-1 (IGF-1)-like signaling and its downstream intracellular signaling molecules have been shown to be associated with lifespan in fruit flies and nematodes. More recently, mammalian models with reduced growth hormone (GH) and/or IGF-1 signaling have also been shown to have extended lifespans as compared to control siblings. Importantly, this research has also shown that these genetic alterations can keep the animals healthy and disease-free for longer periods and can alleviate specific age-related pathologies similar to what is observed for CR individuals. Thus, these mutations may not only extend lifespan but may also improve healthspan, the general health and quality of life of an organism as it ages. In this review, we will provide an overview of how the

  7. IGF-1 Protects Dopamine Neurons Against Oxidative Stress: Association with Changes in Phosphokinases

    Science.gov (United States)

    El Ayadi, Amina; Zigmond, Michael J.; Smith, Amanda D.

    2016-01-01

    Insulin-like growth factor-1 (IGF-1) is an endogenous peptide transported across the blood brain barrier that is protective in several brain injury models, including an acute animal model of Parkinson’s disease (PD). Motor deficits in PD are due largely to the progressive loss of nigrostriatal dopaminergic neurons. Thus, we examined the neuroprotective potential of IGF-1 in a progressive model of dopamine deficiency in which 6-hydroxydopamine (6-OHDA) is infused into the striatum. Rats received intrastriatal IGF-1 (5 or 50 μg) 6 hrs prior to infusion of 4 μg 6-OHDA into the same site and were sacrificed 1 or 4 wks later. Both concentrations of IGF-1 protected tyrosine hydroxylase (TH) immunoreactive terminals in striatum at 4 wks but not at 1 wk, indicating that IGF-induced restoration of the dopaminergic phenotype occurred over several weeks. TH-immunoreactive cell loss was only attenuated with 50 μg IGF-1. We then examined the effect of striatal IGF-1 on the Ras/ERK1/2 and PI3K/Akt pathways to ascertain if their activation correlated with IGF-1-induced protection. Striatal and nigral levels of phospho-ERK1/2 (pERK1/2) were maximal 6 hrs after IGF-1 infusion and, with the exception of an increase in nigral pERK2 at 48 hrs, returned to basal levels by 7 days. Phospho-Akt (Ser473) was elevated 6–24 hrs post-IGF-1 infusion in both striatum and substantia nigra concomitant with inhibition of pro-death GSK-3β, a downstream target of Akt. These results suggest that IGF-1 can protect the nigrostriatal pathway in a progressive PD model and that this protection is preceded by activation of key pro-survival signaling cascades PMID:26894890

  8. IGF-I and NEFA concentrations in fetal fluids of term pregnancy dogs.

    Science.gov (United States)

    Meloni, Tea; Comin, Antonella; Rota, Alessandro; Peric, Tanja; Contri, Alberto; Veronesi, Maria Cristina

    2014-06-01

    Insulin-like growth factor-I (IGF-I) and non-esterified fatty acids (NEFA) play an essential role in fetal growth and development. To date, fetal fluids IGF-I and NEFA levels at term canine pregnancy are unknown and could be related to the neonatal development and breed size. For these reasons, the aims of the present study were as follows: (1) to evaluate IGF-I and NEFA concentrations in fetal fluids collected from normally developed and viable newborn puppies born at term of normal pregnancies; (2) to assess possible differences between IGF-I and NEFA levels in amniotic compared with allantoic fluid; (3) to detect possible relationship between breed body size and IGF-I and NEFA amniotic and allantoic concentrations; (4) to evaluate possible differences in IGF-I fetal fluids levels between male and female puppies; and (5) to assess possible correlations between the two hormones in each type of fluid. The study enrolled 25 pure breed bitches submitted to elective Cesarean section at term because of the high risk of dystocia or previous troubles at parturition. At surgery, amniotic and allantoic fluids were collected and assayed for IGF-I and NEFA. IGF-I and NEFA amounts in both amniotic and allantoic fluids of different breed size bitches (small: ≤10 kg; medium: 11-25 kg; large: 26-40 kg) were detected, as well as the effect of gender on IGF-I levels. On a total of 73 amniotic and 76 allantoic samples collected by normal, viable, and mature newborns, the mean IGF-I concentration was significantly higher in amniotic than in allantoic fluid in all three groups, but the amniotic IGF-I levels were significantly lower in small and medium size bitches when compared with large ones. No significant differences were found in allantoic IGF-I concentrations among size groups. A significant effect of the puppy gender on IGF-I content in both fetal fluids was not reported. Regarding NEFA, in all the three groups, the mean NEFA concentration did not significantly differ

  9. Proline-rich tyrosine kinase 2 (Pyk2 regulates IGF-I-induced cell motility and invasion of urothelial carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Marco Genua

    Full Text Available The insulin-like growth factor receptor I (IGF-IR plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2 modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in bladder cancer has not been established. In this study we demonstrate that FAK was not required for IGF-IR-dependent signaling and motility of invasive urothelial carcinoma cells. On the contrary, Pyk2, which was strongly activated by IGF-I, was critical for IGF-IR-dependent motility and invasion and regulated IGF-I-dependent activation of the Akt and MAPK pathways. Using immunofluorescence and AQUA analysis we further discovered that Pyk2 was overexpressed in bladder cancer tissues as compared to normal tissue controls. Significantly, in urothelial carcinoma tissues there was increased Pyk2 localization in the nuclei as compared to normal tissue controls. These results provide the first evidence of a specific Pyk2 activity in regulating IGF-IR-dependent motility and invasion of bladder cancer cells suggesting that Pyk2 and the IGF-IR may play a critical role in the invasive phenotype in urothelial neoplasia. In addition, Pyk2 and the IGF-IR may serve as novel biomarkers with diagnostic and prognostic significance in bladder cancer.

  10. The Insulin-like Growth Factor (IGF)-I E-Peptides Modulate Cell Entry of the Mature IGF-I Protein

    OpenAIRE

    Pfeffer, Lindsay A.; Brisson, Becky K.; Lei, Hanqin; Barton, Elisabeth R.

    2009-01-01

    Insulin-like growth factor (IGF)-I is a critical protein for cell development and growth. Alternative splicing of the igf1 gene gives rise to multiple isoforms. In rodents, proIGF-IA and proIGF-IB have different carboxy-terminal extensions called the E-peptides (EA and EB) and upon further posttranslational processing, produce the identical mature IGF-I protein. Rodent EB has been reported to have mitogenic and motogenic effects independent of IGF-I. However, effects of EA or EB on mature IGF...

  11. Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays

    International Nuclear Information System (INIS)

    Bang, P.; Eriksson, U.; Wivall, I.-L.; Hall, K.; Sara, V.

    1991-01-01

    Insulin-like growth factor binding proteins interfere in the IGF-I and -II radioimmunoassays. In an attempt to overcome this problem, we have compared the use of truncated IGF-I, with reduced IGFBP affinity, and IGF-I as radioligands for IGF-I RIA measurements in serum separated by acid gel filtration or acid ethanol extraction followed by cryo-precipitation. With truncated IGF-I as radioligand the IGF-I measurements in acid gel filtrates and acid ethanol extracts were significantly correlated in healthy subjects (N=42, r=0.91, p<0.001) and in patients with acromegaly (N=10, r=0.85, p<0.01), GH deficiency (N=10, r=0.88, p<0.001) or Type I diabetes mellitus (N=10, r=0.90, p<0.001). In contrast, the IGF-I concentrations in acid ethanol extracts determined with IGF-I as radioligand did not correlate with those in acid gel filtrates using truncated IGF-I radioligand in patients with acromegaly (r=0.61, NS) or GH deficiency (r=0.46, NS). In the latter group the mean IGF-I concentrations measured in acid ethanol extracts were erroneously elevated by 112%. Low-affinity antibodies used for IGF-II RIA determinations failed to give reliable results in acid ethanol extracts from patients with Type I diabetes mellitus or GH deficiency. In conclusion, erroneously high IGF-I concentrations owing to binding of the radioligand to IGFBPs not completely removed by acid ethanol extraction can be avoided by the use of truncated IGF-I as radioligand. (author)

  12. Plasma and tissue insulin-like growth factor-I receptor (IGF-IR) as a prognostic marker for prostate cancer and anti-IGF-IR agents as novel therapeutic strategy for refractory cases: a review.

    Science.gov (United States)

    Ozkan, Emine Elif

    2011-09-15

    Cancer database analysis indicates that prostate cancer is one of the most seen cancers in men meanwhile composing the leading cause of morbidity and mortality among developed countries. Current available therapies are surgery, radiotherapy and androgene ablation for prostate carcinoma. The response rate is as high nearly 90% however, most of these recur or become refractory and androgene independent (AI). Therefore recent studies intensified on molecular factors playing role on development of prostate carcinoma and novel treatment strategies targetting these factors and their receptors. Insulin-like growth factor-I (IGF-I) and its primary receptor insulin-like growth factor receptor-I (IGF-IR) are among these factors. Biologic functions and role in malign progression are primarily achieved via IGF-IR which is a type 2 tyrosine kinase receptor. IGF-IR plays an important role in mitogenesis, angiogenesis, transformation, apoptosis and cell motility. It also generates intensive proliferative signals leading to carcinogenesis in prostate tissue. So IGF-IR and its associated signalling system have provoked considerable interest over recent years as a novel therapeutic target in cancer. In this paper it is aimed to sum up the lately published literature searching the relation of IGF-IR and prostate cancer in terms of incidence, pathologic features, and prognosis. This is followed by a discussion of the different possible targets within the IGF-1R system, and drugs developed to interact at each target. A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples: growth hormone releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH-717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417

  13. IGF-1R Promotes Symmetric Self-Renewal and Migration of Alkaline Phosphatase+ Germ Stem Cells through HIF-2α-OCT4/CXCR4 Loop under Hypoxia

    Directory of Open Access Journals (Sweden)

    Yung-Che Kuo

    2018-02-01

    Full Text Available Summary: Hypoxia cooperates with endocrine signaling to maintain the symmetric self-renewal proliferation and migration of embryonic germline stem cells (GSCs. However, the lack of an appropriate in vitro cell model has dramatically hindered the understanding of the mechanism underlying this cooperation. Here, using a serum-free system, we demonstrated that hypoxia significantly induced the GSC mesenchymal transition, increased the expression levels of the pluripotent transcription factor OCT4 and migration-associated proteins (SDF-1, CXCR4, IGF-1, and IGF-1R, and activated the cellular expression and translocalization of the CXCR4-downstream proteins ARP3/pFAK. The underlying mechanism involved significant IGF-1/IGF-1R activation of OCT4/CXCR4 expression through HIF-2α regulation. Picropodophyllin-induced inhibition of IGF-1R phosphorylation significantly suppressed hypoxia-induced SDF-1/CXCR4 expression and cell migration. Furthermore, transactivation between IGF-1R and CXCR4 was involved. In summary, we demonstrated that niche hypoxia synergistically cooperates with its associated IGF-1R signaling to regulate the symmetric division (self-renewal proliferation and cell migration of alkaline phosphatase-positive GSCs through HIF-2α-OCT4/CXCR4 during embryogenesis. : In this article, Huang and colleagues demonstrate that niche hypoxia promotes symmetric self-renewal proliferation and migration of PGC-like CD49f+AP+GSCs through IGF-IR regulation. Using a serum-free culture system, the crosstalk between IGF-1R and CXCR4 signaling was discovered. This work demonstrated that embryonic hypoxia synergistically cooperated with IGF-1R signaling to regulate the symmetric self-renewal and migration of PGC-like GSCs through a HIF-2α–OCT4/CXCR4 loop. Keywords: hypoxia, niche, germline stem cells, self-renewal, migration, IGF-1R, HIF-2α, OCT4, SDF-1, CXCR4

  14. Adipose Tissue-Derived Stem Cell Secreted IGF-1 Protects Myoblasts from the Negative Effect of Myostatin

    Directory of Open Access Journals (Sweden)

    Sebastian Gehmert

    2014-01-01

    Full Text Available Myostatin, a TGF-β family member, is associated with inhibition of muscle growth and differentiation and might interact with the IGF-1 signaling pathway. Since IGF-1 is secreted at a bioactive level by adipose tissue-derived mesenchymal stem cells (ASCs, these cells (ASCs provide a therapeutic option for Duchenne Muscular Dystrophy (DMD. But the protective effect of stem cell secreted IGF-1 on myoblast under high level of myostatin remains unclear. In the present study murine myoblasts were exposed to myostatin under presence of ASCs conditioned medium and investigated for proliferation and apoptosis. The protective effect of IGF-1 was further examined by using IGF-1 neutralizing and receptor antibodies as well as gene silencing RNAi technology. MyoD expression was detected to identify impact of IGF-1 on myoblasts differentiation when exposed to myostatin. IGF-1 was accountable for 43.6% of the antiapoptotic impact and 48.8% for the proliferative effect of ASCs conditioned medium. Furthermore, IGF-1 restored mRNA and protein MyoD expression of myoblasts under risk. Beside fusion and transdifferentiation the beneficial effect of ASCs is mediated by paracrine secreted cytokines, particularly IGF-1. The present study underlines the potential of ASCs as a therapeutic option for Duchenne muscular dystrophy and other dystrophic muscle diseases.

  15. IGF-II Promotes Stemness of Neural Restricted Precursors

    Science.gov (United States)

    Ziegler, Amber N.; Schneider, Joel S.; Qin, Mei; Tyler, William A.; Pintar, John E.; Fraidenraich, Diego; Wood, Teresa L.; Levison, Steven W.

    2016-01-01

    Insulin-like growth factor (IGF)-I and IGF-II regulate brain development and growth through the IGF type 1 receptor (IGF-1R). Less appreciated is that IGF-II, but not IGF-I, activates a splice variant of the insulin receptor (IR) known as IR-A. We hypothesized that IGF-II exerts distinct effects from IGF-I on neural stem/progenitor cells (NSPs) via its interaction with IR-A. Immunofluorescence revealed high IGF-II in the medial region of the subventricular zone (SVZ) comprising the neural stem cell niche, with IGF-II mRNA predominant in the adjacent choroid plexus. The IGF-1R and the IR isoforms were differentially expressed with IR-A predominant in the medial SVZ, whereas the IGF-1R was more abundant laterally. Similarly, IR-A was more highly expressed by NSPs, whereas the IGF-1R was more highly expressed by lineage restricted cells. In vitro, IGF-II was more potent in promoting NSP expansion than either IGF-I or standard growth medium. Limiting dilution and differentiation assays revealed that IGF-II was superior to IGF-I in promoting stemness. In vivo, NSPs propagated in IGF-II migrated to and took up residence in periventricular niches while IGF-I-treated NSPs predominantly colonized white matter. Knockdown of IR or IGF-1R using shRNAs supported the conclusion that the IGF-1R promotes progenitor proliferation, whereas the IR is important for self-renewal. Q-PCR revealed that IGF-II increased Oct4, Sox1, and FABP7 mRNA levels in NSPs. Our data support the conclusion that IGF-II promotes the self-renewal of neural stem/progenitors via the IR. By contrast, IGF-1R functions as a mitogenic receptor to increase precursor abundance. PMID:22593020

  16. IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms.

    Science.gov (United States)

    Ashpole, Nicole M; Herron, Jacquelyn C; Mitschelen, Matthew C; Farley, Julie A; Logan, Sreemathi; Yan, Han; Ungvari, Zoltan; Hodges, Erik L; Csiszar, Anna; Ikeno, Yuji; Humphrey, Mary Beth; Sonntag, William E

    2016-02-01

    Advanced aging is associated with increased risk of bone fracture, especially within the vertebrae, which exhibit significant reductions in trabecular bone structure. Aging is also associated with a reduction in circulating levels of insulin-like growth factor (IGF-1). Studies have suggested that the reduction in IGF-1 compromises healthspan, whereas others report that loss of IGF-1 is beneficial because it increases healthspan and lifespan. To date, the effect of decreases in circulating IGF-1 on vertebral bone aging has not been thoroughly investigated. Here, we delineate the consequences of a loss of circulating IGF-1 on vertebral bone aging in male and female Igf(f/f) mice. IGF-1 was reduced at multiple specific time points during the mouse lifespan: early in postnatal development (crossing albumin-cyclic recombinase [Cre] mice with Igf(f/f) mice); and in early adulthood and in late adulthood using hepatic-specific viral vectors (AAV8-TBG-Cre). Vertebrae bone structure was analyzed at 27 months of age using micro-computed tomography (μCT) and quantitative bone histomorphometry. Consistent with previous studies, both male and female mice exhibited age-related reductions in vertebral bone structure. In male mice, reduction of circulating IGF-1 induced at any age did not diminish vertebral bone loss. Interestingly, early-life loss of IGF-1 in females resulted in a 67% increase in vertebral bone volume fraction, as well as increased connectivity density and increased trabecular number. The maintenance of bone structure in the early-life IGF-1-deficient females was associated with increased osteoblast surface and an increased ratio of osteoprotegerin/receptor-activator of NF-κB-ligand (RANKL) levels in circulation. Within 3 months of a loss of IGF-1, there was a 2.2-fold increase in insulin receptor expression within the vertebral bones of our female mice, suggesting that local signaling may compensate for the loss of circulating IGF-1. Together, these data

  17. DA Negatively Regulates IGF-I Actions Implicated in Cognitive Function via Interaction of PSD95 and nNOS in Minimal Hepatic Encephalopathy.

    Science.gov (United States)

    Ding, Saidan; Zhuge, Weishan; Wang, Xuebao; Yang, Jianjing; Lin, Yuanshao; Wang, Chengde; Hu, Jiangnan; Zhuge, Qichuan

    2017-01-01

    Insulin-like growth factor I (IGF-I) has been positively correlated with cognitive ability. Cognitive decline in minimal hepatic encephalopathy (MHE) was shown to be induced by elevated intracranial dopamine (DA). The beneficial effect of IGF-I signaling in MHE remains unknown. In this study, we found that IGF-I content was reduced in MHE rats and that IGF-I administration mitigated cognitive decline of MHE rats. A protective effect of IGF-I on the DA-induced interaction between postsynaptic density protein 95 (PSD95) and neuronal nitric oxide synthase (nNOS) was found in neurons. Ribosomal S6 protein kinase (RSK) phosphorylated nNOS in response to IGF-I by recruiting extracellular signal-regulated kinase (ERK1/2). In turn, DA inactivated the ERK1/2/RSK pathway and stimulated the PSD95-nNOS interaction by downregulating IGF-I. Inhibition of the interaction between PSD95 and nNOS ameliorated DA-induced memory impairment. As DA induced deficits in the ERK1/2/RSK pathway and the interaction between PSD95 and nNOS in MHE brains, IGF-I administration exerted a protective effect via interruption of the interaction between PSD95 and nNOS. These results suggest that IGF-I antagonizes DA-induced cognitive loss by disrupting PSD95-nNOS interactions in MHE.

  18. DA Negatively Regulates IGF-I Actions Implicated in Cognitive Function via Interaction of PSD95 and nNOS in Minimal Hepatic Encephalopathy

    Directory of Open Access Journals (Sweden)

    Saidan Ding

    2017-09-01

    Full Text Available Insulin-like growth factor I (IGF-I has been positively correlated with cognitive ability. Cognitive decline in minimal hepatic encephalopathy (MHE was shown to be induced by elevated intracranial dopamine (DA. The beneficial effect of IGF-I signaling in MHE remains unknown. In this study, we found that IGF-I content was reduced in MHE rats and that IGF-I administration mitigated cognitive decline of MHE rats. A protective effect of IGF-I on the DA-induced interaction between postsynaptic density protein 95 (PSD95 and neuronal nitric oxide synthase (nNOS was found in neurons. Ribosomal S6 protein kinase (RSK phosphorylated nNOS in response to IGF-I by recruiting extracellular signal-regulated kinase (ERK1/2. In turn, DA inactivated the ERK1/2/RSK pathway and stimulated the PSD95–nNOS interaction by downregulating IGF-I. Inhibition of the interaction between PSD95 and nNOS ameliorated DA-induced memory impairment. As DA induced deficits in the ERK1/2/RSK pathway and the interaction between PSD95 and nNOS in MHE brains, IGF-I administration exerted a protective effect via interruption of the interaction between PSD95 and nNOS. These results suggest that IGF-I antagonizes DA-induced cognitive loss by disrupting PSD95–nNOS interactions in MHE.

  19. The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency.

    Science.gov (United States)

    Laron, Zvi

    2008-01-01

    Primary or secondary IGF1 deficiency has been implicated in shortening of lifespan. This paper reviews available data on the influence of IGF1 deficiency on lifespan and longevity in animals and man. It has been shown that inactivation of the IGF1 gene or of the GH receptor in both invertebrates (C-elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1 deficiency, prolong life, particularly in females. In man, evaluation of the 2 largest cohorts of patients with Laron syndrome (inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador revealed that despite their dwarfism and marked obesity, patients are alive at the ages of 75-78 years, with some having reached even more advanced ages. It is assumed that a major contributing factor is their protection from cancer, a major cause of death in the general population.

  20. IGF-II is up-regulated and myofibres are hypertrophied in regenerating soleus of mice lacking FGF6

    International Nuclear Information System (INIS)

    Armand, Anne-Sophie; Lecolle, Sylvie; Launay, Thierry; Pariset, Claude; Fiore, Frederic; Della Gaspera, Bruno; Birnbaum, Daniel; Chanoine, Christophe; Charbonnier, Frederic

    2004-01-01

    Important functions in myogenesis have been proposed for FGF6, a member of the fibroblast growth factor family accumulating almost exclusively in the myogenic lineage. However, the use of FGF6(-/-) mutant mice gave contradictory results and the role of FGF6 during myogenesis remains largely unclear. Using FGF6(-/-) mice, we first analysed the morphology of the regenerated soleus following cardiotoxin injection and showed hypertrophied myofibres in soleus of the mutant mice as compared to wild-type mice. Secondly, to examine the function of the IGF family in the hypertrophy process, we used semiquantitative and real-time RT-PCR assays and Western blots to monitor the expression of the insulin-like growth factors (IGF-I and IGF-II), their receptors [type I IGF receptor (IGF1R) and IGF-II receptor (IGF2R)], and of a binding protein IGFBP-5 in regenerating soleus muscles of FGF6(-/-) knockout mice vs. wild-type mice. In the mutant, both IGF-II and IGF2R, but not IGF-I and IGF1R, were strongly up-regulated, whereas IGFBP5 was down-regulated, strongly suggesting that, in the absence of FGF6, the mechanisms leading to myofibre hypertrophy were mediated specifically by an IGF-II/IGF2R signalling pathway distinct from the classic mechanism involving IGF-I and IGF1R previously described for skeletal muscle hypertrophy. The potential regulating role of IGFBP5 on IGF-II expression is also discussed. This report shows for the first time a specific role for FGF6 in the regulation of myofibre size during a process of in vivo myogenesis

  1. The effect of HMB ingestion on the IGF-I and IGF binding protein response to high intensity military training.

    Science.gov (United States)

    Redd, Michael J; Hoffman, Jay R; Gepner, Yftach; Stout, Jeffrey R; Hoffman, Mattan W; Ben-Dov, Daniel; Funk, Shany; Church, David D; Avital, Guy; Chen, Yacov; Frankel, Hagai; Ostfeld, Ishay

    2017-02-01

    Insulin-like growth factor-I (IGF-I) is a metabolic and anabolic biomarker that has been proposed to reflect physiological adaptations resulting from multistressor environments. The bioactivity of IGF-I is regulated by seven different insulin-like growth factor binding proteins (IGFBPs) which act not only as carriers of IGF-1, but also function as a modulator of IGF-I availability and activity. Supplementing with β-hydroxy-β-methylbutyrate (HMB) has been shown to enhance physiological outcomes associated with intense training, and has been reported to augment the IGF-1 response. The purpose of this study was to examine the effect of 23days of HMB supplementation on circulating levels of IGF-I and IGFBPs in combat soldiers during highly intense military training. Thirteen male soldiers from an elite infantry unit volunteered to participate in this double-blind, parallel design study. Soldiers were provided 3g·day -1 of either HMB (n=6) or placebo (PL; n=7). During the study soldiers performed advanced military training with periods of restricted sleep and severe environmental stressors. Blood samples were obtained prior to (PRE) and approximately 18h following the final supplement consumption (POST). No significant differences were observed for circulating IGF-1 concentrations between HMB and PL (p=0.568). In addition, no differences were seen between the groups for IGFBP-1 (p=1.000), IGFBP-2 (p=0.855), IGFBP-3 (p=0.520), IGFBP-4 (p=0.103), IGFBP-5 (p=0.886), or IGFBP-6 (p=0.775). A significant difference was noted between HMB (169.9±23.0ng·ml -1 ) and PL (207.2±28.0ng·ml -1 ) for IGFBP-7 at POST (p=0.042). Although the results of this study do not support the influence of HMB supplementation on circulating concentrations of IGF-1 or IGFBPs1-6 during high intensity military training, it does present initial evidence that it may lower circulating IGFBP-7 concentrations. This may provide some indication of a reduced stress response, but further investigation on

  2. MiR-223 suppresses cell proliferation by targeting IGF-1R.

    Directory of Open Access Journals (Sweden)

    Cheng You Jia

    Full Text Available To study the roles of microRNA-223 (miR-223 in regulation of cell growth, we established a miR-223 over-expression model in HeLa cells infected with miR-223 by Lentivirus pLL3.7 system. We observed in this model that miR-223 significantly suppressed the proliferation, growth rate, colony formation of HeLa cells in vitro, and in vivo tumorigenicity or tumor formation in nude mice. To investigate the mechanisms involved, we scanned and examined the potential and putative target molecules of miR-223 by informatics, quantitative PCR and Western blot, and found that insulin-like growth factor-1 receptor (IGF-1R was the functional target of miR-223 inhibition of cell proliferation. Targeting IGF-1R by miR-223 was not only seen in HeLa cells, but also in leukemia and hepatoma cells. The downstream pathway, Akt/mTOR/p70S6K, to which the signal was mediated by IGF-1R, was inhibited as well. The relative luciferase activity of the reporter containing wild-type 3'UTR(3'untranslated region of IGF-1R was significantly suppressed, but the mutant not. Silence of IGF-1R expression by vector-based short hairpin RNA resulted in the similar inhibition with miR-223. Contrarily, rescued IGF-1R expression in the cells that over-expressed miR-223, reversed the inhibition caused by miR-223 via introducing IGF-1R cDNA that didn't contain the 3'UTR. Meanwhile, we also noted that miR-223 targeted Rasa1, but the downstream molecules mediated by Rasa1 was neither targeted nor regulated. Therefore we believed that IGF-1R was the functional target for miR-223 suppression of cell proliferation and its downstream PI3K/Akt/mTOR/p70S6K pathway suppressed by miR-223 was by targeting IGF-1R.

  3. IGF-1R mRNA expression is increased in obese children.

    Science.gov (United States)

    Ricco, Rafaela Cristina; Ricco, Rubens Garcia; Queluz, Mariangela Carletti; de Paula, Mariana Teresa Sarti; Atique, Patricia Volpon; Custódio, Rodrigo José; Tourinho Filho, Hugo; Del Roio Liberatori, Raphael; Martinelli, Carlos Eduardo

    2018-04-01

    Obese children are often taller than age-matched subjects. Reports on GH and IGF-I levels in obese individuals are controversial, with normal and reduced GH-IGF-I levels having been reported in this group of patients. Thus, the aim of this study was to analyse insulin-like growth factor type 1 receptor (IGF-IR) mRNA expression in obese children. Forty-seven pre-pubertal children were included in this study: 29 were obese and taller than their target height, and 18 were normal eutrophic controls. Fasting blood samples were collected for IGF-IR mRNA expression in isolated lymphocytes and serum IGF-I, ALS, IGFBP-3, and IGFBP-1 concentration analysis. Relative IGF-IR gene expression (2 -ΔΔCT ) was significantly (P=0.025) higher in obese children (median 1.87) than in controls (1.15). Fourteen of the 29 obese subjects showed 2 -ΔΔCT values greater than or equal to 2, while only 2 individuals in the control group showed values above 2 (P=0.01). Obese children showed significantly (P=0.01) higher IGF-I concentrations than the control group (237ng/ml and 144ng/ml, respectively). Among obese patients, 65.5% had IGF-I values above the 75 percentile of the control group (P=0.02). ALS concentration was significantly (P=0.04) higher in the obese group, while IGFBP-3 levels were similar in obese and control children. IGFBP-1 concentration was lower in obese children, while insulin levels and HOMA-IR index were higher than in controls. The higher IGF-IR mRNA expression observed in obese children, associated with the higher IGF-I and ALS and the lower IGFBP-1 levels, suggest that the higher stature observed in these children may be due to increased IGF-I bioactivity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Synergistic effect of DHT and IGF-1 hyperstimulation in human peripheral blood lymphocytes.

    Science.gov (United States)

    Imperlini, Esther; Spaziani, Sara; Mancini, Annamaria; Caterino, Marianna; Buono, Pasqualina; Orrù, Stefania

    2015-06-01

    The abuse of mixed or combined performance-enhancing drugs is widespread among athletes and amateurs, adults and adolescents. Clinical studies demonstrated that misuse of these doping agents is associated with serious adverse effects to many organs in human. Previously, we demonstrated in human peripheral blood lymphocytes that high doses of anabolic androgenic steroids, such as dihydrotestosterone (DHT) and growth factors, such as insulin-like growth factor-1 (IGF-1), have effects at gene and protein levels. Supraphysiological treatments of DHT and IGF-1 affected the expression of genes involved in skeletal muscle disorders as well as in cell-mediated immunological response. At protein level, DHT hyperdosage affects cell motility and apoptosis; IGF-1 hyperstimulation triggers an active cytoskeletal reorganization and an overproduction of immune response- and inflammation-related cytokines. In this study, we investigate the combined effects of DHT and IGF-1 hyperdosage in peripheral blood lymphocytes using a differential proteomic approach. DHT and IGF-1 combined treatment affects cell adhesion, migration, and survival through modulation of expression levels of cytokines and paxillin-signaling-related proteins, and activation of several pathways downstream focal adhesion kinase. Our results indicate a synergistic effect of DHT and IGF-1 which has potential implications for health risk factors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Research resource: new and diverse substrates for the insulin receptor isoform a revealed by quantitative proteomics after stimulation with igf-ii or insulin

    DEFF Research Database (Denmark)

    Morcavallo, Alaide; Gaspari, Marco; Pandini, Giuseppe

    2011-01-01

    progression. We hypothesized that IGF-II binding to the IR-A elicits a unique signaling pathway. In order to obtain an unbiased evaluation of IR-A substrates differentially involved after IGF-II and insulin stimulation, we performed quantitative proteomics of IR-A substrates recruited to tyrosine......-phosphorylated protein complexes using stable isotope labeling with amino acids in cell culture in combination with antiphosphotyrosine antibody pull down and mass spectrometry. Using cells expressing only the human IR-A and lacking the IGF-I receptor, we identified 38 IR-A substrates. Only 10 were known IR mediators......, whereas 28 substrates were not previously related to IR signaling. Eleven substrates were recruited by stimulation with both ligands: two equally recruited by IGF-II and insulin, three more strongly recruited by IGF-II, and six more strongly recruited by insulin. Moreover, 14 substrates were recruited...

  6. Serum IGF-1, IGFBP-3 and their ratio: Potential biochemical growth maturity indicators.

    Science.gov (United States)

    Jain, Nimisha; Tripathi, Tulika; Gupta, S K; Rai, Priyank; Kanase, Anup; Kalra, Shilpa

    2017-12-01

    Determination of skeletal maturation and remaining growth potential is an essential part of treatment planning in orthodontics. The aim of our study was to determine the relationship between IGF-1 levels, IGFBP-3 levels with CVM staging to track the pre pubertal and pubertal growth spurts in female patients in North Indian population. This cross-sectional study was conducted on ninety female subjects in the age group of 8-20 years. Blood samples were collected and centrifuged and serum samples were then analysed by Human IGF-1 and IGFBP-3 enzyme-linked immunosorbent assay kits, specific for IGF-1 and IGFBP-3, respectively. CVM staging on lateral cephalometric radiograph was determined for all patients. Analysis of variance test followed by a post hoc test was used to compare mean IGF-1 and IGFBP-3 corresponding to six stages of cervical vertebrae maturation stages. Linear Pearson's correlations were performed to determine the trends of IGF-1, IGFBP-3, and its ratio relating to CVM stage. The kappa statistic was used to measure inter and intra examiner reliability. P value IGF-1 levels were found to be highest (403.3 ± 12.3 ng/ml) at CVMI3 stage of CVMI. The post-hoc test revealed a significant difference in IGF-1 levels between all stages of CVMI, thereby indicating a specific range of IGF-1 levels for a specific skeletal stage. Mean serum IGFBP-3 levels were found to be highest (5186.8 ± 1384.2 ng/ml) at CVMI4 stage of CVMI. The mean serum IGFBP-3 levels at CVMI4 were found to be significantly higher than the levels at all other CVMI stages except CVMI3 stage. IGF-1 and IGFBP-3 can serve as a potential biochemical indicator for assessment of skeletal maturity.

  7. A role for IGF-1R-targeted therapies in small-cell lung cancer?

    LENUS (Irish Health Repository)

    Gately, Kathy

    2012-02-01

    BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive disease with a poor prognosis. The insulin-like growth factor-1 receptor (IGF-1R) is an autocrine growth factor and an attractive therapeutic target in many solid tumors, but particularly in lung cancer. PATIENTS AND METHODS: This study examined tumor samples from 23 patients diagnosed with SCLC, 11 resected specimens and 12 nodal biopsies obtained by mediastinoscopy, for expression of IGF-1R using the monoclonal rabbit anti-IGF-1R (clone G11, Ventana Medical Systems, Tucson, AZ) and standard immunohistochemistry (IHC). RESULTS: All 23 tumor samples expressed IGF-1R with a range of stain intensity from weak (1+) to strong (3+). Ten tumors had a score of 3+, 7 tumors 2+, and 6 tumors 1+. Patient survival data were available for all 23 patients. Two patients died < 30 days post biopsy, therefore, the intensity of anti-IGF-1R immunostaining for 21 patients was correlated to survival. Patients with 3+ immunostaining had a poorer prognosis (P = .003). The overall survival of patients who underwent surgical resection was significantly better (median survival not reached) than patients who were not resected (median survival, 7.4 months) (P = .006). CONCLUSION: IGF-1R targeted therapies may have a role in the treatment of SCLC in combination with chemotherapy or as maintenance therapy. Further studies on the clinical benefit of targeting IGF-1R in SCLC are needed.

  8. Insulin-like growth factor-1 (IGF-1) promotes primordial follicle growth and reduces DNA fragmentation through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signalling pathway.

    Science.gov (United States)

    Bezerra, Maria É S; Barberino, Ricássio S; Menezes, Vanúzia G; Gouveia, Bruna B; Macedo, Taís J S; Santos, Jamile M S; Monte, Alane P O; Barros, Vanessa R P; Matos, Maria H T

    2018-05-30

    We investigated the effects of insulin-like growth factor 1 (IGF-1) on the morphology and follicular activation of ovine preantral follicles cultured in situ and whether the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is involved in IGF-1 action in the sheep ovary. Ovine ovarian fragments were fixed for histological and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) analyses (fresh control) or cultured in supplemented alpha-minimum essential medium (α-MEM+; control) or α-MEM+ with IGF-1 (1, 10, 50, 100 or 200ngmL-1) for 7 days. Follicles were classified as normal or atretic, primordial or growing and the oocyte and follicle diameters were measured. DNA fragmentation was evaluated by TUNEL assay. Proliferating cell nuclear antigen (PCNA) immunohistochemistry was performed on the fresh control, α-MEM+ and 100ngmL-1 IGF-1 samples. Inhibition of PI3K activity was performed through pretreatment with the PI3K inhibitor LY294002 and phosphorylated AKT (pAKT) expression was analysed after culture in the absence or presence of LY294002. IGF-1 at 100ngmL-1 increased (PIGF-1. LY294002 significantly inhibited follicular activation stimulated by α-MEM+ and 100ngmL-1 IGF-1 and reduced pAKT expression in follicles. Overall, IGF-1 at 100ngmL-1 promoted primordial follicle activation, cell proliferation and reduced DNA fragmentation after in situ culture through the PI3K/AKT pathway.

  9. Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production.

    Science.gov (United States)

    Courtland, Hayden-William; Sun, Hui; Beth-On, Mordechay; Wu, Yingjie; Elis, Sebastien; Rosen, Clifford J; Yakar, Shoshana

    2011-04-01

    Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effects of endocrine (serum) IGF-1 from autocrine/paracrine IGF-1. However, LID mice also have two- to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF-1 levels (but normal tissue IGF-1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF-1 levels by 8 weeks of age, compared with the mean values of vehicle-treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle-treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF-1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole-bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF-1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions. Copyright © 2011 American Society for

  10. Imp2 regulates GBM progression by activating IGF2/PI3K/Akt pathway.

    Science.gov (United States)

    Mu, Qingchun; Wang, Lijun; Yu, Fengbo; Gao, Haijun; Lei, Ting; Li, Peiwen; Liu, Pengfei; Zheng, Xu; Hu, Xitong; Chen, Yong; Jiang, Zhenfeng; Sayari, Arash J; Shen, Jia; Huang, Haiyan

    2015-01-01

    Glioblastomas multiforme (GBM) are the most frequently occurring malignant brain cancers. Treatment for GBM consists of surgical resection and subsequent adjuvant radiation therapy and chemotherapy. Despite this, GBM patient survival is limited to 12-15 months, and researchers are continually trying to develop improved therapy options. Insulin-like growth factor 2 mRNA-binding protein 2 (Imp2) is known to be upregulated in many cancers and is known to regulate the signaling activity of insulin-like growth factor 2 (IGF2). However, relatively little is known about its role in malignant development of GBM. In this study, we first found Imp2 is upregulated in GBM tissues by using clinical samples and public database search. Studies with loss and gain of Imp2 expression in in vitro GBM cell culture system demonstrated the role of Imp2 in promoting GBM cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT). Additionally, our results show that Imp2 regulates the activity of IGF2, which further activates PI3K/Akt signaling, thereby to promote GBM malignancy. Inhibition of Imp2 was also found to sensitize GBM to temozolomide treatment. These observations add to the current knowledge of GBM biology, and may prove useful in development of more effective GBM therapy.

  11. Bioactive insulin-like growth factor (IGF) I and IGF-binding protein-1 in anorexia nervosa

    DEFF Research Database (Denmark)

    Støving, René; Chen, Jian-Wen; Glintborg, Dorte

    2007-01-01

    CONTEXT: Regulation of IGF-I activity appears crucial in anorexia nervosa (AN) during adaptation to chronic starvation as well as during the regenerative processes on nutritional restoration. OBJECTIVE: The objective of this study was to examine the relationship between IGF-I bioactivity and IGF...

  12. Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila.

    Directory of Open Access Journals (Sweden)

    Hua Bai

    2013-11-01

    Full Text Available Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling.

  13. Unbound (bioavailable IGF1 enhances somatic growth

    Directory of Open Access Journals (Sweden)

    Sebastien Elis

    2011-09-01

    Understanding insulin-like growth factor-1 (IGF1 biology is of particular importance because, apart from its role in mediating growth, it plays key roles in cellular transformation, organ regeneration, immune function, development of the musculoskeletal system and aging. IGF1 bioactivity is modulated by its binding to IGF-binding proteins (IGFBPs and the acid labile subunit (ALS, which are present in serum and tissues. To determine whether IGF1 binding to IGFBPs is necessary to facilitate normal growth and development, we used a gene-targeting approach and generated two novel knock-in mouse models of mutated IGF1, in which the native Igf1 gene was replaced by Des-Igf1 (KID mice or R3-Igf1 (KIR mice. The KID and KIR mutant proteins have reduced affinity for the IGFBPs, and therefore present as unbound IGF1, or ‘free IGF1’. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels. Ternary complex formation of IGF1 with the IGFBPs and the ALS was markedly reduced in sera from KID and KIR mice compared with wild type. Both mutant mice showed increased body weight, body and bone lengths, and relative lean mass. We found selective organomegaly of the spleen, kidneys and uterus, enhanced mammary gland complexity, and increased skeletal acquisition. The KID and KIR models show unequivocally that IGF1-complex formation with the IGFBPs is fundamental for establishing normal body and organ size, and that uncontrolled IGF bioactivity could lead to pathological conditions.

  14. IGF-1 prevents ANG II-induced skeletal muscle atrophy via Akt- and Foxo-dependent inhibition of the ubiquitin ligase atrogin-1 expression

    Science.gov (United States)

    Yoshida, Tadashi; Semprun-Prieto, Laura; Sukhanov, Sergiy

    2010-01-01

    Congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. Angiotensin II (ANG II) has been shown to increase muscle proteolysis and decrease circulating and skeletal muscle IGF-1. We have shown previously that skeletal muscle-specific overexpression of IGF-1 prevents proteolysis and apoptosis induced by ANG II. These findings indicated that downregulation of IGF-1 signaling in skeletal muscle played an important role in the wasting effect of ANG II. However, the signaling pathways and mechanisms whereby IGF-1 prevents ANG II-induced skeletal muscle atrophy are unknown. Here we show ANG II-induced transcriptional regulation of two ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1) that precedes the reduction of skeletal muscle IGF-1 expression, suggesting that activation of atrogin-1 and MuRF-1 is an initial mechanism leading to skeletal muscle atrophy in response to ANG II. IGF-1 overexpression in skeletal muscle prevented ANG II-induced skeletal muscle wasting and the expression of atrogin-1, but not MuRF-1. Dominant-negative Akt and constitutively active Foxo-1 blocked the ability of IGF-1 to prevent ANG II-mediated upregulation of atrogin-1 and skeletal muscle wasting. Our findings demonstrate that the ability of IGF-1 to prevent ANG II-induced skeletal muscle wasting is mediated via an Akt- and Foxo-1-dependent signaling pathway that results in inhibition of atrogin-1 but not MuRF-1 expression. These data suggest strongly that atrogin-1 plays a critical role in mechanisms of ANG II-induced wasting in vivo. PMID:20228261

  15. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1

    OpenAIRE

    Guan, Jian; Gluckman, Peter; Yang, Panzao; Krissansen, Geoff; Sun, Xueying; Zhou, Yongzhi; Wen, Jingyuan; Phillips, Gemma; Shorten, Paul R.; McMahon, Chris D.; Wake, Graeme C.; Chan, Wendy H. K.; Thomas, Mark F.; Ren, April; Moon, Steve

    2014-01-01

    The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation ...

  16. Involvement of IGF-1 and MEOX2 in PI3K/Akt1/2 and ERK1/2 pathways mediated proliferation and differentiation of perivascular adipocytes.

    Science.gov (United States)

    Liu, Ping; Kong, Feng; Wang, Jue; Lu, Qinghua; Xu, Haijia; Qi, Tonggang; Meng, Juan

    2015-02-01

    Perivascular adipocyte (PVAC) proliferation and differentiation were closely involved in cardiovascular disease. We aimed to investigate whether phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways enhance PVAC functions activated by insulin-like growth factor 1(IGF-1) and suppressed by mesenchyme homeobox 2 (MEOX2). In this study, PVACs from primary culture were cultured and induced to differentiate. Cell viability assays demonstrated that IGF-1 promoted PVAC proliferation and differentiation. However MEOX2 counteracted these IGF-1-mediated actions. Flow Cytometry revealed that IGF-1 increased S phase cells and decreased apoptosis; however, MEOX2 decreased S phase cells, increased G0-G1 phase cells, and promoted apoptosis. During PVAC proliferation and differentiation, IGF-1 activated PI3K/Akt1/2 and ERK1/2 signaling pathways, upregulated the expression of these signaling proteins and FAS, and increased PVAC lipid content. In contrast, MEOX2 constrained the phosphorylation of ERK1/2 and Akt1/2 protein, down-regulated these signaling molecules and FAS, and decreased PVAC lipid content. Instead, MEOX2 knockdown enhanced the ERK1/2 and Akt1/2 phosphorylation, augmented the expression of these signaling molecules and FAS, and increased PVAC lipid content. Our findings suggested that PI3K/Akt1/2 and ERK1/2 activation mediated by IGF-1 is essential for PVAC proliferation and differentiation, and MEOX2 is a promising therapeutic gene to intervene in the signaling pathways and inhibit PVAC functions. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Regulation of insulin-like growth factor (IGF) I receptor expression during muscle cell differentiation. Potential autocrine role of IGF-II.

    OpenAIRE

    Rosenthal, S M; Brunetti, A; Brown, E J; Mamula, P W; Goldfine, I D

    1991-01-01

    Muscle is an important target tissue for insulin-like growth factor (IGF) action. The presence of specific, high affinity IGF receptors, as well as the expression of IGF peptides and binding proteins by muscle suggest that a significant component of IGF action in this tissue is mediated through autocrine and/or paracrine mechanisms. To explore autocrine/paracrine action of IGFs in muscle, we studied the regulation of the IGF-I receptor and the expression of IGF peptides during differentiation...

  18. Let-7b Regulates Myoblast Proliferation by Inhibiting IGF2BP3 Expression in Dwarf and Normal Chicken

    Science.gov (United States)

    Lin, Shumao; Luo, Wen; Ye, Yaqiong; Bekele, Endashaw J.; Nie, Qinghua; Li, Yugu; Zhang, Xiquan

    2017-01-01

    The sex-linked dwarf chicken is caused by the mutation of growth hormone receptor (GHR) gene and characterized by shorter shanks, lower body weight, smaller muscle fiber diameter and fewer muscle fiber number. However, the precise regulatory pathways that lead to the inhibition of skeletal muscle growth in dwarf chickens still remain unclear. Here we found a let-7b mediated pathway might play important role in the regulation of dwarf chicken skeletal muscle growth. Let-7b has higher expression in the skeletal muscle of dwarf chicken than in normal chicken, and the expression of insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which is a translational activator of IGF2, showed opposite expression trend to let-7b. In vitro cellular assays validated that let-7b directly inhibits IGF2BP3 expression through binding to its 3′UTR region, and the protein level but not mRNA level of IGF2 would be reduced in let-7b overexpressed chicken myoblast. Let-7b can inhibit cell proliferation and induce cell cycle arrest in chicken myoblast through let-7b-IGF2BP3-IGF2 signaling pathway. Additionally, let-7b can also regulate skeletal muscle growth through let-7b-GHR-GHR downstream genes pathway, but this pathway is non-existent in dwarf chicken because of the deletion mutation of GHR 3′UTR. Notably, as the loss binding site of GHR for let-7b, let-7b has enhanced its binding and inhibition on IGF2BP3 in dwarf myoblast, suggesting that the miRNA can balance its inhibiting effect through dynamic regulate its binding to target genes. Collectively, these results not only indicate that let-7b can inhibit skeletal muscle growth through let-7b-IGF2BP3-IGF2 signaling pathway, but also show that let-7b regulates myoblast proliferation by inhibiting IGF2BP3 expression in dwarf and normal chickens. PMID:28736533

  19. Early programming of the IGF-I axis

    DEFF Research Database (Denmark)

    Larnkjær, Anni; Ingstrup, Helga Kristensen; Schack-Nielsen, Lene

    2009-01-01

    -I production. Conversely, studies suggest that later in childhood, those breastfed are taller and have higher IGF-I levels. Therefore, it has been suggested that the IGF-I axis may be programmed by diet during infancy. The association between IGF-I in infancy and later life is not known. OBJECTIVE: To examine...... for gender, breastfeeding, and other covariates. Likelihood ratio test based on residual log likelihood was applied for analysis including all measurements during infancy. RESULTS: There was an inverse association between IGF-I at 9 months and 17 years (r=-0.39, P=0.014, and n=40). A 1 ng/ml higher IGF...... covariates except IGF-I at 2 months which was significantly negatively associated with IGF-I at 17 years (P=0.030) corresponding to a 0.96 ng/ml lower IGF-I concentration at 17 years per ng/ml IGF-I at 2 months. Inclusion of all measurements during infancy showed a negative association with 17-year values (r...

  20. Comparisons of mRNA expression for insulin-like growth factor (IGF) type 2 receptor (IGF2R) and IGF-1 in small ovarian follicles between cattle selected and not selected for twin ovulations

    Science.gov (United States)

    Both IGF-1 and -2 stimulate ovarian follicular cell proliferation and antral follicle development. Actions of IGF-1 and -2 are mediated through the IGF type 1 receptor, whereas binding of IGF-2 to the IGF2R results in its degradation. Information on the role of IGF2R in regulating bovine follicula...

  1. IGF-1 and insulin as growth hormones.

    Science.gov (United States)

    Laron, Zvi

    2004-01-01

    IGF-1 generated in the liver is the anabolic effector and linear growth promoting hormone of the pituitary growth hormone (GH). This is evidenced by dwarfism in states of congenital IGF-1 deficiency, Igf1 gene mutation/deletions or knockouts, and in Laron syndrome (LS), due to GH receptor gene mutations/deletions or IGF-1 receptor blocking. In a positive way, daily IGF-1 administration to stunted patients with LS or hGH gene deletion accelerates linear growth velocity. IGF-1 acts on the proliferative cells of the epiphyseal cartilage. IGF-1 also induces organ and tissue growth; its absence causing organomicria. Insulin shares a common ancestry with IGF-1 and with 45% amino acid homology, as well as very close relationships in the structure of its receptors and post-receptor cascade, also acts as a growth hormone. It has protein anabolic activity and stimulates IGF-1 synthesis. Pancreas agenesis causes short babies, and obese children with hyperinsulinism, with or without pituitary GH, have an accelerated growth rate and skeletal maturation; so do babies with macrosomia. Whether the insulin growth effect is direct, or mediated by IGF-1 or leptin is controversial.

  2. Platycodon grandiflorum (PG) reverses angiotensin II-induced apoptosis by repressing IGF-IIR expression.

    Science.gov (United States)

    Lin, Yuan-Chuan; Lin, Chih-Hsueh; Yao, Hsien-Tsung; Kuo, Wei-Wen; Shen, Chia-Yao; Yeh, Yu-Lan; Ho, Tsung-Jung; Padma, V Vijaya; Lin, Yu-Chen; Huang, Chih-Yang; Huang, Chih-Yang

    2017-06-09

    Platycodon grandiflorum (PG) is a Chinese medical plant used for decades as a traditional prescription to eliminate phlegm, relieve cough, reduce inflammation and lower blood pressure. PG also has a significant effect on the cardiovascular systems. The aqueous extract of Platycodon grandiflorum (JACQ.) A. DC. root was screened for inhibiting Ang II-induced IGF-IIR activation and apoptosis pathway in H9c2 cardiomyocytes. The effects were also studied in spontaneously hypertensive rats (five groups, n=5) using low and high doses of PG for 50 days. The Ang II-induced IGF-IIR activation was analyzed by luciferase reporter, RT-PCR, western blot and surface IGF-IIR expression assay. Furthermore, the major active constituent of PG was carried out by high performance liquid chromatography-mass spectrometry (HPLC-MS). Our results indicate that a crude extract of PG significantly suppresses the Ang II-induced IGF-IIR signaling pathway to prevent cardiomyocyte apoptosis. PG extract inhibits Ang II-mediated JNK activation and SIRT1 degradation to reduce IGF-IIR activity. Moreover, PG maintains SIRT1 stability to enhance HSF1-mediated IGF-IIR suppression, which prevents cardiomyocyte apoptosis. In animal models, the administration of PG markedly reduced this apoptotic pathway in the heart of SHRs. Taken together, PG may be considered as an effective treatment for cardiac diseases in hypertensive patients. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  3. Involvement of IGF-1 and MEOX2 in PI3K/Akt1/2 and ERK1/2 pathways mediated proliferation and differentiation of perivascular adipocytes

    International Nuclear Information System (INIS)

    Liu, Ping; Kong, Feng; Wang, Jue; Lu, Qinghua; Xu, Haijia; Qi, Tonggang; Meng, Juan

    2015-01-01

    Perivascular adipocyte (PVAC) proliferation and differentiation were closely involved in cardiovascular disease. We aimed to investigate whether phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways enhance PVAC functions activated by insulin-like growth factor 1(IGF-1) and suppressed by mesenchyme homeobox 2 (MEOX2). In this study, PVACs from primary culture were cultured and induced to differentiate. Cell viability assays demonstrated that IGF-1 promoted PVAC proliferation and differentiation. However MEOX2 counteracted these IGF-1-mediated actions. Flow Cytometry revealed that IGF-1 increased S phase cells and decreased apoptosis; however, MEOX2 decreased S phase cells, increased G0–G1 phase cells, and promoted apoptosis. During PVAC proliferation and differentiation, IGF-1 activated PI3K/Akt1/2 and ERK1/2 signaling pathways, upregulated the expression of these signaling proteins and FAS, and increased PVAC lipid content. In contrast, MEOX2 constrained the phosphorylation of ERK1/2 and Akt1/2 protein, down-regulated these signaling molecules and FAS, and decreased PVAC lipid content. Instead, MEOX2 knockdown enhanced the ERK1/2 and Akt1/2 phosphorylation, augmented the expression of these signaling molecules and FAS, and increased PVAC lipid content. Our findings suggested that PI3K/Akt1/2 and ERK1/2 activation mediated by IGF-1 is essential for PVAC proliferation and differentiation, and MEOX2 is a promising therapeutic gene to intervene in the signaling pathways and inhibit PVAC functions. - Highlights: • IGF-1 activated PI3K/Akt2 and ERK1/2 pathways to mediate PVAC proliferation and differentiation. • The expression of ERK1, ERK 2, PI3K, Akt1 and Akt2 showed different change trends between PVAC proliferation and differentiation. • MEOX2 effectively expressed in PVAC, increased early and late cellular apoptosis, and inhibited its proliferation. • MEOX2 depressed PVAC differentiation and FAS expression

  4. Involvement of IGF-1 and MEOX2 in PI3K/Akt1/2 and ERK1/2 pathways mediated proliferation and differentiation of perivascular adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Ping, E-mail: lping@sdu.edu.cn [Department of Cardiology, The Second Hospital of Shandong University, No. 247, Beiyuan Road, Shandong, Jinan 250033 (China); Kong, Feng; Wang, Jue [Central Laboratory, The Second Hospital of Shandong University, Shandong, Jinan 250033 (China); Lu, Qinghua [Department of Cardiology, The Second Hospital of Shandong University, No. 247, Beiyuan Road, Shandong, Jinan 250033 (China); Xu, Haijia [Department of Cardiology, Wendeng Central Hospital of Weihai City, Shandong, Weihai 264400 (China); Qi, Tonggang [Central Laboratory, The Second Hospital of Shandong University, Shandong, Jinan 250033 (China); Meng, Juan [Department of Cardiology, The Second Hospital of Shandong University, No. 247, Beiyuan Road, Shandong, Jinan 250033 (China)

    2015-02-01

    Perivascular adipocyte (PVAC) proliferation and differentiation were closely involved in cardiovascular disease. We aimed to investigate whether phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways enhance PVAC functions activated by insulin-like growth factor 1(IGF-1) and suppressed by mesenchyme homeobox 2 (MEOX2). In this study, PVACs from primary culture were cultured and induced to differentiate. Cell viability assays demonstrated that IGF-1 promoted PVAC proliferation and differentiation. However MEOX2 counteracted these IGF-1-mediated actions. Flow Cytometry revealed that IGF-1 increased S phase cells and decreased apoptosis; however, MEOX2 decreased S phase cells, increased G0–G1 phase cells, and promoted apoptosis. During PVAC proliferation and differentiation, IGF-1 activated PI3K/Akt1/2 and ERK1/2 signaling pathways, upregulated the expression of these signaling proteins and FAS, and increased PVAC lipid content. In contrast, MEOX2 constrained the phosphorylation of ERK1/2 and Akt1/2 protein, down-regulated these signaling molecules and FAS, and decreased PVAC lipid content. Instead, MEOX2 knockdown enhanced the ERK1/2 and Akt1/2 phosphorylation, augmented the expression of these signaling molecules and FAS, and increased PVAC lipid content. Our findings suggested that PI3K/Akt1/2 and ERK1/2 activation mediated by IGF-1 is essential for PVAC proliferation and differentiation, and MEOX2 is a promising therapeutic gene to intervene in the signaling pathways and inhibit PVAC functions. - Highlights: • IGF-1 activated PI3K/Akt2 and ERK1/2 pathways to mediate PVAC proliferation and differentiation. • The expression of ERK1, ERK 2, PI3K, Akt1 and Akt2 showed different change trends between PVAC proliferation and differentiation. • MEOX2 effectively expressed in PVAC, increased early and late cellular apoptosis, and inhibited its proliferation. • MEOX2 depressed PVAC differentiation and FAS expression

  5. Favorable prognostic value of SOCS2 and IGF-I in breast cancer

    International Nuclear Information System (INIS)

    Haffner, Michael C; Petridou, Barbara; Peyrat, Jean Phillipe; Révillion, Françoise; Müller-Holzner, Elisabeth; Daxenbichler, Günter; Marth, Christian; Doppler, Wolfgang

    2007-01-01

    Suppressor of cytokine signaling (SOCS) proteins comprise a protein family, which has initially been described as STAT induced inhibitors of the Jak/Stat pathway. Recent in vivo and in vitro studies suggest that SOCS proteins are also implicated in cancer. The STAT5 induced IGF-I acts as an endocrine and para/autocrine growth and differentiation factor in mammary gland development. Whereas high levels of circulating IGF-I have been associated with increased cancer risk, the role of autocrine acting IGF-I is less clear. The present study is aimed to elucidate the clinicopathological features associated with SOCS1, SOCS2, SOCS3, CIS and IGF-I expression in breast cancer. We determined the mRNA expression levels of SOCS1, SOCS2, SOCS3, CIS and IGF-I in 89 primary breast cancers by reverse transcriptase PCR. SOCS2 protein expression was further evaluated by immuno-blot and immunohistochemistry. SOCS2 expression inversely correlated with histopathological grade and ER positive tumors exhibited higher SOCS2 levels. Patients with high SOCS2 expression lived significantly longer (108.7 vs. 77.7 months; P = 0.015) and high SOCS2 expression proved to be an independent predictor for good prognosis (HR = 0.45, 95% CI 0.23 – 0.91, P = 0.026). In analogy to SOCS2, high IGF-I expression was an independent predictor for good prognosis in the entire patient cohort. In the subgroup of patients with lymph-node negative disease, high IGF-I was a strong predictor for favorable outcome in terms of overall survival and relapse free survival (HR = 0.075, 95% CI 0.014 – 0.388, P = 0.002). This is the first report on the favorable prognostic value of high SOCS2 expression in primary mammary carcinomas. Furthermore a strong association of high IGF-I expression levels with good prognosis was observed especially in lymph-node negative patients. Our results suggest that high expression of the STAT5 target genes SOCS2 and IGF-I is a feature of differentiated and less malignant tumors

  6. Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes

    NARCIS (Netherlands)

    Zhang, Y.; Moerkens, M.; Ramaiahgari, S.; Bont, de H.J.G.M.; Price, L.; Meerman, J.H.N.; Water, van de B.

    2011-01-01

    INTRODUCTION: Insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) is phosphorylated in all breast cancer subtypes. Past findings have shown that IGF-1R mediates antiestrogen resistance through cross-talk with estrogen receptor (ER) signaling and via its action upstream of the epidermal growth

  7. Insulin/IGF signaling-related gene expression in the brain of a sporadic Alzheimer's disease monkey model induced by intracerebroventricular injection of streptozotocin.

    Science.gov (United States)

    Lee, Youngjeon; Kim, Young-Hyun; Park, Sang-Je; Huh, Jae-Won; Kim, Sang-Hyun; Kim, Sun-Uk; Kim, Ji-Su; Jeong, Kang-Jin; Lee, Kyoung-Min; Hong, Yonggeun; Lee, Sang-Rae; Chang, Kyu-Tae

    2014-01-01

    We reported previously that the intracerebroventricular streptozotocin (icv-STZ)-treated cynomolgus monkey showed regionally specific glucose hypometabolism in FDG-PET imaging, similar to that observed in the early stages of sporadic Alzheimer's disease (sAD). However, further pathological analyses of this model at the molecular level are needed to validate it as a feasible model for sAD. Two cynomolgus monkeys were injected with 2 mg/kg STZ into the cerebellomedullary cistern at day 1, 7 and 14. Two control monkeys were given normal saline. At 5 months after injection, the expression levels of genes encoding 9 upstream molecules in insulin/insulin-like growth factor (IGF) signaling and markers for 4 cell-type populations in the frontal cortex, hippocampus, posterior cingulate, precuneus, and occipital cortex of control and icv-STZ treated cynomolgus monkeys were examined. Real-time quantitative PCR analyses demonstrated that the overall mRNA expression of insulin/IGF signaling-related genes was mainly impaired in the anterior part of the cerebrum, frontal cortex, and hippocampus, similar to the early stage of sAD. The changes were accompanied by the loss of oligodendrocytes and neurons. The posterior part of the cerebrum did not show degenerative alterations. The present study provides important fundamental information on the icv-STZ monkey model for sAD. These results may help guide future studies using this model for the investigation of pathological mechanisms and the development of drugs for sAD.

  8. Genetic and Dietary Determinants of Insulin-Like Growth Factor (IGF)-1 and IGF Binding Protein (BP)-3 Levels among Chinese Women

    Science.gov (United States)

    Li, Hui; McCullough, Lauren E.; Qi, Ya-na; Li, Jia-yuan; Zhang, Jing; Miller, Erline; Yang, Chun-xia; Smith, Jennifer S.

    2014-01-01

    Background Higher insulin-like growth factor (IGF)-1 and lower IGF binding protein (BP)-3 levels have been associated with higher commoncancer risk, including breast cancer. Dietary factors, genetic polymorphisms, and the combination of both may influence circulating IGF-1 and IGFBP-3 serum concentrations. Methods From September 2011 to July 2012, we collected demographic, reproductive and dietary data on 143 women (≥40 years). We genotyped IGF-1 rs1520220 and IGFBP-3 rs2854744 and measured circulating IGF-1 and IGFBP-3 levels in serum. Covariance analyses were used to estimate the associations of serum levels of IGF-1 and IGFBP-3, and the molar ratio of IGF-1to IGFBP-3 with IGF-1 rs1520220 and IGFBP-3 rs2854744 genotypes. We subsequently assessed the combined influence of genetics and diet (daily intake of protein, fat and soy isoflavones) on IGF-1 and IGFBP-3 levels. Results Among women aged less than 50 years, circulating IGF-1 serum levels were significantly lower for those with CC genotype for IGF-1 rs1520220 than levels for those with the GC or GG genotypes (in recessive model: P = 0.007).In gene-diet analyses among these women, we found carrying CC genotype for IGF-1 rs1520220 and high soy isoflavone intake tend to be associated with lower circulating IGF-1 levels synthetically (P = 0.002). Women with GG or GC genotypes for IGF-1 rs1520220 and with low intake of soy isoflavones had the highest levels of circulating IGF-1 (geometric mean [95% CI]: 195 [37, 1021] µg/L). Comparatively, women with both the CC genotype and high soy intake had the lowest levels of circulating IGF-1 (geometric mean [95% CI]: 120 [38,378] µg/L). Conclusions IGF-1 serum levels are significantly lower among women with the CC genotype for IGF-1-rs1520220. High soy isoflavone intake may interact with carrying CC genotype for IGF-1-rs1520220 to lower women's serum IGF-1 levels more. PMID:25285521

  9. E-Peptides Control Bioavailability of IGF-1

    Science.gov (United States)

    Piszczek, Agnieszka; Perlas, Emarald; Winn, Nadine; Nastasi, Tommaso; Rosenthal, Nadia

    2012-01-01

    Insulin-like growth factor 1 (IGF-1) is a potent cytoprotective growth factor that has attracted considerable attention as a promising therapeutic agent. Transgenic over-expression of IGF-1 propeptides facilitates protection and repair in a broad range of tissues, although transgenic mice over-expressing IGF-1 propeptides display little or no increase in IGF-1 serum levels, even with high levels of transgene expression. IGF-1 propeptides are encoded by multiple alternatively spliced transcripts including C-terminal extension (E) peptides, which are highly positively charged. In the present study, we use decellularized mouse tissue to show that the E-peptides facilitate in vitro binding of murine IGF-1 to the extracellular matrix (ECM) with varying affinities. This property is independent of IGF-1, since proteins consisting of the E-peptides fused to relaxin, a related member of the insulin superfamily, bound equally avidly to decellularized ECM. Thus, the E-peptides control IGF-1 bioavailability by preventing systemic circulation, offering a potentially powerful way to tether IGF-1 and other therapeutic proteins to the site of synthesis and/or administration. PMID:23251442

  10. Forkhead box A1 (FOXA1) is a key mediator of insulin-like growth factor I (IGF-I) activity.

    Science.gov (United States)

    Potter, Adam S; Casa, Angelo J; Lee, Adrian V

    2012-01-01

    The insulin-like growth factor receptor (IGF-IR) has been implicated in a number of human tumors, including breast cancer. Data from human breast tumors has demonstrated that IGF-IR is over-expressed and hyper-phosphorylated. Additionally, microarray analysis has shown that IGF-I treatment of MCF7 cells leads to a gene signature comprised of induced and repressed genes, which correlated with luminal B tumors. FOXA1, a forkhead family transcription factor, has been shown to be crucial for mammary ductal morphogenesis, similar to IGF-IR, and expressed at high levels in luminal subtype B breast tumors. Here, we investigated the relationship between FOXA1 and IGF-I action in breast cancer cells. We show that genes regulated by IGF-I are enriched for FOXA1 binding sites, and knock down of FOXA1 blocked the ability of IGF-I to regulate gene expression. IGF-I treatment of MCF7 cells increased the half-life of FOXA1 protein and this increase in half-life appeared to be dependent on canonical IGF-I signal transduction through both MAPK and AKT pathways. Finally, knock down of FOXA1 led to a decreased ability of IGF-I to induce proliferation and protect against apoptosis. Together, these results demonstrate that IGF-I can increase the stability of FOXA1 protein expression and place it as a critical mediator of IGF-I regulation of gene expression and IGF-I-mediated biological responses. Copyright © 2011 Wiley Periodicals, Inc.

  11. Central Application of IGF-1 Postpones Time of Vaginal Opening in Normally Fed, but Not in Food-Restricted Rats

    NARCIS (Netherlands)

    Zeinoaldini, S.; Swarts, J.J.M.; Heijning, van de B.J.M.

    2006-01-01

    Background/Aims: Central but also peripheral IGF-1 is suggested to play a role in the initiation of puberty as it directly affects GnRH synthesis and release. A possible intermediate in the effects of IGF-1 on puberty might be the adiposity-signaling hormone leptin, whose plasma levels are decreased

  12. ROS accumulation and IGF-IR inhibition contribute to fenofibrate/PPARα -mediated inhibition of Glioma cell motility in vitro

    Directory of Open Access Journals (Sweden)

    Del Valle Luis

    2010-06-01

    Full Text Available Abstract Background Glioblastomas are characterized by rapid cell growth, aggressive CNS infiltration, and are resistant to all known anticancer regimens. Recent studies indicate that fibrates and statins possess anticancer potential. Fenofibrate is a potent agonist of peroxisome proliferator activated receptor alpha (PPARα that can switch energy metabolism from glycolysis to fatty acid β-oxidation, and has low systemic toxicity. Fenofibrate also attenuates IGF-I-mediated cellular responses, which could be relevant in the process of glioblastoma cell dispersal. Methods The effects of fenofibrate on Glioma cell motility, IGF-I receptor (IGF-IR signaling, PPARα activity, reactive oxygen species (ROS metabolism, mitochondrial potential, and ATP production were analyzed in human glioma cell lines. Results Fenofibrate treatment attenuated IGF-I signaling responses and repressed cell motility of LN-229 and T98G Glioma cell lines. In the absence of fenofibrate, specific inhibition of the IGF-IR had only modest effects on Glioma cell motility. Further experiments revealed that PPARα-dependent accumulation of ROS is a strong contributing factor in Glioma cell lines responses to fenofibrate. The ROS scavenger, N-acetyl-cysteine (NAC, restored cell motility, improved mitochondrial potential, and increased ATP levels in fenofibrate treated Glioma cell lines. Conclusions Our results indicate that although fenofibrate-mediated inhibition of the IGF-IR may not be sufficient in counteracting Glioma cell dispersal, PPARα-dependent metabolic switch and the resulting ROS accumulation strongly contribute to the inhibition of these devastating brain tumor cells.

  13. Low Levels of IGF-1 Contribute to Alveolar Macrophage Dysfunction in Cystic Fibrosis1

    Science.gov (United States)

    Bessich, Jamie L.; Nymon, Amanda B.; Moulton, Lisa A; Dorman, Dana; Ashare, Alix

    2013-01-01

    Alveolar macrophages are major contributors to lung innate immunity. Although alveolar macrophages from CFTR−/− mice have impaired function, no study has investigated primary alveolar macrophages in adults with cystic fibrosis (CF). CF patients have low levels of insulin-like growth factor 1 (IGF-1), and our prior studies demonstrate a relationship between IGF-1 and macrophage function. We hypothesize that reduced IGF-1 in CF leads to impaired alveolar macrophage function and chronic infections. Serum and bronchoalveolar lavage (BAL) samples were obtained from 8 CF subjects and 8 healthy subjects. Macrophages were isolated from BAL fluid. We measured the ability of alveolar macrophages to kill Pseudomonas aeruginosa. Subsequently, macrophages were incubated with IGF-1 prior to inoculation with bacteria to determine the effect of IGF-1 on bacterial killing. We found a significant decrease in bacterial killing by CF alveolar macrophages compared to controls. CF subjects had lower serum and BAL IGF-1 levels compared to healthy controls. Exposure to IGF-1 enhanced alveolar macrophage macrophages in both groups. Finally, exposing healthy alveolar macrophages to CF BAL fluid decreased bacterial killing, and this was reversed by the addition of IGF-1, while IGF-1 blockade worsened bacterial killing. Our studies demonstrate that alveolar macrophage function is impaired in patients with CF. Reductions in IGF-1 levels in CF contribute to the impaired alveolar macrophage function. Exposure to IGF-1 ex vivo, results in improved function of CF alveolar macrophages. Further studies are needed to determine whether alveolar macrophage function can be enhanced in vivo with IGF-1 treatment. PMID:23698746

  14. IGF-IR cooperates with ERα to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ECM molecules

    DEFF Research Database (Denmark)

    Afratis, Nikolaos A; Bouris, Panagiotis; Skandalis, Spyros S

    2017-01-01

    IGF-IR is highly associated with the behaviour of breast cancer cells. In ERα-positive breast cancer, IGF-IR is present at high levels. In clinical practice, prolonged treatment with anti-estrogen agents results in resistance to the therapy with activation of alternative signaling pathways. Recep...

  15. Hyperoxia exposure induced hormesis decreases mitochondrial superoxide radical levels via Ins/IGF-1 signaling pathway in a long-lived age-1 mutant of Caenorhabditis elegans

    International Nuclear Information System (INIS)

    Yanase, Sumino; Ishii, Naoaki

    2008-01-01

    The hormetic effect, which extends the lifespan by various stressors, has been confirmed in Caenorhabditis elegans (C. elegans). We have previously reported that oxidative stress resistance in a long-lived mutant age-1 is associated with the hormesis. In the age-1 allele, which activates an insulin/insulin-like growth factor-1 (Ins/IGF-1) signaling pathway, the superoxide dismutase (SOD) and catalase activities increased during normal aging. We now demonstrate changes in the mitochondrial superoxide radical (O 2 - ) levels of the hormetic conditioned age-related strains. The O 2 - levels in age-1 strain significantly decreased after intermittent hyperoxia exposure. On the other hand, this phenomenon was not observed in a daf-16 null mutant. This hormesis-dependent reduction of the O 2 - levels was observed even if the mitochondrial Mn-SOD was experimentally reduced. Therefore, it is indicated that the hormesis is mediated by events that suppress the mitochondrial O 2 - production. Moreover, some SOD gene expressions in the hormetic conditioned age-1 mutant were induced over steady state messenger ribonucleic acid (mRNA) levels. These data suggest that oxidative stress-inducible hormesis is associated with a reduction of the mitochondrial O 2 - production by activation of the antioxidant system via the Ins/IGF-1 signaling pathway. (author)

  16. Increased cardiogenesis in P19-GFP teratocarcinoma cells expressing the propeptide IGF-1Ea

    Energy Technology Data Exchange (ETDEWEB)

    Poudel, Bhawana [Heart Science Centre, National Heart and Lung Institute, Imperial College, London (United Kingdom); Bilbao, Daniel [EMBL, Mouse Biology Unit, Monterotondo (Italy); Sarathchandra, Padmini; Germack, Renee [Heart Science Centre, National Heart and Lung Institute, Imperial College, London (United Kingdom); Rosenthal, Nadia [Heart Science Centre, National Heart and Lung Institute, Imperial College, London (United Kingdom); Australian Regenerative Medicine Institute, Monash University, Melbourne (Australia); Santini, Maria Paola, E-mail: m.santini@imperial.ac.uk [Heart Science Centre, National Heart and Lung Institute, Imperial College, London (United Kingdom)

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer In this study, we explored the function of IGF-1Ea propeptide in inducing cardiogenesis of stem cells. Black-Right-Pointing-Pointer IGF-1Ea promoted cardiac mesodermal induction in uncommitted cells. Black-Right-Pointing-Pointer Under differentiation condition, IGF-1Ea increased expression of cardiac differentiation markers. Black-Right-Pointing-Pointer Furthermore, it promoted formation of finely organized sarcomeric structure. Black-Right-Pointing-Pointer IGF-1Ea propeptide may be a good candidate to improve production of cardiomyocytes from pluripotent cells. -- Abstract: The mechanism implicated in differentiation of endogenous cardiac stem cells into cardiomyocytes to regenerate the heart tissue upon an insult remains elusive, limiting the therapeutical goals to exogenous cell injection and/or gene therapy. We have shown previously that cardiac specific overexpression of the insulin-like growth factor 1 propeptide IGF-1Ea induces beneficial myocardial repair after infarct. Although the mechanism is still under investigation, the possibility that this propeptide may be involved in promoting stem cell differentiation into the cardiac lineage has yet to be explored. To investigate whether IGF-1Ea promote cardiogenesis, we initially modified P19 embryonal carcinoma cells to express IGF-1Ea. Taking advantage of their cardiomyogenic nature, we analyzed whether overexpression of this propeptide affected cardiac differentiation program. The data herein presented showed for the first time that constitutively overexpressed IGF-1Ea increased cardiogenic differentiation program in both undifferentiated and DMSO-differentiated cells. In details, IGF-1Ea overexpression promoted localization of alpha-actinin in finely organized sarcomeric structure compared to control cells and upregulated the cardiac mesodermal marker NKX-2.5 and the ventricular structural protein MLC2v. Furthermore, activated IGF-1 signaling promoted cardiac

  17. Increased cardiogenesis in P19-GFP teratocarcinoma cells expressing the propeptide IGF-1Ea

    International Nuclear Information System (INIS)

    Poudel, Bhawana; Bilbao, Daniel; Sarathchandra, Padmini; Germack, Renee; Rosenthal, Nadia; Santini, Maria Paola

    2011-01-01

    Highlights: ► In this study, we explored the function of IGF-1Ea propeptide in inducing cardiogenesis of stem cells. ► IGF-1Ea promoted cardiac mesodermal induction in uncommitted cells. ► Under differentiation condition, IGF-1Ea increased expression of cardiac differentiation markers. ► Furthermore, it promoted formation of finely organized sarcomeric structure. ► IGF-1Ea propeptide may be a good candidate to improve production of cardiomyocytes from pluripotent cells. -- Abstract: The mechanism implicated in differentiation of endogenous cardiac stem cells into cardiomyocytes to regenerate the heart tissue upon an insult remains elusive, limiting the therapeutical goals to exogenous cell injection and/or gene therapy. We have shown previously that cardiac specific overexpression of the insulin-like growth factor 1 propeptide IGF-1Ea induces beneficial myocardial repair after infarct. Although the mechanism is still under investigation, the possibility that this propeptide may be involved in promoting stem cell differentiation into the cardiac lineage has yet to be explored. To investigate whether IGF-1Ea promote cardiogenesis, we initially modified P19 embryonal carcinoma cells to express IGF-1Ea. Taking advantage of their cardiomyogenic nature, we analyzed whether overexpression of this propeptide affected cardiac differentiation program. The data herein presented showed for the first time that constitutively overexpressed IGF-1Ea increased cardiogenic differentiation program in both undifferentiated and DMSO-differentiated cells. In details, IGF-1Ea overexpression promoted localization of alpha-actinin in finely organized sarcomeric structure compared to control cells and upregulated the cardiac mesodermal marker NKX-2.5 and the ventricular structural protein MLC2v. Furthermore, activated IGF-1 signaling promoted cardiac mesodermal induction in undifferentiated cells independently of cell proliferation. This analysis suggests that IGF-1Ea may be a

  18. A fractionation method to identify qauntitative changes in protein expression mediated by IGF-1 on the proteome of murine C2C12 myoblasts

    Directory of Open Access Journals (Sweden)

    Friedmann Theodore

    2009-08-01

    Full Text Available Abstract Although much is known about signal transduction downstream of insulin-like growth factor-1 (IGF-1, relatively little is known about the global changes in protein expression induced by this hormone. In this study, the acute effects of IGF-1 on the proteome of murine C2C12 cells were examined. Cells were treated with IGF-1 for up to 24 hours, lysed, and fractionated into cytosolic, nuclear, and insoluble portions. Proteins from the cytosolic fraction were further separated using a new batch ion-exchange chromatography method to reduce sample complexity, followed by two-dimensional (2D electrophoresis, and identification of selected proteins by mass spectrometry. PDQuest software was utilized to identify and catalogue temporal changes in protein expression during IGF-1 stimulation. In response to IGF-1 stimulation, expression of 23 proteins increased at least three-fold and expression of 17 proteins decreased at least three-fold compared with control un-stimulated C2C12 cells. Changes in expression of selected proteins from each group, including Rho-GDI, cofillin, RAD50, enolase, IκB kinase b (IκBKb and Hsp70 were confirmed by Western blotting. Additionally, the position of 136 'landmark' proteins whose expression levels and physicochemical properties did not change appreciably or consistently during IGF-1 treatment were mapped and identified. This characterization of large-scale changes in protein expression in response to growth factor stimulation of C2C12 cells will further help to establish a comprehensive understanding of the networks and pathways involved in the action of IGF-1.

  19. Circulating levels of IGF-1, IGFBP-3, and IGF-1/IGFBP-3 molar ratio and colorectal adenomas: A meta-analysis.

    Science.gov (United States)

    Yoon, Yeong Sook; Keum, NaNa; Zhang, Xuehong; Cho, Eunyoung; Giovannucci, Edward L

    2015-12-01

    Insulin-like growth factor-1(IGF-1) promotes cell proliferation and inhibits apoptosis, and is thereby implicated in carcinogenesis. Insulin-like growth factor binding protein-3 (IGFBP-3) may antagonize IGF-1 action, leading to inhibition of the potential tumorigenicity of IGF-1. We conducted this meta-analysis to estimate the association between IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio and the risk of colorectal adenomas (CRAs). Further, we investigated whether this association was different between occurrent and recurrent CRA, by adjustment for obesity, and by advanced CRA. Pubmed and Embase were searched up to April, 2015 to identify relevant observational studies and summary odds ratio (OR) and the corresponding 95% confidence interval (95% CI) was estimated using a random-effects model. A total of 12 studies (11 studies including 3038 cases for IGF-1, 12 studies including 3208 cases for IGFBP-3, and 7 studies including 1867 cases for IGF-1/IGFBP-3 ratio) were included in this meta-analysis. The summary ORs of occurrent CRA for the highest versus lowest category of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio were 1.13 (95% CI: 0.95-1.34), 0.99 (0.84-1.16), and 1.05 (0.86-1.29), respectively. Higher IGF-1 and IGF-1/IGFBP-3 ratio were significantly associated with decreased risk of recurrent CRA (OR for IGF-1=0.60 [95% CI: 0.42-0.85]; IGF-1/IGFBP-3 ratio=0.65 [0.44-0.96]). A stratified analysis by advancement of occurrent CRA produced a significant summary OR of IGF-1 for advanced CRA (OR=2.21 [1.08-4.52]) but not for non-advanced CRA (OR=0.89 [0.55-1.45]). We did not find significant publication bias or heterogeneity. Circulating levels of IGF-1, IGFBP-3 and their molar ratio were not associated with the risk of occurrence of CRA, but IGF-1 was associated with the increased risk for occurrence of advanced CRA. Copyright © 2015. Published by Elsevier Ltd.

  20. IGF-1 and Survival in ESRD

    Science.gov (United States)

    Jia, Ting; Gama Axelsson, Thiane; Heimbürger, Olof; Bárány, Peter; Stenvinkel, Peter; Qureshi, Abdul Rashid

    2014-01-01

    Summary Background and objectives IGF-1 deficiency links to malnutrition in CKD patients; however, it is not clear to what extent it associates with survival among these patients. Design, setting, participants, & measurements Serum IGF-1 and other biochemical, clinical (subjective global assessment), and densitometric (dual energy x-ray absorptiometry) markers of nutritional status and mineral and bone metabolism were measured in a cohort of 365 Swedish clinically stable CKD stage 5 patients (median age of 53 years) initiating dialysis between 1994 and 2009; in 207 patients, measurements were also taken after 1 year of dialysis. Deaths were registered during a median follow-up of 5 years. Associations of mortality with baseline IGF-1 and changes of IGF-1 after 1 year of dialysis were evaluated by Cox models. Results At baseline, IGF-1 concentrations associated negatively with age, diabetes mellitus, cardiovascular disease, poor nutritional status, IL-6, and osteoprotegerin and positively with body fat mass, bone mineral density, serum phosphate, calcium, and fibroblast growth factor-23. At 1 year, IGF-1 had increased by 33%. In multivariate regression, low age, diabetes mellitus, and high serum phosphate and calcium associated with IGF-1 at baseline, and in a mixed model, these factors, together with high fat body mass, associated with changes of IGF-1 during the first 1 year of dialysis. Adjusting for calendar year of inclusion, age, sex, diabetes mellitus, cardiovascular disease, IL-6, and poor nutritional status, a 1 SD higher level of IGF-1 at baseline associated with lower mortality risk (hazard ratio, 0.57; 95% confidence interval, 0.32 to 0.98). Persistently low or decreasing IGF-1 levels during the first 1 year on dialysis predicted worse survival (adjusted hazard ratio, 2.19; 95% confidence interval, 1.06 to 4.50). Conclusion In incident dialysis patients, low serum IGF-1 associates with body composition and markers of mineral and bone metabolism, and it

  1. Insulin-like growth factor (IGF) binding protein from human decidua inhibits the binding and biological action of IGF-I in cultured choriocarcinoma cells

    International Nuclear Information System (INIS)

    Ritvos, O.; Ranta, T.; Jalkanen, J.; Suikkari, A.M.; Voutilainen, R.; Bohn, H.; Rutanen, E.M.

    1988-01-01

    The placenta expresses genes for insulin-like growth factors (IGFs) and possesses IGF-receptors, suggesting that placental growth is regulated by IGFs in an autocrine manner. We have previously shown that human decidua, but not placenta, synthesizes and secretes a 34 K IGF-binding protein (34 K IGF-BP) called placental protein 12. We now used human choriocarcinoma JEG-3 cell monolayer cultures and recombinant (Thr59)IGF-I as a model to study whether the decidual 34 K IGF-BP is able to modulate the receptor binding and biological activity of IGFs in trophoblasts. JEG-3 cells, which possess type I IGF receptors, were unable to produce IGF-BPs. Purified 34 K IGF-BP specifically bound [125I]iodo-(Thr59)IGF-I. Multiplication-stimulating activity had 2.5% the potency of (Thr59)IGF-I, and insulin had no effect on the binding of [125I] iodo-(Thr59)IGF-I. 34 K IGF-BP inhibited the binding of [125I] iodo-(Thr59)IGF-I to JEG-3 monolayers in a concentration-dependent manner by forming with the tracer a soluble complex that could not bind to the cell surface as demonstrated by competitive binding and cross-linking experiments. After incubating the cell monolayers with [125I]iodo-(Thr59)IGF-I in the presence of purified binding protein, followed by cross-linking, no affinity labeled bands were seen on autoradiography. In contrast, an intensely labeled band at 40 K was detected when the incubation medium was analyzed, suggesting that (Thr59)IGF-I and 34 K IGF-BP formed a complex in a 1:1 molar ratio. Also, 34 K IGF-BP inhibited both basal and IGF-I-stimulated uptake of alpha-[3H]aminoisobutyric acid in JEG-3 cells. RNA analysis revealed that IGF-II is expressed in JEG-3 cells

  2. Maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3 and the hypertensive disorders of pregnancy.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2010-07-01

    To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational hypertension and pre-eclampsia (PET).

  3. IGF-IR promotes prostate cancer growth by stabilizing α5β1 integrin protein levels.

    Directory of Open Access Journals (Sweden)

    Aejaz Sayeed

    Full Text Available Dynamic crosstalk between growth factor receptors, cell adhesion molecules and extracellular matrix is essential for cancer cell migration and invasion. Integrins are transmembrane receptors that bind extracellular matrix proteins and enable cell adhesion and cytoskeletal organization. They also mediate signal transduction to regulate cell proliferation and survival. The type 1 insulin-like growth factor receptor (IGF-IR mediates tumor cell growth, adhesion and inhibition of apoptosis in several types of cancer. We have previously demonstrated that β1 integrins regulate anchorage-independent growth of prostate cancer (PrCa cells by regulating IGF-IR expression and androgen receptor-mediated transcriptional functions. Furthermore, we have recently reported that IGF-IR regulates the expression of β1 integrins in PrCa cells. We have dissected the mechanism through which IGF-IR regulates β1 integrin expression in PrCa. Here we report that IGF-IR is crucial for PrCa cell growth and that β1 integrins contribute to the regulation of proliferation by IGF-IR. We demonstrate that β1 integrin regulation by IGF-IR does not occur at the mRNA level. Exogenous expression of a CD4 - β1 integrin cytoplasmic domain chimera does not interfere with such regulation and fails to stabilize β1 integrin expression in the absence of IGF-IR. This appears to be due to the lack of interaction between the β1 cytoplasmic domain and IGF-IR. We demonstrate that IGF-IR stabilizes the β1 subunit by protecting it from proteasomal degradation. The α5 subunit, one of the binding partners of β1, is also downregulated along with β1 upon IGF-IR knockdown while no change is observed in the expression of the α2, α3, α4, α6 and α7 subunits. Our results reveal a crucial mechanistic role for the α5β1 integrin, downstream of IGF-IR, in regulating cancer growth.

  4. Kinase inhibitors of the IGF-1R as a potential therapeutic agent for rheumatoid arthritis.

    Science.gov (United States)

    Tsushima, Hiroshi; Morimoto, Shinji; Fujishiro, Maki; Yoshida, Yuko; Hayakawa, Kunihiro; Hirai, Takuya; Miyashita, Tomoko; Ikeda, Keigo; Yamaji, Ken; Takamori, Kenji; Takasaki, Yoshinari; Sekigawa, Iwao; Tamura, Naoto

    2017-08-01

    We have previously shown that the inhibition of connective tissue growth factor (CTGF) is a potential therapeutic strategy against rheumatoid arthritis (RA). CTGF consists of four distinct modules, including the insulin-like growth factor binding protein (IGFBP). In serum, insulin-like growth factors (IGFs) bind IGFBPs, interact with the IGF-1 receptor (IGF-1 R), and regulate anabolic effects and bone metabolism. We investigated the correlation between IGF-1 and the pathogenesis of RA, and the inhibitory effect on osteoclastogenesis and angiogenesis of the small molecular weight kinase inhibitor of the IGF-1 R, NVP-AEW541, against pathogenesis of RA in vitro. Cell proliferation was evaluated by cell count and immunoblotting. The expression of IGF-1 and IGF-1 R was evaluated by RT-PCR. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay, and osteoclast-specific enzyme production. Angiogenesis was evaluated by a tube formation assay using human umbilical vein endothelial cells (HUVECs). The proliferation of MH7A cells was found to be inhibited in the presence of NVP-AEW541, and the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was downregulated in MH7A cells. IGF-1 and IGF-1 R mRNA expression levels were upregulated during formation of M-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)-mediated osteoclast formation. Moreover, osteoclastogenesis was suppressed in the presence of NVP-AEW541. The formation of the tubular network was enhanced by IGF-1, and this effect was neutralized by NVP-ARE541. Our findings suggest that NVP-AEW541 may be utilized as a potential therapeutic agent in the treatment of RA.

  5. Type 1 IGF Receptor Localization in Paediatric Gliomas: Significant Association with WHO Grading and Clinical Outcome.

    Science.gov (United States)

    Clément, Florencia; Martin, Ayelen; Venara, Marcela; de Luján Calcagno, Maria; Mathó, Cecilia; Maglio, Silvana; Lombardi, Mercedes García; Bergadá, Ignacio; Pennisi, Patricia A

    2018-06-01

    Nuclear localization of insulin-like growth factor receptor type 1 (IGF-1R) has been described as adverse prognostic factor in some cancers. We studied the expression and localization of IGF-1R in paediatric patients with gliomas, as well as its association with World Health Organization (WHO) grading and survival. We conducted a single cohort, prospective study of paediatric patients with gliomas. Samples were taken at the time of the initial surgery; IGF-1R expression and localization were characterized by immunohistochemistry (IHC), subcellular fractionation and western blotting. Tumours (47/53) showed positive staining for IGF-1R by IHC. IGF-1R nuclear labelling was observed in 10/47 cases. IGF-1R staining was mostly non-nuclear in low-grade tumours, while IGF-1R nuclear labelling was predominant in high-grade gliomas (p = 0.0001). Survival was significantly longer in patients with gliomas having non-nuclear IGF-1R localization than in patients with nuclear IGF-1R tumours (p = 0.016). In gliomas, IGF-1R nuclear localization was significantly associated with both high-grade tumours and increased risk of death. Based on a prospective design, we provide evidence of a potential usefulness of intracellular localization of IGF-1R as prognostic factor in paediatric patients with gliomas.

  6. Identification of signaling pathways associated with cancer protection in Laron syndrome.

    Science.gov (United States)

    Lapkina-Gendler, Lena; Rotem, Itai; Pasmanik-Chor, Metsada; Gurwitz, David; Sarfstein, Rive; Laron, Zvi; Werner, Haim

    2016-05-01

    The growth hormone (GH)-insulin-like growth factor-1 (IGF1) pathway emerged in recent years as a critical player in cancer biology. Enhanced expression or activation of specific components of the GH-IGF1 axis, including the IGF1 receptor (IGF1R), is consistently associated with a transformed phenotype. Recent epidemiological studies have shown that patients with Laron syndrome (LS), the best-characterized entity among the congenital IGF1 deficiencies, seem to be protected from cancer development. To identify IGF1-dependent genes and signaling pathways associated with cancer protection in LS, we conducted a genome-wide analysis using immortalized lymphoblastoid cells derived from LS patients and healthy controls of the same gender, age range, and ethnic origin. Our analyses identified a collection of genes that are either over- or under-represented in LS-derived lymphoblastoids. Gene differential expression occurs in several gene families, including cell cycle, metabolic control, cytokine-cytokine receptor interaction, Jak-STAT signaling, and PI3K-AKT signaling. Major differences between LS and healthy controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. Our results highlight the key role of the GH-IGF1 axis in the initiation and progression of cancer. Furthermore, data are consistent with the concept that homozygous congenital IGF1 deficiency may confer protection against future tumor development. © 2016 Society for Endocrinology.

  7. Dexras1 links glucocorticoids to insulin-like growth factor-1 signaling in adipogenesis

    Science.gov (United States)

    Kim, Hyo Jung; Cha, Jiyoung Y.; Seok, Jo Woon; Choi, Yoonjeong; Yoon, Bo Kyung; Choi, Hyeonjin; Yu, Jung Hwan; Song, Su Jin; Kim, Ara; Lee, Hyemin; Kim, Daeun; Han, Ji Yoon; Kim, Jae-woo

    2016-01-01

    Glucocorticoids are associated with obesity, but the underlying mechanism by which they function remains poorly understood. Previously, we showed that small G protein Dexras1 is expressed by glucocorticoids and leads to adipocyte differentiation. In this study, we explored the mechanism by which Dexras1 mediates adipogenesis and show a link to the insulin-like growth factor-1 (IGF-1) signaling pathway. Without Dexras1, the activation of MAPK and subsequent phosphorylation of CCAAT/enhancer binding protein β (C/EBPβ) is abolished, thereby inhibiting mitotic clonal expansion and further adipocyte differentiation. Dexras1 translocates to the plasma membrane upon insulin or IGF-1 treatment, for which the unique C-terminal domain (amino acids 223–276) is essential. Dexras1-dependent MAPK activation is selectively involved in the IGF-1 signaling, because another Ras protein, H-ras localized to the plasma membrane independently of insulin treatment. Moreover, neither epidermal growth factor nor other cell types shows Dexras1-dependent MAPK activation, indicating the importance of Dexras1 in IGF-1 signaling in adipogenesis. Dexras1 interacts with Shc and Raf, indicating that Dexras1-induced activation of MAPK is largely dependent on the Shc-Grb2-Raf complex. These results suggest that Dexras1 is a critical mediator of the IGF-1 signal to activate MAPK, linking glucocorticoid signaling to IGF-1 signaling in adipogenesis. PMID:27345868

  8. Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays; Improvement of determinations in acid ethanol extracts by the use of truncated IGF-I as radioligand

    Energy Technology Data Exchange (ETDEWEB)

    Bang, P; Eriksson, U; Wivall, I -L; Hall, K [Department of Endocrinology, Karolinska Institute, Stockholm (Sweden); Sara, V [Department of Pathology, Karolinska Institute, Stockholm (Sweden)

    1991-01-01

    Insulin-like growth factor binding proteins interfere in the IGF-I and -II radioimmunoassays. In an attempt to overcome this problem, we have compared the use of truncated IGF-I, with reduced IGFBP affinity, and IGF-I as radioligands for IGF-I RIA measurements in serum separated by acid gel filtration or acid ethanol extraction followed by cryo-precipitation. With truncated IGF-I as radioligand the IGF-I measurements in acid gel filtrates and acid ethanol extracts were significantly correlated in healthy subjects (N=42, r=0.91, p<0.001) and in patients with acromegaly (N=10, r=0.85, p<0.01), GH deficiency (N=10, r=0.88, p<0.001) or Type I diabetes mellitus (N=10, r=0.90, p<0.001). In contrast, the IGF-I concentrations in acid ethanol extracts determined with IGF-I as radioligand did not correlate with those in acid gel filtrates using truncated IGF-I radioligand in patients with acromegaly (r=0.61, NS) or GH deficiency (r=0.46, NS). In the latter group the mean IGF-I concentrations measured in acid ethanol extracts were erroneously elevated by 112%. Low-affinity antibodies used for IGF-II RIA determinations failed to give reliable results in acid ethanol extracts from patients with Type I diabetes mellitus or GH deficiency. In conclusion, erroneously high IGF-I concentrations owing to binding of the radioligand to IGFBPs not completely removed by acid ethanol extraction can be avoided by the use of truncated IGF-I as radioligand. (author).

  9. IGF-1 levels, complex formation, and IGF bioactivity in growth hormone-treated children with Prader-Willi syndrome

    NARCIS (Netherlands)

    Bakker, N. E.; Van Doorn, J.; Renes, J. S.; Donker, G. H.; Hokken-Koelega, A. C S

    2015-01-01

    Context: Children with Prader-Willi syndrome (PWS) attain high-serum immunoreactive IGF-1 levels during a standard-dose GH treatment, which leads to concern, but lowering the dose deteriorates their body composition. Objective: The objective of the study was to evaluate serum IGF-1, IGF binding

  10. Detection of exogenous gene doping of IGF-I by a real-time quantitative PCR assay.

    Science.gov (United States)

    Zhang, Jin-Ju; Xu, Jing-Feng; Shen, Yong-Wei; Ma, Shi-Jiao; Zhang, Ting-Ting; Meng, Qing-Lin; Lan, Wen-Jun; Zhang, Chun; Liu, Xiao-Mei

    2017-07-01

    Gene doping can be easily concealed since its product is similar to endogenous protein, making its effective detection very challenging. In this study, we selected insulin-like growth factor I (IGF-I) exogenous gene for gene doping detection. First, the synthetic IGF-I gene was subcloned to recombinant adeno-associated virus (rAAV) plasmid to produce recombinant rAAV2/IGF-I-GFP vectors. Second, in an animal model, rAAV2/IGF-I-GFP vectors were injected into the thigh muscle tissue of mice, and then muscle and blood specimens were sampled at different time points for total DNA isolation. Finally, real-time quantitative PCR was employed to detect the exogenous gene doping of IGF-I. In view of the characteristics of endogenous IGF-I gene sequences, a TaqMan probe was designed at the junction of exons 2 and 3 of IGF-I gene to distinguish it from the exogenous IGF-I gene. In addition, an internal reference control plasmid and its probe were used in PCR to rule out false-positive results through comparison of their threshold cycle (Ct) values. Thus, an accurate exogenous IGF-I gene detection approach was developed in this study. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

  11. Favorable prognostic value of SOCS2 and IGF-I in breast cancer

    Directory of Open Access Journals (Sweden)

    Daxenbichler Günter

    2007-07-01

    Full Text Available Abstract Background Suppressor of cytokine signaling (SOCS proteins comprise a protein family, which has initially been described as STAT induced inhibitors of the Jak/Stat pathway. Recent in vivo and in vitro studies suggest that SOCS proteins are also implicated in cancer. The STAT5 induced IGF-I acts as an endocrine and para/autocrine growth and differentiation factor in mammary gland development. Whereas high levels of circulating IGF-I have been associated with increased cancer risk, the role of autocrine acting IGF-I is less clear. The present study is aimed to elucidate the clinicopathological features associated with SOCS1, SOCS2, SOCS3, CIS and IGF-I expression in breast cancer. Methods We determined the mRNA expression levels of SOCS1, SOCS2, SOCS3, CIS and IGF-I in 89 primary breast cancers by reverse transcriptase PCR. SOCS2 protein expression was further evaluated by immuno-blot and immunohistochemistry. Results SOCS2 expression inversely correlated with histopathological grade and ER positive tumors exhibited higher SOCS2 levels. Patients with high SOCS2 expression lived significantly longer (108.7 vs. 77.7 months; P = 0.015 and high SOCS2 expression proved to be an independent predictor for good prognosis (HR = 0.45, 95% CI 0.23 – 0.91, P = 0.026. In analogy to SOCS2, high IGF-I expression was an independent predictor for good prognosis in the entire patient cohort. In the subgroup of patients with lymph-node negative disease, high IGF-I was a strong predictor for favorable outcome in terms of overall survival and relapse free survival (HR = 0.075, 95% CI 0.014 – 0.388, P = 0.002. Conclusion This is the first report on the favorable prognostic value of high SOCS2 expression in primary mammary carcinomas. Furthermore a strong association of high IGF-I expression levels with good prognosis was observed especially in lymph-node negative patients. Our results suggest that high expression of the STAT5 target genes SOCS2 and IGF

  12. Gengnianchun Extends the Lifespan of Caenorhabditis elegans via the Insulin/IGF-1 Signalling Pathway

    Directory of Open Access Journals (Sweden)

    Fanhui Meng

    2018-01-01

    Full Text Available Gengnianchun (GNC, a traditional Chinese medicine (TCM, is believed to have beneficial effects on ageing-related diseases, such as antioxidant properties and effects against Aβ-induced toxicity. We previously found that GNC extended the lifespan of Caenorhabditis elegans. However, the mechanism underlying this effect was unclear. In this study, we further explored the mechanisms of GNC using a C. elegans model. GNC significantly increased the lifespan of C. elegans and enhanced oxidative and thermal stress resistance. Moreover, chemotaxis increased after GNC treatment. RNA-seq analysis showed that GNC regulated genes associated with longevity. We also conducted lifespan assays with a series of worm mutants. The results showed that GNC significantly extended the lifespan of several mutant strains, including eat-2 (ad465, rsks-1 (ok1255, and glp-1 (e2144, suggesting that the prolongevity effect of GNC is independent of the function of these genes. However, GNC failed to extend the lifespan of daf-2 (e1370, age-1 (hx546, and daf-16 (mu86 mutant strains. Our findings suggest that GNC extends the lifespan of C. elegans via the insulin/IGF-1 signalling pathway and may be a potential antiageing agent.

  13. Bone Growth Mechanical Stimulus and IGF-I

    National Research Council Canada - National Science Library

    Gilsanz, Vicente

    2003-01-01

    .... This study also examines the possible relations between the cross-sectional properties of bone and circulating levels of IGF-I, IGF-binding protein-3, and IGF-I genotypes in teenagers ages 15 to 20...

  14. INFLUENCE OF INTRAMUSCULAR APPLICATION OF AUTOLOGOUS CONDITIONED PLASMA ON SYSTEMIC CIRCULATING IGF-1

    Directory of Open Access Journals (Sweden)

    Gert Schippinger

    2011-09-01

    Full Text Available Platelet-rich plasma (PRP to increase levels of platelets and growth factors has been used for the treatment of sports injuries suggesting to improve healing and regeneration. This method offers some potential especially for elite athletes. However, the insulin like growth factor-1 (IGF-1 is prohibited by the World Anti Doping Agency and, in addition, there may be a possible link between increased levels of IGF-1 and cancer risk. Aim of the study was to evaluate a systemic increase of IGF-1 after local intramuscular administration of PRP in young healthy moderately trained male subjects. Blood samples were drawn and PRP preparation was performed by means of centrifugation. Enriched plasma was injected into the gluteus muscle. Venous blood was collected and serum prepared before as well as after 0.5, 3 and 24 hours after PRP administration. IGF-1 analysis was performed applying an ELISA test kit. No significant systemic increase of mean IGF-1 was found after the PRP injection. Only one subject showed an increase after 24 h, but all IGF-1 values were found within reference limits. We conclude that a single intramuscular application of PRP does not significantly increase systemic IGF-1 levels. Therefore, a single application of PRP is safe with respect to systemic IGF-1 response and cancer risk and this should be allowed for treatment of muscle injuries in elite athletes

  15. CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling

    OpenAIRE

    Manara, Maria Cristina; Terracciano, Mario; Mancarella, Caterina; Sciandra, Marika; Guerzoni, Clara; Pasello, Michela; Grilli, Andrea; Zini, Nicoletta; Picci, Piero; Colombo, Mario P.; Morrione, Andrea; Scotlandi, Katia

    2016-01-01

    CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD9...

  16. The single IGF-1 partial deficiency is responsible for mitochondrial dysfunction and is restored by IGF-1 replacement therapy.

    Science.gov (United States)

    Olleros Santos-Ruiz, M; Sádaba, M C; Martín-Estal, I; Muñoz, U; Sebal Neira, C; Castilla-Cortázar, I

    2017-08-01

    We previously described in cirrhosis and aging, both conditions of IGF-1 deficiency, a clear hepatic mitochondrial dysfunction with increased oxidative damage. In both conditions, the hepatic mitochondrial function was improved with low doses of IGF-1. The aim of this work was to explore if the only mere IGF-1 partial deficiency, without any exogenous insult, is responsible for hepatic mitochondrial dysfunction. Heterozygous (igf1 +/- ) mice were divided into two groups: untreated and treated mice with low doses of IGF-1. WT group was used as controls. Parameters of hepatic mitochondrial function were determined by flow cytometry, antioxidant enzyme activities were determined by spectrophotometry, and electron chain transport enzyme levels were determined by immunohistochemistry and immunofluorescence analyses. Liver expression of genes coding for proteins involved in mitochondrial protection and apoptosis was studied by microarray analysis and RT-qPCR. Hz mice showed a significant reduction in hepatic mitochondrial membrane potential (MMP) and ATPase activity, and an increase in intramitochondrial free radical production and proton leak rates, compared to controls. These parameters were normalized by IGF-1 replacement therapy. No significant differences were found between groups in oxygen consumption and antioxidant enzyme activities, except for catalase, whose activity was increased in both Hz groups. Relevant genes coding for proteins involved in mitochondrial protection and survival were altered in Hz group and were reverted to normal in Hz+IGF-1 group. The mere IGF-1 partial deficiency is per se associated with hepatic mitochondrial dysfunction sensitive to IGF-1 replacement therapy. Results in this work prove that IGF-1 is involved in hepatic mitochondrial protection, because it is able to reduce free radical production, oxidative damage and apoptosis. All these IGF-1 actions are mediated by the modulation of the expression of genes encoding citoprotective

  17. Relationships Between IGF-1, IGF-Binding Proteins and Diet in African American and Caucasian Men

    National Research Council Canada - National Science Library

    Agurs-Collins, Tanya

    2003-01-01

    .... The proposed study will help to explain the increased risk of prostate cancer for African American men and the role of specific nutrients in influencing IGF-1 and IGF-binding protein concentrations...

  18. Relationships Between IGF-1, IGF-Binding Proteins and Diet in African American and Caucasian Men

    National Research Council Canada - National Science Library

    Agura-Collins, Tanya

    2001-01-01

    .... The proposed study will help to explain the increased risk of prostate cancer for African American men and the role of specific nutrients in influencing IGF-1 and IGF-binding protein concentrations...

  19. Relationships Between IGF-1, IGF-Binding Proteins and Diet in African American and Caucasian Men

    National Research Council Canada - National Science Library

    Agurs-Collins, Tanya

    2002-01-01

    .... The proposed study will help to explain the increased risk of prostate cancer for African American men and the role of specific nutrients in influencing IGF-1 and IGF-binding protein concentrations...

  20. The C. elegans Ortholog of USP7 controls DAF-16 stability in Insulin/IGF-1-like signaling.

    Science.gov (United States)

    Heimbucher, Thomas; Hunter, Tony

    2015-01-01

    FOXO family transcription factors are downstream effectors of Insulin/IGF-1 signaling (IIS) and are regulated by posttranslational modification and coregulators, including components of the ubiquitin-proteasome system (UPS). Cofactors promoting DAF-16/FOXO protein stability and function in IIS have not been described yet. In a recent study, we have identified the deubiquitylating enzyme MATH-33, the ortholog of mammalian USP7/HAUSP, as an essential DAF-16 coregulator. We found that MATH-33 actively stabilizes DAF-16 protein levels when IIS is downregulated. Here we discuss how DAF-16/FOXO transcription factors are regulated by the UPS, in particular by the interplay of E3-ubiquitin ligases and deubiquitylating enzymes, which is critical for balancing DAF-16/FOXO activity and degradation. Recent findings raise the intriguing possibility that regulated oscillations in DAF-16/FOXO steady state levels play an integral role in mechanisms controlling healthspan and lifespan extension.

  1. IGF-IR targeted therapy: Past, present and future

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); A.J. Varewijck (Aimee)

    2014-01-01

    textabstractThe IGF-I receptor (IGF-IR) has been studied as an anti-cancer target. However, monotherapy trials with IGF-IR targeted antibodies or with IGF-IR specific tyrosine kinase inhibitors have, overall, been very disappointing in the clinical setting. This review discusses potential reasons

  2. Investigation of PAX3/7-FKHR fusion genes and IGF2 gene expression in rhabdomyosarcoma tumors.

    Science.gov (United States)

    de Souza, Robson Ramos; Oliveira, Indhira Dias; Caran, Eliana Maria Monteiro; Alves, Maria Teresa de Seixas; Abib, Simone; Toledo, Silvia Regina Caminada

    2012-12-01

    The purpose of our study was to investigate the prevalence of the PAX3/7-FKHR fusion genes and quantify the IGF2 gene expression in rhabdomyosarcoma (RMS) samples. Soft tissue sarcomas account 5% of childhood cancers and 50% of them are RMS. Morphological evaluation of pediatric RMS has defined two histological subtypes, embryonal (ERMS) and alveolar (ARMS). Chromosomal analyses have demonstrated two translocations associated with ARMS, resulting in the PAX3/7-FKHR rearrangements. Reverse transcriptase-polymerase chain reaction (RT-PCR) is extremely useful in the diagnosis of ARMS positive for these rearrangements. Additionally, several studies have shown a significant involvement of IGF pathway in the pathogenesis of RMS. The presence of PAX3/7-FKHR gene fusions was studied in 25 RMS samples from patients attending the IOP-GRAACC/UNIFESP and three RMS cell lines by RT-PCR. IGF2 gene expression was quantified by qPCR and related with clinic pathological parameters. Of the 25 samples, nine (36%) were ARMS and 16 (64%) were ERMS. PAX3/7-FKHR gene fusions expression was detected in 56% of ARMS tumor samples. IGF2 overexpression was observed in 80% of samples and could indicate an important role of this pathway in RMS biology. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. What Happened to the IGF Binding Proteins?

    Science.gov (United States)

    Bach, Leon A

    2018-02-01

    Insulinlike growth factor (IGF) binding proteins (IGFBPs) 1 to 6 are high-affinity regulators of IGF activity. They generally inhibit IGF actions by preventing binding to the IGF-I receptor but can also enhance their actions under some conditions. Posttranslational modifications such as glycosylation and phosphorylation modulate IGFBP properties, and IGFBP proteolysis results in IGF release. IGFBPs have more recently been shown to have IGF-independent actions. A number of mechanisms are involved, including modulation of other growth factor pathways, nuclear localization and transcriptional regulation, interaction with the sphingolipid pathway, and binding to non-IGF biomolecules in the extracellular space and matrix, on the cell surface and intracellularly. IGFBPs modulate important biological processes, including cell proliferation, survival, migration, senescence, autophagy, and angiogenesis. Their actions have been implicated in growth, metabolism, cancer, stem cell maintenance and differentiation, and immune regulation. Recent studies have shown that epigenetic mechanisms are involved in the regulation of IGFBP abundance. A more complete understanding of IGFBP biology is necessary to further define their cellular roles and determine their therapeutic potential. Copyright © 2018 Endocrine Society.

  4. IGF-IEc expression is increased in secondary compared to primary foci in neuroendocrine neoplasms.

    Science.gov (United States)

    Alexandraki, Krystallenia I; Philippou, Anastassios; Boutzios, Georgios; Theohari, Irini; Koutsilieris, Michael; Delladetsima, Ioanna Kassiani; Kaltsas, Gregory A

    2017-10-03

    Different Insulin-like growth factor-I (IGF-I) mRNA transcripts are produced by alternative splicing and particularly the IGF-IEc isoform has been implicated in the development and/or progression of various types of cancer. In the present study, we examined the potential role of IGF-IEc expression as a new immunohistochemical marker of aggressiveness in neuroendocrine neoplasms (NENs). We utilized immunohistochemical analysis in tissue specimens of 47 patients with NENs, to evaluate the expression of IGF-IEc (%) and Ki-67 proliferation index (%). Specimens from patients with tumors of different tissue origin, of either primary or metastatic lesions and of different grade were examined. Cytoplasmic IGF-IEc staining was found in 23 specimens of NENs or NECs: 10 pancreatic, 4 small bowel, 3 gastric, 1 lung, 1 uterine and 4 poorly differentiated of unknown primary origin. Ki-67 and IGF-IEc expression was positively correlated in all the samples studied (r=0.31, p=0.03). IGF-1Ec expression was more prevalent in specimens originating from metastatic foci with high Ki-67 compared to primary sites with low Ki-67 expression (p=0.036). These findings suggest a possible role of IGF-IEc in NEN tumorigenesis and progression to metastases that could be used as an additional new marker of a more aggressive behavior and a potential drugable target.

  5. Serum Levels Of Free And Total Insulin-Like Growth Factor (IGF)-1 And IGF Binding Protein-3 In Normal And Growth Hormone Deficient Children

    International Nuclear Information System (INIS)

    Shousha, M.A.; Soliman, S.E.T.; Hafez, M.H.

    2006-01-01

    Serum levels of total insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) reflect the endogenous GH secretion in healthy children, which makes them good diagnostic markers for screening growth hormone deficiency (GHD) in short children, although some controversy still exists. Only a minor fraction of the total IGF-1 circulates in its free form, which is believed to be the biologically active form. Serum levels of free IGF-1, total IGF-I and IGFBP-3 were measured in 144 healthy children (72 boys and 72 girls, aged from 0 to 16 years) and in 12 pre-pubertal GH deficient (GHD) children to study the correlation between the age and free IGF-1, total IGF-1 and IGFBP-3 levels. In healthy subjects (both sexes), serum free IGF-1, total IGF-1 and IGFBP-3 levels were low in infancy, increasing during puberty and declining thereafter. Free IGF-1 in serum occupied about 0.97-1.45 % of the total IGF-1 values, and the ratios of free IGF-1 to total IGF-1 were significantly increased in the pubertal age groups than in the pre-pubertal age groups. Serum levels of free IGF-1 showed significant positive correlation with those of total IGF-I and IGFBP-3. Serum free IGF-1, total IGF-1 and IGFBP-3 levels in patients with GHD were decreased significantly with increasing the degree of hypopituitarism. These observations suggest that the increase in serum free IGF-1 level during puberty was caused by a dramatic increase in total IGF-1 rather than IGFBP-3. Also, high levels of these hormones may play an important role in pubertal growth spurt and may become a useful tool for diagnosing GHD and predicting growth response to long term GH therapy

  6. Serum levels of free and total insulin-link growth factor (IGF)-1 and (IGF) binding protein-3 in normal and growth hormone deficient children

    International Nuclear Information System (INIS)

    Shousha, M.A.; Soliman, S.E.T.; Hafez, H.M.

    2008-01-01

    Serum levels of total insulin-like growth factor- 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) reflect endogenous GH secretion in healthy children, which makes them good diagnostic markers for screening GH deficiency (GHD) in short children, although some controversy still exists. Only a minor fraction of the total IGF-1 circulates in its free form, which is believed to be the biologically active form. Serum levels of free IGF-1, total IGF-I and IGFBP-3 were measured in 144 healthy children (72 boys and 72 girls, aged from 0 to 16 years) and in 12 prepubertal GH. deficient (GHD) children to study correlation between the age and free IGF-1, total IGF-1 and IGFBP-3 levels. In healthy subjects (both sexes), serum free IGF-1, total IGF-1 and IGFBP-3 levels were low in infancy, increasing during puberty and declining thereafter. Free IGF-1 in serum occupied about 0.97. 1.45 % of the total IGF-1 values, and the ratios of free IGF-1 to total IGF-1 were significantly increased in the pubertal age groups than in the prepubertal age groups. Serum levels of free IGF-1 showed significant positive correlation with those of total IGF-I and IGFBP-3. Serum free IGF-1, total IGF-1 and IGFBP-3 levels in patients with GHD decreased significantly with increasing degree of hypopituitarism. These observations suggest that the increase in serum free IGF-1 level during puberty was caused by a dramatic increase in total IGF-1 rather than IGFBP-3. Also, high levels of these hormones may play an important role in pubertal growth spurt and may become a useful tool for diagnosing GHD and predicting growth response to long term GH therapy

  7. IGF-II transgenic mice display increased aberrant colon crypt multiplicity and tumor volume after 1,2-dimethylhydrazine treatment

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    Oesterle Doris

    2006-01-01

    Full Text Available Abstract In colorectal cancer insulin-like growth factor II (IGF-II is frequently overexpressed. To evaluate, whether IGF-II affects different stages of tumorigenesis, we induced neoplastic alterations in the colon of wild-type and IGF-II transgenic mice using 1,2-dimethylhydrazine (DMH. Aberrant crypt foci (ACF served as markers of early lesions in the colonic mucosa, whereas adenomas and carcinomas characterized the endpoints of tumor development. DMH-treatment led initially to significantly more ACF in IGF-II transgenic than in wild-type mice. This increase in ACF was especially prominent for those consisting of ≥three aberrant crypts (AC. Nevertheless, adenomas and adenocarcinomas of the colon, present after 34 weeks in both genetic groups, were not found at different frequency. Tumor volumes, however, were significantly higher in IGF-II transgenic mice and correlated with serum IGF-II levels. Immunohistochemical staining for markers of proliferation and apoptosis revealed increased cell proliferation rates in tumors of IGF-II transgenic mice without significant affection of apoptosis. Increased proliferation was accompanied by elevated localization of β-catenin in the cytosol and cell nuclei and reduced appearance at the inner plasma membrane. In conclusion, we provide evidence that IGF-II, via activation of the β-catenin signaling cascade, promotes growth of ACF and tumors without affecting tumor numbers.

  8. Serum levels of IGF-1 and IGF-BP3 are associated with event-free survival in adult Ewing sarcoma patients treated with chemotherapy

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    de Groot S

    2017-06-01

    Full Text Available Stefanie de Groot,1 Hans Gelderblom,1 Marta Fiocco,2,3 Judith VMG Bovée,4 Jacobus JM van der Hoeven,1 Hanno Pijl,5 Judith R Kroep1 1Department of Medical Oncology, 2Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 3Mathematical Department, Leiden University, 4Department of Pathology, 5Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands Background: Activation of the insulin-like growth factor 1 (IGF-1 pathway is involved in cell growth and proliferation and is associated with tumorigenesis, tumor progression, and therapy resistance in solid tumors. We examined whether variability in serum levels of IGF-1, IGF-2, and IGF-binding protein 3 (IGF-BP3 can predict event-free survival (EFS and overall survival (OS in Ewing sarcoma patients treated with chemotherapy.Patients and methods: Serum levels of IGF-1, IGF-2, and IGF-BP3 of 22 patients with localized or metastasized Ewing sarcoma treated with six cycles of vincristine/ifosfamide/doxorubicin/etoposide (VIDE chemotherapy were recorded. Baseline levels were compared with presixth cycle levels using paired t-tests and were tested for associations with EFS and OS. Continuous variables were dichotomized according to the Contal and O’Quigley procedure. Survival analyses were performed using Cox regression analysis.Results: High baseline IGF-1 and IGF-BP3 serum levels were associated with EFS (hazard ratio [HR] 0.075, 95% confidence interval [CI] 0.009–0.602 and HR 0.090, 95% CI 0.011–0.712, respectively in univariate and multivariate analyses (HR 0.063, 95% CI 0.007–0.590 and HR 0.057, 95% CI 0.005–0.585, respectively. OS was improved, but this was not statistically significant. IGF-BP3 and IGF-2 serum levels increased during treatment with VIDE chemotherapy (P=0.055 and P=0.023, respectively.Conclusion: High circulating serum levels of IGF-1 and IGF-BP3 and the molar ratio of IGF-1:IGF-BP3 serum levels were associated

  9. A polymorphism in the IGF-I gene influences the age-related decline in circulating total IGF-I levels

    NARCIS (Netherlands)

    I. Rietveld (Ingrid); J.A.M.J.L. Janssen (Joseph); A. Hofman (Albert); C.M. van Duijn (Cornelia); S.W.J. Lamberts (Steven); H.A.P. Pols (Huib)

    2003-01-01

    markdownabstractOBJECTIVE: Recent studies have demonstrated an association between a 192 bp polymorphism of the IGF-I gene and total IGF-I serum levels, birth weight, body height and the risk of developing diabetes and cardiovascular diseases later on in life. This IGF-I gene polymorphism in the

  10. Shifting the IGF-axis: An age-related decline in human tear IGF-1 correlates with clinical signs of dry eye.

    Science.gov (United States)

    Patel, Roshni; Zhu, Meifang; Robertson, Danielle M

    2018-02-06

    The human corneal epithelium expresses both the insulin-like growth factor type 1 receptor (IGF-1R) and the IGF-1R/insulin receptor (INSR) hybrid. Despite the previous identification of IGF-1 in human tear fluid, little is known regarding the regulation of IGF-1 in tear fluid and its role in corneal epithelial homeostasis. In the present study, we investigated the impact of biological parameters on the concentration of human tear levels of IGF-1. Tear levels of IGF-1 were measured in 41 healthy, human volunteers without any reported symptoms of dry eye. All volunteers underwent standard biomicroscopic examination of the cornea and tear film. In a subgroup of volunteers, corneal staining with sodium fluorescein, tear film break up time and tear production using a Schirmer's test strip were measured to assess clinical signs of dry eye. Tears were collected from the inferior tear meniscus using glass microcapillary tubes and IGF-1 levels were measured using a solid phase sandwich ELISA. Tear levels of IGF-1 were highest in young adults and significantly decreased in older adults (P = 0.003). There were no differences in tear IGF-1 between males and females (P = 0.628). Tear IGF-1 levels were correlated with tear film break up time (R = 0.738) and tear production (R = 0.826). These data indicate that there is a progressive decline in tear IGF-1 due to aging that is associated with clinical signs of dry eye. This effect is likely due to age-related changes in the lacrimal gland. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Isolation of an inhibitory insulin-like growth factor (IGF) binding protein from bone cell-conditioned medium: A potential local regulator of IGF action

    International Nuclear Information System (INIS)

    Mohan, S.; Bautista, C.M.; Wergedal, J.; Baylink, D.J.

    1989-01-01

    Inhibitory insulin-like growth factor binding protein (In-IGF-BP) has been purified to homogeneity from medium conditioned by TE89 human osteosarcoma cells by two different methods using Sephadex G-100 gel filtration, FPLC Mono Q ion-exchange, HPLC C 4 reverse-phase, HPLC CN reverse-phase and affinity chromatographies. In-IGF-BP thus purified appeared to be homogeneous and unique by the following criteria. (i) N-terminal sequence analysis yielded a unique sequence (Asp-Glu-Ala-Ile-His-Cys-Pro-Pro-Glu-Ser-Glu-Ala-Lys-Leu-Ala). (ii) Amino acid composition of In-IGF-BP revealed marked differences with the amino acid compositions of other known PBs. (iii) In-IGF-BP exhibited a single band with molecular mass of 25 kDa under reducing conditions on sodium dodecyl sulfate/polyacrylamide gels. IGF-I and IGF-II but not insulin displaced the binding of 125 I-labeled IGF-I or 125 I-labeled IGF-II binding to In-IGF-BP. In-IGF-BP inhibited basal, IGF-stimulated bone cell proliferation and serum-stimulated bone cell proliferation. Forskolin increases synthesis of In-IGF-BP in TE85 human osteosarcoma cells in a dose-dependent manner. Based on these findings, the authors conclude that In-IGF-BP is a protein that has a unique sequence and significant biological actions on bone cells

  12. Gene Expression of IGF1, IGF1R, and IGFBP3 in Epiretinal Membranes of Patients with Proliferative Diabetic Retinopathy: Preliminary Study

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    Dorota Romaniuk

    2013-01-01

    Full Text Available The molecular mechanism formation of secondary epiretinal membranes (ERMs after proliferative diabetic retinopathy (PDR or primary idiopathic ERMs is still poorly understood. Therefore, the present study focused on the assessment of IGF1, IGF1R, and IGFBP3 mRNA levels in ERMs and PBMCs from patients with PDR. The examined group comprised 6 patients with secondary ERMs after PDR and the control group consisted of 11 patients with idiopathic ERMs. Quantification of IGF1, IGF1R, and IGFBP3 mRNAs was performed by real-time QRT-PCR technique. In ERMs, IGF1 and IGF1R mRNA levels were significantly higher in patients with diabetes compared to control subjects. In PBMCs, there were no statistically significant differences of IGF1, IGF1R, and IGFBP3 expression between diabetic and nondiabetic patients. In conclusion, our study indicated IGF1 and IGF1R differential expression in ERMs, but not in PBMCs, of diabetic and nondiabetic patients, suggesting that these factors can be involved in the pathogenesis or progression of proliferative vitreoretinal disorders. This trial is registered with NCT00841334.

  13. Organ-Specific and Age-Dependent Expression of Insulin-like Growth Factor-I (IGF-I) mRNA Variants: IGF-IA and IB mRNAs in the Mouse

    OpenAIRE

    Ohtsuki, Takashi; Otsuki, Mariko; Murakami, Yousuke; Maekawa, Tetsuya; Yamamoto, Takashi; Akasaka, Koji; Takeuchi, Sakae; Takahashi, Sumio

    2005-01-01

    Insulin-like growth factor-I (IGF-I) gene generates several IGF-I mRNA variants by alternative splicing. Two promoters are present in mouse IGF-I gene. Each promoter encodes two IGF-I mRNA variants (IGF-IA and IGF-IB mRNAs). Variants differ by the presence (IGF-IB) or absence (IGF-IA) of a 52-bp insert in the E domain-coding region. Functional differences among IGF-I mRNAs, and regulatory mechanisms for alternative splicing of IGF-I mRNA are not yet known. We analyzed the expression of mouse ...

  14. A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis

    International Nuclear Information System (INIS)

    Dearth, Robert K; Kuiatse, Isere; Wang, Yu-Fen; Liao, Lan; Hilsenbeck, Susan G; Brown, Powel H; Xu, Jianming; Lee, Adrian V

    2011-01-01

    Epidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth. We crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic), TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt). Virgin females were palpated twice a week and harvested when tumors reached 1000 mm 3 . For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice. TTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65). Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23). There were no morphological differences in tumor type (solid adenocarcinomas) between bigenic and ErbB2 mammary glands. Using the first transgenic animal model to

  15. Normal Values of Circulating IGF-I Bioactivity in the Healthy Population: Comparison with five widely used IGF-I immunoassays

    NARCIS (Netherlands)

    M.P. Brugts (Michael); M.B. Ranke (Michael); L.J. Hofland (Leo); K. van der Wansem (Katy); K. Weber (Karin); J. Frystyk (Jan); S.W.J. Lamberts (Steven); J.A.M.J.L. Janssen (Joseph)

    2008-01-01

    textabstractBackground: IGF-I immunoassays are primarily used to estimate IGF-I bioactivity. Recently, an IGFI specific Kinase Receptor Activation Assay (KIRA) has been developed as an alternative method. However, no normative values have been established for the IGF-I KIRA. Objective: To

  16. Insulin-Like Growth Factor (IGF System in Liver Diseases

    Directory of Open Access Journals (Sweden)

    Agnieszka Adamek

    2018-04-01

    Full Text Available Hepatocyte differentiation, proliferation, and apoptosis are affected by growth factors produced in liver. Insulin-like growth factor 1 and 2 (IGF1 and IGF2 act in response to growth hormone (GH. Other IGF family components include at least six binding proteins (IGFBP1 to 6, manifested by both IGFs develop due to interaction through the type 1 receptor (IGF1R. The data based on animal models and/or in vitro studies suggest the role of IGF system components in cellular aspects of hepatocarcinogenesis (cell cycle progression, uncontrolled proliferation, cell survival, migration, inhibition of apoptosis, protein synthesis and cell growth, and show that systemic IGF1 administration can reduce fibrosis and ameliorate general liver function. In epidemiologic and clinicopathological studies on chronic liver disease (CLD, lowered serum levels, decreased tissue expression of IGF1, elevated production of IGF1R and variable IGF2 expression has been noted, from the start of preneoplastic alterations up to the developed hepatocellular carcinoma (HCC stage. These changes result in well-known clinical symptoms of IGF1 deficiency. This review summarized the current data of the complex role of IGF system components in the most common CLD (nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma. Better recognition and understanding of this system can contribute to discovery of new and improved versions of current preventive and therapeutic actions in CLD.

  17. Estimated Prestroke Peak VO2 Is Related to Circulating IGF-1 Levels During Acute Stroke.

    Science.gov (United States)

    Mattlage, Anna E; Rippee, Michael A; Abraham, Michael G; Sandt, Janice; Billinger, Sandra A

    2017-01-01

    Background Insulin-like growth factor-1 (IGF-1) is neuroprotective after stroke and is regulated by insulin-like binding protein-3 (IGFBP-3). In healthy individuals, exercise and improved aerobic fitness (peak oxygen uptake; peak VO 2 ) increases IGF-1 in circulation. Understanding the relationship between estimated prestroke aerobic fitness and IGF-1 and IGFBP-3 after stroke may provide insight into the benefits of exercise and aerobic fitness on stroke recovery. Objective The purpose of this study was to determine the relationship of IGF-1 and IGFBP-3 to estimated prestroke peak VO 2 in individuals with acute stroke. We hypothesized that (1) estimated prestroke peak VO 2 would be related to IGF-1 and IGFBP-3 and (2) individuals with higher than median IGF-1 levels will have higher estimated prestroke peak VO 2 compared to those with lower than median levels. Methods Fifteen individuals with acute stroke had blood sampled within 72 hours of hospital admission. Prestroke peak VO 2 was estimated using a nonexercise prediction equation. IGF-1 and IGFBP-3 levels were quantified using enzyme-linked immunoassay. Results Estimated prestroke peak VO 2 was significantly related to circulating IGF-1 levels (r = .60; P = .02) but not IGFBP-3. Individuals with higher than median IGF-1 (117.9 ng/mL) had significantly better estimated aerobic fitness (32.4 ± 6.9 mL kg -1 min -1 ) than those with lower than median IGF-1 (20.7 ± 7.8 mL kg -1 min -1 ; P = .03). Conclusions Improving aerobic fitness prior to stroke may be beneficial by increasing baseline IGF-1 levels. These results set the groundwork for future clinical trials to determine whether high IGF-1 and aerobic fitness are beneficial to stroke recovery by providing neuroprotection and improving function. © The Author(s) 2016.

  18. Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-α activation via the mitogen-activated protein kinase pathway

    International Nuclear Information System (INIS)

    Thordarson, Gudmundur; Slusher, Nicole; Leong, Harriet; Ochoa, Dafne; Rajkumar, Lakshmanaswamy; Guzman, Raphael; Nandi, Satyabrata; Talamantes, Frank

    2004-01-01

    Pregnancy protects against breast cancer development in humans and rats. Parous rats have persistently reduced circulating levels of growth hormone, which may affect the activity of the growth hormone/insulin-like growth factor (IGF)-I axis. We investigated the effects of IGF-I on parity-associated protection against mammary cancer. Three groups of rats were evaluated in the present study: IGF-I-treated parous rats; parous rats that did not receive IGF-I treatment; and age-matched virgin animals, which also did not receive IGF-I treatment. Approximately 60 days after N-methyl-N-nitrosourea injection, IGF-I treatment was discontinued and all of the animal groups were implanted with a silastic capsule containing 17β-estradiol and progesterone. The 17β-estradiol plus progesterone treatment continued for 135 days, after which the animals were killed. IGF-I treatment of parous rats increased mammary tumor incidence to 83%, as compared with 16% in parous rats treated with 17β-estradiol plus progesterone only. Tumor incidence and average number of tumors per animal did not differ between IGF-I-treated parous rats and age-matched virgin rats. At the time of N-methyl-N-nitrosourea exposure, DNA content was lowest but the α-lactalbumin concentration highest in the mammary glands of untreated parous rats in comparison with age-matched virgin and IGF-I-treated parous rats. The protein levels of estrogen receptor-α in the mammary gland was significantly higher in the age-matched virgin animals than in untreated parous and IGF-I-treated parous rats. Phosphorylation (activation) of the extracellular signal-regulated kinase-1/2 (ERK1/2) and expression of the progesterone receptor were both increased in IGF-I-treated parous rats, as compared with those in untreated parous and age-matched virgin rats. Expressions of cyclin D 1 and transforming growth factor-β 3 in the mammary gland were lower in the age-matched virgin rats than in the untreated parous and IGF-I-treated parous

  19. Insulin-like growth factor II (IGF II) in human brain: regional distribution of IGF II and of higher molecular mass forms

    International Nuclear Information System (INIS)

    Haselbacher, G.K.; Schwab, M.E.; Pasi, A.; Humbel, R.E.

    1985-01-01

    Twenty-four distinct areas of human brain were analyzed for the presence of insulin-like growth factor (IGF). As reported for cerebrospinal fluid, only IGF II-like immunoreactivity, but no significant amounts of IGF I-like immunoreactivity, could be found. Upon gel permeation chromatography, two to five distinct size classes were separated on the basis of their immunoreactivity. Radioimmunoassays and a bioassay also gave results indistinguishable from those of serum IGF II. The highest amounts of IGF II-like immunoreactivity occur in the anterior pituitary. This is up to 100 times more than in most other brain regions analyzed. The higher molecular mass immunoreactive species were partially characterized. After immunoaffinity purification, the 38- and 26-kDa species are active in a bioassay. Specific IGF-binding protein activity could be shown after purification of the 38- and 26-kDa species on an IGF-affinity column. The 13-kDa species released significant amounts of 7.5-kDa material. The results are interpreted as evidence for the presence of IGF II synthesized locally in human brain

  20. Altered expression of IGF-I system in neurons of the inflamed spinal cord during acute experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Parvaneh Tafreshi, Azita; Talebi, Farideh; Ghorbani, Samira; Bernard, Claude; Noorbakhsh, Farshid

    2017-10-01

    There is growing evidence that the impaired IGF-I system contributes to neurodegeneration. In this study, we examined the spinal cords of the EAE, the animal model of multiple sclerosis, to see if the expression of the IGF-I system is altered. To induce EAE, C57/BL6 mice were immunized with the Hooke lab MOG kit, sacrificed at the peak of the disease and their spinal cords were examined for the immunoreactivities (ir) of the IGF-I, IGF binding protein-1 (IGFBP-1) and glycogen synthase kinase 3β (GSK3β), as one major downstream molecule in the IGF-I signaling. Although neurons in the non EAE spinal cords did not show the IGF-I immunoreactivity, they were numerously positive for the IGFBP-1. In the inflamed EAE spinal cord however, the patterns of expressions were reversed, that is, a significant increased number of IGF-I expressing neurons versus a reduced number of IGFBP-1 positive neurons. Moreover, while nearly all IGF-I-ir neurons expressed GSK3β, some expressed it more intensely. Considering our previous finding where we showed a significant reduced number of the inactive (phosphorylated) but not that of the total GSK3β expressing neurons in the EAE spinal cord, it is conceivable that the intense total GSK3β expression in the IGF-I-ir neurons belongs to the active form of GSK3β known to exert neuroinflammatory effects. We therefore suggest that the altered expression of the IGF-I system including GSK3β in spinal cord neurons might involve in pathophysiological events during the EAE. © 2017 Wiley Periodicals, Inc.

  1. IGF-1 Promotes Brn-4 Expression and Neuronal Differentiation of Neural Stem Cells via the PI3K/Akt Pathway

    Science.gov (United States)

    Zhang, Xinhua; Zhang, Lei; Cheng, Xiang; Guo, Yuxiu; Sun, Xiaohui; Chen, Geng; Li, Haoming; Li, Pengcheng; Lu, Xiaohui; Tian, Meiling; Qin, Jianbing; Zhou, Hui; Jin, Guohua

    2014-01-01

    Our previous studies indicated that transcription factor Brn-4 is upregulated in the surgically denervated hippocampus in vivo, promoting neuronal differentiation of hippocampal neural stem cells (NSCs) in vitro. The molecules mediating Brn-4 upregulation in the denervated hippocampus remain unknown. In this study we examined the levels of insulin-like growth factor-1 (IGF-1) in hippocampus following denervation. Surgical denervation led to a significant increase in IGF-1 expression in vivo. We also report that IGF-1 treatment on NSCs in vitro led to a marked acceleration of Brn-4 expression and cell differentiation down neuronal pathways. The promotion effects were blocked by PI3K-specific inhibitor (LY294002), but not MAPK inhibitor (PD98059); levels of phospho-Akt were increased by IGF-1 treatment. In addition, inhibition of IGF-1 receptor (AG1024) and mTOR (rapamycin) both attenuated the increased expression of Brn-4 induced by IGF-1. Together, the results demonstrated that upregulation of IGF-1 induced by hippocampal denervation injury leads to activation of the PI3K/Akt signaling pathway, which in turn gives rise to upregulation of the Brn-4 and subsequent stem cell differentiation down neuronal pathways. PMID:25474202

  2. The role of the IGF axis in IGFBP-1 and IGF-I induced renal enlargement in Snell dwarf mice

    NARCIS (Netherlands)

    M. van Kleffens (Marjolein); D.J. Lindenbergh-Kortleve (Dicky); J.G. Koster; J.W. van Neck (Han); A. Flyvbjerg (Allan); R. Rasch; S.L.S. Drop (Stenvert); S.C. van Buul-Offers

    2001-01-01

    textabstractInsulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is generally believed to inhibit IGF action in the circulation. In contrast, IGFBP-1 has been reported to interact with cell surfaces and enhance IGF-I action locally in some tissues. Renal IGFBP-1 levels are

  3. β-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma.

    Science.gov (United States)

    Xu, Chuan; Xie, Dan; Yu, Shi-Cang; Yang, Xiao-Jun; He, Li-Ru; Yang, Jing; Ping, Yi-Fang; Wang, Bin; Yang, Lang; Xu, Sen-Lin; Cui, Wei; Wang, Qing-Liang; Fu, Wen-Juan; Liu, Qing; Qian, Cheng; Cui, You-Hong; Rich, Jeremy N; Kung, Hsiang-Fu; Zhang, Xia; Bian, Xiu-Wu

    2013-05-15

    Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3β/β-catenin cascade. POU5F1 could form a novel complex with β-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with β-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR-mediated POU5F1 expression to form a complex with β-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, β-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma. ©2013 AACR.

  4. The Role of Type I Insulin Like Growth Factor Receptor (IGF-IR) in Adult and Childhood Acute Lymphoblastic Leukemia

    International Nuclear Information System (INIS)

    KAMEL, M.M.; HAMMAM, A.A.; ELHOSEINY, Sh.M.; MOKHLES, A.; MOHSEN, E.

    2008-01-01

    Background: Type 1 insulin like growth factor receptor (IGF-IR) is over expressed in many tumors including hematological cancers. It is a critical signaling molecule for tumor cell proliferation and survival. Data suggest that IGF-IR antibodies can effectively and specifically inhibit cancer cell growth in vitro and in vivo. Blockage of IGF-IR expression could be a promising therapeutic approach for the management of cancer patients. Aim of Work: To characterize the expression pattern of IGF-IR gene in malignant lymphoblasts of children and adults suffering from ALL in relation to clinical features at diagnosis. Patients and Methods: The expression of IGF-IR was analyzed in 60 patients with ALL, 30 childhood ALL (16 newly diagnosed and 14 in complete remission) and 30 adulthood ALL (15 newly diagnosed and 15 in complete remission) together with 20 normal age and sex matched healthy controls using a Real-Time Quantitative Reverse- Transcriptase Polymerase Chain Reaction (RTQ-PCR) to assess the possible relation, association or correlation between IGF-IR expression and ALL clinical and laboratory features at diagnosis. Results: IGF-IR was expressed in all 60 patients with ALL; the expression levels of IGF-IR were significantly higher in newly diagnosed patients than in patients in complete remission (CR) and controls (p<0.001). There were no statistically significant differences in the expression of IGF-IR between patients with different clinical and laboratory features. Conclusion: IGF-1R seems to play a crucial role in patients with ALL since it is expressed in all ALL cases (adulthood and childhood). Therefore, new therapeutic agents targeting IGF-1R may provide a better chance for those patients

  5. IGF-1R Promotes Symmetric Self-Renewal and Migration of Alkaline Phosphatase+ Germ Stem Cells through HIF-2α-OCT4/CXCR4 Loop under Hypoxia.

    Science.gov (United States)

    Kuo, Yung-Che; Au, Heng-Kien; Hsu, Jue-Liang; Wang, Hsiao-Feng; Lee, Chiung-Ju; Peng, Syue-Wei; Lai, Ssu-Chuan; Wu, Yu-Chih; Ho, Hong-Nerng; Huang, Yen-Hua

    2018-02-13

    Hypoxia cooperates with endocrine signaling to maintain the symmetric self-renewal proliferation and migration of embryonic germline stem cells (GSCs). However, the lack of an appropriate in vitro cell model has dramatically hindered the understanding of the mechanism underlying this cooperation. Here, using a serum-free system, we demonstrated that hypoxia significantly induced the GSC mesenchymal transition, increased the expression levels of the pluripotent transcription factor OCT4 and migration-associated proteins (SDF-1, CXCR4, IGF-1, and IGF-1R), and activated the cellular expression and translocalization of the CXCR4-downstream proteins ARP3/pFAK. The underlying mechanism involved significant IGF-1/IGF-1R activation of OCT4/CXCR4 expression through HIF-2α regulation. Picropodophyllin-induced inhibition of IGF-1R phosphorylation significantly suppressed hypoxia-induced SDF-1/CXCR4 expression and cell migration. Furthermore, transactivation between IGF-1R and CXCR4 was involved. In summary, we demonstrated that niche hypoxia synergistically cooperates with its associated IGF-1R signaling to regulate the symmetric division (self-renewal proliferation) and cell migration of alkaline phosphatase-positive GSCs through HIF-2α-OCT4/CXCR4 during embryogenesis. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. Experimental approach to IGF-1 therapy in CCl4-induced acute liver damage in healthy controls and mice with partial IGF-1 deficiency.

    Science.gov (United States)

    Morales-Garza, Luis A; Puche, Juan E; Aguirre, Gabriel A; Muñoz, Úrsula; García-Magariño, Mariano; De la Garza, Rocío G; Castilla-Cortazar, Inma

    2017-05-04

    Cell necrosis, oxidative damage, and fibrogenesis are involved in cirrhosis development, a condition in which insulin-like growth factor 1 (IGF-1) levels are diminished. This study evaluates whether the exogenous administration of low doses of IGF-1 can induce hepatoprotection in acute carbon tetrachloride (CCl 4 )-induced liver damage compared to healthy controls (Wt Igf +/+ ). Additionally, the impact of IGF-1 deficiency on a damaged liver was investigated in mice with a partial deficit of this hormone (Hz Igf1 +/- ). Three groups of 25 ± 5-week-old healthy male mice (Wt Igf +/+ ) were included in the protocol: untreated controls (Wt). Controls that received CCl 4 (Wt + CCl 4 ) and Wt + CCl 4 were treated subcutaneously with IGF-1 (2 µg/100 g body weight/day) for 10 days (Wt + CCl 4  + IGF1). In parallel, three IGF-1-deficient mice (Hz Igf1 +/- ) groups were studied: untreated Hz, Hz + CCl 4 , and Hz + CCl 4  + IGF-1. Microarray and real-time quantitative polymerase chain reaction (RT-qPCR) analyses, serum aminotransferases levels, liver histology, and malondialdehyde (MDA) levels were assessed at the end of the treatment in all groups. All data represent mean ± SEM. An altered gene coding expression pattern for proteins of the extracellular matrix, fibrosis, and cellular protection were found, as compared to healthy controls, in which IGF-1 therapy normalized in the series including healthy mice. Liver histology showed that Wt + CCl 4  + IGF1 mice had less oxidative damage, fibrosis, lymphocytic infiltrate, and cellular changes when compared to the Wt + CCl 4 . Moreover, there was a correlation between MDA levels and the histological damage score (Pearson's r = 0.858). In the IGF-1-deficient mice series, similar findings were identified, denoting a much more vulnerable hepatic parenchyma. IGF1 treatment improved the biochemistry, histology, and genetic expression of pro-regenerative and cytoprotective factors in both series

  7. Role of insulin-like growth factor-1 (IGF-1) in regulating cell cycle progression

    International Nuclear Information System (INIS)

    Ma, Qi-lin; Yang, Tian-lun; Yin, Ji-ye; Peng, Zhen-yu; Yu, Min; Liu, Zhao-qian; Chen, Fang-ping

    2009-01-01

    Aims: Insulin-like growth factor-1 (IGF-1) is a polypeptide protein hormone, similar in molecular structure to insulin, which plays an important role in cell migration, cell cycle progression, cell survival and proliferation. In this study, we investigated the possible mechanisms of IGF-1 mediated cell cycle redistribution and apoptosis of vascular endothelial cells. Method: Human umbilical vein endothelial cells (HUVECs) were pretreated with 0.1, 0.5, or 2.5 μg/mL of IGF-1 for 30 min before the addition of Ang II. Cell cycle redistribution and apoptosis were examined by flow cytometry. Expression of Ang II type 1 (AT 1 ) mRNA and cyclin E protein were determined by RT-PCR and Western blot, respectively. Results: Ang II (1 μmol/L) induced HUVECs arrested at G 0 /G 1 , enhanced the expression level of AT 1 mRNA in a time-dependent manner, reduced the enzymatic activity of nitric oxide synthase (NOS) and nitric oxide (NO) content as well as the expression level of cyclin E protein. However, IGF-1 enhanced NOS activity, NO content, and the expression level of cyclin E protein, and reduced the expression level of AT 1 mRNA. L-NAME significantly counteracted these effects of IGF-1. Conclusions: Our data suggests that IGF-1 can reverse vascular endothelial cells arrested at G 0 /G 1 and apoptosis induced by Ang II, which might be mediated via a NOS-NO signaling pathway and is likely associated with the expression levels of AT1 mRNA and cyclin E proteins.

  8. IGF-1 and PDGF-bb Suppress IL-1β-Induced Cartilage Degradation through Down-Regulation of NF-κB Signaling: Involvement of Src/PI-3K/AKT Pathway

    Science.gov (United States)

    Mobasheri, Ali; Buhrmann, Constanze; Aldinger, Constance; Rad, Jafar Soleimani; Shakibaei, Mehdi

    2011-01-01

    Objective Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that plays a key role in the pathogenesis of osteoarthritis (OA). Growth factors (GFs) capable of antagonizing the catabolic actions of cytokines may have therapeutic potential in the treatment of OA. Herein, we investigated the potential synergistic effects of insulin-like growth factor (IGF-1) and platelet-derived growth factor (PDGF-bb) on different mechanisms participating in IL-1β-induced activation of nuclear transcription factor-κB (NF-κB) and apoptosis in chondrocytes. Methods Primary chondrocytes were treated with IL-1β to induce dedifferentiation and co-treated with either IGF-1 or/and PDGF-bb and evaluated by immunoblotting and electron microscopy. Results Pretreatment of chondrocytes with IGF-1 or/and PDGF-bb suppressed IL-1β-induced NF-κB activation via inhibition of IκB-α kinase. Inhibition of IκB-α kinase by GFs led to the suppression of IκB-α phosphorylation and degradation, p65 nuclear translocation and NF-κB-regulated gene products involved in inflammation and cartilage degradation (COX-2, MMPs) and apoptosis (caspase-3). GFs or BMS-345541 (specific inhibitor of the IKK) reversed the IL-1β-induced down-regulation of collagen type II, cartilage specific proteoglycans, β1-integrin, Shc, activated MAPKinase, Sox-9 and up-regulation of active caspase-3. Furthermore, the inhibitory effects of IGF-1 or/and PDGF-bb on IL-1β-induced NF-κB activation were sensitive to inhibitors of Src (PP1), PI-3K (wortmannin) and Akt (SH-5), suggesting that the pathway consisting of non-receptor tyrosine kinase (Src), phosphatidylinositol 3-kinase and protein kinase B must be involved in IL-1β signaling. Conclusion The results presented suggest that IGF-1 and PDGF-bb are potent inhibitors of IL-1β-mediated activation of NF-κB and apoptosis in chondrocytes, may be mediated in part through suppression of Src/PI-3K/AKT pathway, which may contribute to their anti-inflammatory effects. PMID

  9. Stimulation of liver IGF-1 expression promotes peak bone mass achievement in growing rats: a study with pomegranate seed oil.

    Science.gov (United States)

    Bachagol, Deepa; Joseph, Gilbert Stanley; Ellur, Govindraj; Patel, Kalpana; Aruna, Pamisetty; Mittal, Monika; China, Shyamsundar Pal; Singh, Ravendra Pratap; Sharan, Kunal

    2018-02-01

    Peak bone mass (PBM) achieved at adulthood is a strong determinant of future onset of osteoporosis, and maximizing it is one of the strategies to combat the disease. Recently, pomegranate seed oil (PSO) has been shown to have bone-sparing effect in ovariectomized mice. However, its effect on growing skeleton and its molecular mechanism remain unclear. In the present study, we evaluated the effect of PSO on PBM in growing rats and associated mechanism of action. PSO was given at various doses to 21-day-old growing rats for 90 days by oral gavage. The changes in bone parameters were assessed by micro-computed tomography and histology. Enzyme-linked immunosorbent assay was performed to analyze the levels of serum insulin-like growth factor type 1 (IGF-1). Western blotting from bone and liver tissues was done. Chromatin immunoprecipitation assay was performed to study the histone acetylation levels at IGF-1 gene. The results of the study show that PSO treatment significantly increases bone length, bone formation rate, biomechanical parameters, bone mineral density and bone microarchitecture along with enhancing muscle and brown fat mass. This effect was due to the increased serum levels of IGF-1 and stimulation of its signaling in the bones. Studies focusing on acetylation of histones in the liver, the major site of IGF-1 synthesis, showed enrichment of acetylated H3K9 and H3K14 at IGF-1 gene promoter and body. Further, the increased acetylation at H3K9 and H3K14 was associated with a reduced HDAC1 protein level. Together, our data suggest that PSO promotes the PBM achievement via increased IGF-1 expression in liver and IGF-1 signaling in bone. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link

    Science.gov (United States)

    Bowers, Laura W.; Rossi, Emily L.; O’Flanagan, Ciara H.; deGraffenried, Linda A.; Hursting, Stephen D.

    2015-01-01

    Numerous epidemiological and pre-clinical studies have demonstrated that the insulin/insulin-like growth factor (IGF) system plays a key role in the development and progression of several types of cancer. Insulin/IGF signaling, in cooperation with chronic low-grade inflammation, is also an important contributor to the cancer-promoting effects of obesity. However, clinical trials for drugs targeting different components of this system have produced largely disappointing results, possibly due to the lack of predictive biomarker use and problems with the design of combination therapy regimens. With careful attention to the identification of likely patient responders and optimal drug combinations, the outcome of future trials may be improved. Given that insulin/IGF signaling is known to contribute to obesity-associated cancer, further investigation regarding the efficacy of drugs targeting this system and its downstream effectors in the obese patient population is warranted. PMID:26029167

  11. Heat shock factor-1 intertwines insulin/IGF-1, TGF-β and cGMP signaling to control development and aging

    Directory of Open Access Journals (Sweden)

    Barna János

    2012-11-01

    Full Text Available Abstract Background Temperature affects virtually all cellular processes. A quick increase in temperature challenges the cells to undergo a heat shock response to maintain cellular homeostasis. Heat shock factor-1 (HSF-1 functions as a major player in this response as it activates the transcription of genes coding for molecular chaperones (also called heat shock proteins that maintain structural integrity of proteins. However, the mechanisms by which HSF-1 adjusts fundamental cellular processes such as growth, proliferation, differentiation and aging to the ambient temperature remain largely unknown. Results We demonstrate here that in Caenorhabditis elegans HSF-1 represses the expression of daf-7 encoding a TGF-β (transforming growth factor-beta ligand, to induce young larvae to enter the dauer stage, a developmentally arrested, non-feeding, highly stress-resistant, long-lived larval form triggered by crowding and starvation. Under favorable conditions, HSF-1 is inhibited by crowding pheromone-sensitive guanylate cyclase/cGMP (cyclic guanosine monophosphate and systemic nutrient-sensing insulin/IGF-1 (insulin-like growth factor-1 signaling; loss of HSF-1 activity allows DAF-7 to promote reproductive growth. Thus, HSF-1 interconnects the insulin/IGF-1, TGF-β and cGMP neuroendocrine systems to control development and longevity in response to diverse environmental stimuli. Furthermore, HSF-1 upregulates another TGF-β pathway-interacting gene, daf-9/cytochrome P450, thereby fine-tuning the decision between normal growth and dauer formation. Conclusion Together, these results provide mechanistic insight into how temperature, nutrient availability and population density coordinately influence development, lifespan, behavior and stress response through HSF-1.

  12. Correlation between GH and IGF-1 during treatment for acromegaly.

    Science.gov (United States)

    Oldfield, Edward H; Jane, John A; Thorner, Michael O; Pledger, Carrie L; Sheehan, Jason P; Vance, Mary Lee

    2017-06-01

    OBJECTIVE The relationship between growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly as serial levels drop over time after treatment has not been examined previously. Knowledge of this relationship is important to correlate pretreatment levels that best predict response to treatment. To examine the correlation between GH and IGF-1 and IGF-1 z-scores over a wide range of GH levels, the authors examined serial GH and IGF-1 levels at intervals before and after surgery and radiosurgery for acromegaly. METHODS This retrospective analysis correlates 414 pairs of GH and IGF-1 values in 93 patients with acromegaly. RESULTS Absolute IGF-1 levels increase linearly with GH levels only up to a GH of 4 ng/ml, and with IGF-1 z-scores only to a GH level of 1 ng/ml. Between GH levels of 1 and 10 ng/ml, increases in IGF-1 z-scores relative to changes in GH diminish and then plateau at GH concentrations of about 10 ng/ml. From patient to patient there is a wide range of threshold GH levels beyond which IGF-1 increases are no longer linear, GH levels at which the IGF-1 response plateaus, IGF-1 levels at similar GH values after the IGF-1 response plateaus, and of IGF-1 levels at similar GH levels. CONCLUSIONS In acromegaly, although IGF-1 levels represent a combination of the integrated effects of GH secretion and GH action, the tumor produces GH, not IGF-1. Nonlinearity between GH and IGF-1 occurs at GH levels far below those previously recognized. To monitor tumor activity and tumor viability requires measurement of GH levels.

  13. Branchial expression and localization of the insulin-like growth factor 1 (IGF-1) receptor and changes in plasma IGF-1 and IGF-1 binding protein in striped bass during salinity acclimation

    DEFF Research Database (Denmark)

    Tipsmark, Christian Kølbæk; Madsen, Steffen; Borski, Russell

    2006-01-01

    In euryhaline teleosts the insulin-like growth factor 1 (IGF-1)/growth hormone axis is known to affect salinity tolerance and gill Na,K-ATPase activity. However, virtually nothing is known on expression and cellular localization of the IGF-1 receptor (IGF-1R) in the teleost gill during salinity a...

  14. The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing

    OpenAIRE

    Kenyon, Cynthia

    2011-01-01

    Inhibiting insulin/IGF-1 signalling extends lifespan and delays age-related disease in species throughout the animal kingdom. This life-extension pathway, the first to be defined, was discovered through genetic studies in the small roundworm Caenorhabditis elegans. This discovery is described here.

  15. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 levels are increased in central precocious puberty

    DEFF Research Database (Denmark)

    Juul, A; Scheike, Thomas Harder; Nielsen, C T

    1995-01-01

    between IGF-I and IGFBP-3 (i.e. free biologically active IGF-I) declined concomitantly with a decrease in growth velocity. Serum levels of IGF-I and IGFBP-3 (expressed as the SD score for bone age), but not those of estradiol, correlated with height velocity before and during treatment (r = 0.34; P ...Central precocious puberty (CPP) is characterized by early activation of the pituitary-gonadal axis, which leads to increased growth velocity and development of secondary sexual characteristics. It is generally believed that gonadal sex steroids stimulate pulsatile GH secretion, which, in turn......, stimulates insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) production. However, little is known about GH, IGF-I, and IGFBP-3 serum levels in children with precocious puberty. Treatment of CPP by GnRH agonists has become the treatment of choice. However, the effect of long term...

  16. Diagnostic value of combined tet of cPSA, IGF-1 and TGFα for prostate cancer

    International Nuclear Information System (INIS)

    Dai Feng; Yang Qingling

    2006-01-01

    To assess the clinical value of serum complexed prostate specific antigen (cPSA), insulinlike growth factor(IGF-1),transforming growth factor a (TGFα) in the diagnosis of pros- tate cancer (PCα), serum samples were obtained from 46 men with PCa, 64 men with untreated benign prostatic hyperplasia(BPH) and 73 men of a healthy control group. The levels of cPSA, IGF-1 and TGFα were determined by autoimmunochemistry luminescence method, IRMA and RIA method. Postoperative observation was conducted for the change of cPSA, IGF-1 and TGFa in the serum from men with PCa obtained in one month, three months and six months after the operations. Results showed that the levels of cPSA, IGF-1 and TGFα in PCa serum were significantly higher than the BPH group and control group(P 0.05). The combined test of cPSA, IGF-1 and TGFα is meaningful for the prevision, diagnosis and therapy of PCa. (authors)

  17. IGFBP-1 and IGF-I as markers for advanced fibrosis in NAFLD - a pilot study.

    Science.gov (United States)

    Hagström, Hannes; Stål, Per; Hultcrantz, Rolf; Brismar, Kerstin; Ansurudeen, Ishrath

    2017-12-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. Advanced fibrosis (stage 3-4) is the most robust marker for future mortality, but diagnosis requires liver biopsy. Current non-invasive scoring systems aimed to identify advanced fibrosis are imperfect. Insulin-like growth factor I (IGF-I) and its binding protein IGFBP-1 are liver derived proteins, that are involved in various liver disorders. The aim of this study was to examine the possible association between advanced fibrosis and IGF-I and IGFBP-1 in NAFLD. Fasting blood samples were obtained from 52 patients diagnosed with NAFLD by liver biopsy. Total IGF-I and IGFBP-1 concentrations were determined in serum by in-house radio-immuno-assays. IGF-I levels were age-standardized (IGF-SD). A logistic regression model was used to investigate the association of IGF-SD and IGFBP-1 with advanced fibrosis (stage 3-4). Patients with advanced fibrosis (stage 3-4 vs. 0-2) had lower IGF-SD (-1.17 vs. 0.11, p = .01) and higher mean levels of IGFBP-1 (29.9 vs. 18.8 µg/l, p = .02). IGFBP-1 was associated with presence of advanced fibrosis (OR 1.04 per unit increase, 95%CI 1.0-1.07, p = .05), while IGF-1 was negatively associated with advanced fibrosis (OR 0.63 per standard deviation, 95%CI 0.44-0.92, p = .02). This pilot study suggests an association between serum IGFBP-1 and IGF-I levels with advanced fibrosis in NAFLD patients. IGFBP1 and IGF-1 could be of interest as future biomarkers. Similar studies in larger cohorts are needed.

  18. Interaction of IGF2 and PTEN in ( M alignant Breast T issues

    Directory of Open Access Journals (Sweden)

    Preetha J Shetty

    2012-07-01

    Full Text Available Background: Breast Cancer (BC is one of the leading malignancies affecting women worldwide. Epigenetic mechanisms regulate gene expression playing an important role in the pathophysiology of cancer. In the present study IGF2 and PTEN genes in AKT pathway were selected for evaluation. Objective: To investigate the role of methylation and interaction of IGF2 and PTEN and in the pathoetiology of BC. Methods: Paraffin embedded archival breast tumor and adjacent normal tissue samples were used for carrying out PCR based methylation assay, genomic PCR, immunohistochemistry and qRT PCR. Results: In-Silico study indicated the absence of hormone responsive elements in the promoters of the selected genes. Methylation results indicated significant loss of methylation in IGF2 exon 9 CpG cluster and significant gain of PTEN promoter methylation in tumors. Immunohistochemistry revealed enhanced cytoplasmic expression o f IGF2 protein (p< 0.0001 and decreased nuclear localization of PTEN protein (p=0.0069 in the breast tumors. RT-PCR results indicated an increased IGF2 (p=0.024 and decreased PTEN transcripts (p<0.0001 in the tumors. Conclusion: Increased IGF2 in normal tissues increases PTEN which acts as a negative regulator of AKT pathway in the cytoplasm controlling excessive proliferation while in tumors this regulation is lost. PTEN acts as a negative regulator of MAPK pathway in the nucleus, plays an important role in cell cycle arrest in normal breast tissue. Reduction of PTEN in tumor tissue affects this pathway leading to cell survival. IGF2 and PTEN have a role in breast cancer and these molecular factors can be used for targeting therapy in future.

  19. Changes in circulating level of IGF-I and IGF-binding protein-1 from the first to second trimester as predictors of preeclampsia

    DEFF Research Database (Denmark)

    Vatten, Lars J; Nilsen, Tom I L; Juul, Anders

    2008-01-01

    To assess whether circulating IGF-I and IGF-binding protein-1 (IGFBP-1) in the first and second trimester are associated with subsequent risk of preterm and term preeclampsia.......To assess whether circulating IGF-I and IGF-binding protein-1 (IGFBP-1) in the first and second trimester are associated with subsequent risk of preterm and term preeclampsia....

  20. Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency.

    Science.gov (United States)

    Rayes, Roni F; Milette, Simon; Fernandez, Maria Celia; Ham, Boram; Wang, Ni; Bourdeau, France; Perrino, Stephanie; Yakar, Shoshana; Brodt, Pnina

    2018-03-20

    The growth of cancer metastases in the liver depends on a permissive interaction with the hepatic microenvironment and neutrophils can contribute to this interaction, either positively or negatively, depending on their phenotype. Here we investigated the role of IGF-I in the control of the tumor microenvironment in the liver, using mice with a conditional, liver-specific, IGF-I deficiency (iLID) induced by a single tamoxifen injection. In mice that had a sustained (3 weeks) IGF-I deficiency prior to the intrasplenic/portal inoculation of colon carcinoma MC-38 cells, we observed an increase in neutrophil accumulation in the liver relative to controls. However, unlike controls, these neutrophils did not acquire the (anti-inflammatory) tumor-promoting phenotype, as evidenced by retention of high ICAM-1 expression and nitric oxide production and low CXCR4, CCL5, and VEGF expression and arginase production, all characteristic of the (pro-inflammatory) phenotype. This coincided with an increase in apoptotic tumor cells and reduced metastasis. Neutrophils isolated from these mice also had reduced IGF-IR expression levels. These changes were not observed in iLID mice with a short-term (2 days) IGF-I depletion, despite a 70% reduction in their circulating IGF-I levels, indicating that a sustained IGF-I deficiency was necessary to alter the neutrophil phenotype. Similar results were obtained with the highly metastatic Lewis lung carcinoma subline H-59 cells and in mice injected with an IGF-Trap that blocks IGF-IR signaling by reducing ligand bioavailability. Our results implicate the IGF axis in neutrophil polarization and the induction of a pro-metastatic microenvironment in the liver.

  1. Serum insulin-like growth factor-I (IGF-I) levels during long-term IGF-I treatment of children and adults with primary GH resistance (Laron syndrome).

    Science.gov (United States)

    Laron, Z; Klinger, B; Silbergeld, A

    1999-01-01

    Serum IGF-I levels were measured in 14 patients (9 children and 5 adults) with Laron syndrome (LS) during long-term treatment by IGF-I. Recombinant IGF-I (FK-780, Fujisawa Pharmaceutical Co. Ltd., Japan) was administered once daily subcutaneously before breakfast for 3-5 years to the children and for 9 months to the adults. The initial daily dose was 150 micrograms/kg for children and 120 micrograms/kg for adults. Before initiation of treatment the mean overnight fasting levels of serum IGF-I in the children was 3.2 +/- 0.8 nmol/l (mean +/- SEM), rising to 10 +/- 1.7 nmol/l during long-term treatment even on a dose of 120 micrograms/kg/day. The serum IGF-I levels 4 hours after injection rose from 31.2 +/- 3.5 to 48 +/- 2 nmol/l. In the adult patients, the initial basal IGF-I was 4.1 +/- 0.7 nmol/l, rising to 16.1 +/- 3.84 nmol/l after 8-9 months treatment. Serum IGF-I levels at 4 hours after injection rose in the adult patients from 24.1 +/- 5.8 up to 66.8 +/- 15.4 nmol/l. A progressively increasing half-life during long term exogenous administration of IGF-I to patients with Laron syndrome was demonstrated by following serum IGF-I dynamics after injection. Based on the fact that no antibodies to IGF-I were detected and on findings in previous studies, it is speculated that the increasing serum IGF-I levels during long-term IGF-I treatment are caused by an increase in serum IGFBP-3 induced by chronic IGF-I administration. It is concluded that treatment with IGF-I necessitates regular monitoring of serum IGF-I levels; in patients in whom the age adjusted maximal levels are exceeded, a reduction of the daily IGF-I dose is indicated to avoid undesirable effects.

  2. IGF-1 protects SH-SY5Y cells against MPP+-induced apoptosis via PI3K/PDK-1/Akt pathway.

    Science.gov (United States)

    Kim, Chanyang; Park, Seungjoon

    2018-03-01

    Insulin-like growth factor (IGF)-1 is a well-known anti-apoptotic pro-survival factor and phosphatidylinositol-3-kinase (PI3K)/Akt pathway is linked to cell survival induced by IGF-1. It is also reported that Akt signaling is modulated by 3-phosphoinositide-dependent kinase-1 (PDK1). In the current study, we investigated whether the anti-apoptotic effect of IGF-1 in SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP + ) is associated with the activity of PI3K/PDK1/Akt pathway. Treatment of cells with IGF-1 inhibited MPP + -induced apoptotic cell death. IGF-1-induced activation of Akt and the protective effect of IGF-1 on MPP + -induced apoptosis were abolished by chemical inhibition of PDK1 (GSK2334470) or PI3K (LY294002). The phosphorylated levels of Akt and PDK1 were significantly suppressed after MPP + exposure, while IGF-1 treatment completely restored MPP+-induced reductions in phosphorylation. IGF-1 protected cells from MPP + insult by suppressing intracellular reactive oxygen species (ROS) production and malondialdehyde levels and increasing superoxide dismutase activity. Mitochondrial ROS levels were also increased during MPP + exposure, which were attenuated by IGF-1 treatment. In addition, IGF-1-treated cells showed increased activities of succinate dehydrogenase and citrate synthase, stabilization of mitochondrial transmembrane potential, increased ratio of Bcl-2 to Bax, prevention of cytochrome c release and inhibition of caspase-3 activation with PARP cleavage. Furthermore, the protective effects of IGF-1 on oxidative stress and mitochondrial dysfunction were attenuated when cells were preincubated with GSK2334470 or LY294002. Our data suggest that IGF-1 protects SH-SY5Y cells against MPP + -associated oxidative stress by preserving mitochondrial integrity and inhibiting mitochondrial apoptotic cascades via the activation of PI3K/PDK1/Akt pathway. © 2018 The authors.

  3. Interstitial fluid contains higher in vitro IGF bioactivity than serum

    DEFF Research Database (Denmark)

    Espelund, Ulrick; Søndergaard, Klaus; Bjerring, Peter

    2012-01-01

    MEASURE: Serum and SBF concentrations of bioactive IGF (determined in vitro by specific IGF-I receptor (IGF-IR) phosphorylation assay), immunoreactive IGF and IGF binding protein (IGFBP) levels, Western ligand blotting (WLB) of IGFBPs and IGFBP-3 Western immunoblotting (WiB). RESULTS: The ability of SBF...... to phosphorylate the IGF-IR in vitro was 41±27% higher than that of serum (P=0.007 by repeated measures ANOVA). By contrast, immunoreactive IGF and IGFBP-concentrations were approximately 50% lower in SBF than in serum (all P≤0.002). A marked difference in the composition of IGFBPs between serum and SBF...... was observed, including 3-fold elevated amounts of IGFBP-3 fragments in SBF (Pvitro IGF bioactivity was higher in SBF than in serum. This may...

  4. Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts

    International Nuclear Information System (INIS)

    Flier, J.S.; Usher, P.; Moses, A.C.

    1986-01-01

    Insulin and insulin-like growth factor type I (IGF-I) stimulate an overlapping spectrum of biological responses in human skin fibroblasts. Although insulin and IGF-I are known to stimulate the incorporation of [ 3 H]thymidine into DNA in these cells, the identify of the receptor(s) that mediates this effect has not been fully clarified. The mouse anti-human IGF-I receptor antibody αIR-3 binds with specificity to IGF-I but not to insulin receptors in human placental membranes; it also specifically inhibits the binding of 125 I-labeled IGF-I but not 125 I-labeled insulin to suspensions of human skin fibroblasts in a dose-dependent manner. αIR-3 competitively inhibits IGF-I-mediated stimulation of [ 3 H]thymidine incorporation into DNA. This inhibition is dependent on the concentration of αIR-3 and in the presence of a fixed antibody concentration can be partially overcome by high concentrations of IGF-I. In contrast, at concentrations of 3 H]thymidine incorporation is not inhibited by αIR-3. However, the incremental effects of higher concentrations (> 1 μg/ml) of insulin on [ 3 H]thymidine incorporation are inhibited by αIR-3. αIR-3 is a highly specific antagonist of IGF-I receptor-mediated mitogenesis in human skin fibroblasts. By using this antibody, it is shown directly that insulin can act through the IGF-I receptor to stimulate DNA synthesis but can also activate this effect through the insulin receptor itself

  5. IGF-1 promotes Brn-4 expression and neuronal differentiation of neural stem cells via the PI3K/Akt pathway.

    Directory of Open Access Journals (Sweden)

    Xinhua Zhang

    Full Text Available Our previous studies indicated that transcription factor Brn-4 is upregulated in the surgically denervated hippocampus in vivo, promoting neuronal differentiation of hippocampal neural stem cells (NSCs in vitro. The molecules mediating Brn-4 upregulation in the denervated hippocampus remain unknown. In this study we examined the levels of insulin-like growth factor-1 (IGF-1 in hippocampus following denervation. Surgical denervation led to a significant increase in IGF-1 expression in vivo. We also report that IGF-1 treatment on NSCs in vitro led to a marked acceleration of Brn-4 expression and cell differentiation down neuronal pathways. The promotion effects were blocked by PI3K-specific inhibitor (LY294002, but not MAPK inhibitor (PD98059; levels of phospho-Akt were increased by IGF-1 treatment. In addition, inhibition of IGF-1 receptor (AG1024 and mTOR (rapamycin both attenuated the increased expression of Brn-4 induced by IGF-1. Together, the results demonstrated that upregulation of IGF-1 induced by hippocampal denervation injury leads to activation of the PI3K/Akt signaling pathway, which in turn gives rise to upregulation of the Brn-4 and subsequent stem cell differentiation down neuronal pathways.

  6. Insulin-like growth factor (IGF)-I binding to a cell membrane associated IGF binding protein-3 acid-labile subunit complex in human anterior pituitary gland

    NARCIS (Netherlands)

    Wilczak, N; Kuhl, N; Chesik, D; Geerts, A; Luiten, P; De Keyser, J

    The binding characteristics of [(125) I]insulin-like growth factor (IGF)-I were studied in human brain and pituitary gland. Competition binding studies with DES(1-3)IGF-I and R-3 -IGF-I, which display high affinity for the IGF-I receptor and low affinity for IGF binding proteins (IGFBPs), were

  7. Role of insulin-like growth factor-1 (IGF-1) in regulating cell cycle progression

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Qi-lin; Yang, Tian-lun [Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China); Yin, Ji-ye [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya School of Medicine, Central South University, Changsha 410078, Hunan (China); Peng, Zhen-yu [Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China); Yu, Min [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya School of Medicine, Central South University, Changsha 410078, Hunan (China); Liu, Zhao-qian, E-mail: liuzhaoqian63@126.com [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya School of Medicine, Central South University, Changsha 410078, Hunan (China); Chen, Fang-ping, E-mail: xychenfp@public.cs.hn.Cn [Department of Haematology, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China)

    2009-11-06

    Aims: Insulin-like growth factor-1 (IGF-1) is a polypeptide protein hormone, similar in molecular structure to insulin, which plays an important role in cell migration, cell cycle progression, cell survival and proliferation. In this study, we investigated the possible mechanisms of IGF-1 mediated cell cycle redistribution and apoptosis of vascular endothelial cells. Method: Human umbilical vein endothelial cells (HUVECs) were pretreated with 0.1, 0.5, or 2.5 {mu}g/mL of IGF-1 for 30 min before the addition of Ang II. Cell cycle redistribution and apoptosis were examined by flow cytometry. Expression of Ang II type 1 (AT{sub 1}) mRNA and cyclin E protein were determined by RT-PCR and Western blot, respectively. Results: Ang II (1 {mu}mol/L) induced HUVECs arrested at G{sub 0}/G{sub 1}, enhanced the expression level of AT{sub 1} mRNA in a time-dependent manner, reduced the enzymatic activity of nitric oxide synthase (NOS) and nitric oxide (NO) content as well as the expression level of cyclin E protein. However, IGF-1 enhanced NOS activity, NO content, and the expression level of cyclin E protein, and reduced the expression level of AT{sub 1} mRNA. L-NAME significantly counteracted these effects of IGF-1. Conclusions: Our data suggests that IGF-1 can reverse vascular endothelial cells arrested at G{sub 0}/G{sub 1} and apoptosis induced by Ang II, which might be mediated via a NOS-NO signaling pathway and is likely associated with the expression levels of AT1 mRNA and cyclin E proteins.

  8. Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI.

    Science.gov (United States)

    Guerard, Marie; Robin, Thomas; Perron, Pascal; Hatat, Anne-Sophie; David-Boudet, Laurence; Vanwonterghem, Laetitia; Busser, Benoit; Coll, Jean-Luc; Lantuejoul, Sylvie; Eymin, Beatrice; Hurbin, Amandine; Gazzeri, Sylvie

    2018-04-28

    Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xenografts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin. Amphiregulin allows the binding of IGF1R to importin-β1 and promotes its nuclear transport. The nuclear accumulation of IGF1R by amphiregulin induces cell cycle arrest through p21 WAF1/CIP1 upregulation, and prevents the induction of apoptosis in response to gefitinib. These results identify amphiregulin as the first nuclear localization signal-containing protein that interacts with IGF1R and allows its nuclear translocation. Furthermore they indicate that nuclear expression of IGF1R contributes to EGFR-TKI resistance in lung cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. Role of IGF-I in follistatin-induced skeletal muscle hypertrophy.

    Science.gov (United States)

    Barbé, Caroline; Kalista, Stéphanie; Loumaye, Audrey; Ritvos, Olli; Lause, Pascale; Ferracin, Benjamin; Thissen, Jean-Paul

    2015-09-15

    Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth. Copyright © 2015 the American Physiological Society.

  10. Small interfering RNA targeted to IGF-IR delays tumor growth and induces proinflammatory cytokines in a mouse breast cancer model.

    Directory of Open Access Journals (Sweden)

    Tiphanie Durfort

    Full Text Available Insulin-like growth factor I (IGF-I and its type I receptor (IGF-IR play significant roles in tumorigenesis and in immune response. Here, we wanted to know whether an RNA interference approach targeted to IGF-IR could be used for specific antitumor immunostimulation in a breast cancer model. For that, we evaluated short interfering RNA (siRNAs for inhibition of in vivo tumor growth and immunological stimulation in immunocompetent mice. We designed 2'-O-methyl-modified siRNAs to inhibit expression of IGF-IR in two murine breast cancer cell lines (EMT6, C4HD. Cell transfection of IGF-IR siRNAs decreased proliferation, diminished phosphorylation of downstream signaling pathway proteins, AKT and ERK, and caused a G0/G1 cell cycle block. The IGF-IR silencing also induced secretion of two proinflammatory cytokines, TNF- α and IFN-γ. When we transfected C4HD cells with siRNAs targeting IGF-IR, mammary tumor growth was strongly delayed in syngenic mice. Histology of developing tumors in mice grafted with IGF-IR siRNA treated C4HD cells revealed a low mitotic index, and infiltration of lymphocytes and polymorphonuclear neutrophils, suggesting activation of an antitumor immune response. When we used C4HD cells treated with siRNA as an immunogen, we observed an increase in delayed-type hypersensitivity and the presence of cytotoxic splenocytes against wild-type C4HD cells, indicative of evolving immune response. Our findings show that silencing IGF-IR using synthetic siRNA bearing 2'-O-methyl nucleotides may offer a new clinical approach for treatment of mammary tumors expressing IGF-IR. Interestingly, our work also suggests that crosstalk between IGF-I axis and antitumor immune response can mobilize proinflammatory cytokines.

  11. Cross-talk between insulin and Wnt signaling in preadipocytes

    DEFF Research Database (Denmark)

    Palsgaard, Jane; Emanuelli, Brice; Winnay, Jonathon N

    2012-01-01

    and appears to be due to an inducible interaction between LRP5 and the insulin receptor as demonstrated by co-immunoprecipitation. These data demonstrate that Wnt and insulin signaling pathways exhibit cross-talk at multiple levels. Wnt induces phosphorylation of Akt, ERK1/2, and GSK3β, and this is dependent...... and LRP6 and with and without knock-out of insulin and IGF-1 receptors. We find that Wnt stimulation leads to phosphorylation of insulin signaling key mediators, including Akt, GSK3β, and ERK1/2, although with a lower fold stimulation and slower time course than observed for insulin. These Wnt effects...... are insulin/IGF-1 receptor-dependent and are lost in insulin/IGF-1 receptor double knock-out cells. Conversely, in LRP5 knockdown preadipocytes, insulin-induced phosphorylation of IRS1, Akt, GSK3β, and ERK1/2 is highly reduced. This effect is specific to insulin, as compared with IGF-1, stimulation...

  12. IGF2BP3 functions as a potential oncogene and is a crucial target of miR-34a in gastric carcinogenesis.

    Science.gov (United States)

    Zhou, Yuhang; Huang, Tingting; Siu, Ho Lam; Wong, Chi Chun; Dong, Yujuan; Wu, Feng; Zhang, Bin; Wu, William K K; Cheng, Alfred S L; Yu, Jun; To, Ka Fai; Kang, Wei

    2017-04-11

    Gastric cancer (GC) is one of the frequent causes of cancer-related death in eastern Asian population. IGF2BP2 lists in the top rank up-regulated genes in GC, but its functional role is unclear. The expression of IGF2BP3 in GC cell lines and primary samples was examined by qRT-PCR and Western blot. The biological role of IGF2BP3 was revealed by a series of functional in vitro studies. Its regulation by microRNAs (miRNAs) was predicted by TargetScan and confirmed by luciferase assays and rescue experiments. IGF2BP3 ranked the No.1 of the up-regulated genes by expression microarray analysis in GC cell lines. The expression level of IGF2BP3 was observed in GC tissues comparing with non-tumorous gastric epitheliums. The up-regulated IGF2BP3 expression was associated with poor disease specific survival. IGF2BP3 knockdown significantly inhibited cell proliferation and invasion. Apart from copy number gain, IGF2BP3 has been confirmed to be negatively regulated by tumor-suppressive miRNA, namely miR-34a. The expression of miR-34a showed negative correlation with IGF2BP3 mRNA expression in primary GC samples and more importantly, re-overexpression of IGF2BP3 rescued the inhibitory effect of miR-34a. We compressively revealed the oncogenic role of IGF2BP3 in gastric tumorigenesis and confirmed its activation is partly due to the silence of miR-34a. Our findings identified useful prognostic biomarker and provided clinical translational potential.

  13. Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling?

    Science.gov (United States)

    Gems, David; McElwee, Joshua J

    2005-03-01

    Our recent survey of genes regulated by insulin/IGF-1 signaling (IIS) in Caenorhabditis elegans suggests a role for a number of gene classes in longevity assurance. Based on these findings, we propose a model for the biochemistry of longevity assurance and ageing, which is as follows. Ageing results from molecular damage from highly diverse endobiotic toxins. These are stochastic by-products of diverse metabolic processes, of which reactive oxygen species (ROS) are likely to be only one component. Our microarray analysis suggests a major role in longevity assurance of the phase 1, phase 2 detoxification system involving cytochrome P450 (CYP), short-chain dehydrogenase/reductase (SDR) and UDP-glucuronosyltransferase (UGT) enzymes. Unlike superoxide and hydrogen peroxide detoxification, this system is energetically costly, and requires the excretion from the cell of its products. Given such costs, its activity may be selected against, as predicted by the disposable soma theory. CYP and UGT enzymes target lipophilic molecular species; insufficient activity of this system is consistent with age-pigment (lipofuscin) accumulation during ageing. We suggest that IIS-regulated longevity assurance involves: (a) energetically costly detoxification and excretion of molecular rubbish, and (b) conservation of existing proteins via molecular chaperones. Given the emphasis in this theory on investment in cellular waste disposal, and on protein conservation, we have dubbed it the green theory.

  14. Decreased Serum IGF-1/IGFBP-3 Molar Ratio is Associated with Executive Function Behaviors in Type 2 Diabetic Patients with Mild Cognitive Impairment.

    Science.gov (United States)

    Huang, Rong; Wang, Pin; Han, Jing; Xia, Wenqing; Cai, Rongrong; Sun, Haixia; Sun, Jie; Wang, Shaohua

    2015-01-01

    Insulin-like growth factor (IGF)-1, through insulin/IGF-1 signaling pathway, is involved in the pathogenesis of type 2 diabetes mellitus (T2DM) and Alzheimer's disease. This study aimed to assess the association of serum IGF-1 and IGF binding protein (IGFBP)-3 levels with cognition status and to determine whether IGF-1 rs972936 polymorphism is associated with T2DM with mild cognitive impairment (MCI). A total of 150 T2DM patients, 75 satisfying the MCI diagnostic criteria and 75 exhibiting healthy cognition, were enrolled in this study. The cognitive function of the subjects was extensively assessed. Serum IGF-1 and IGFBP-3 levels were measured through enzyme-linked immunosorbent assay; IGF-1/IGFBP-3 molar ratio was calculated. Single nucleotide polymorphisms of the IGF-1-(rs972936) gene were analyzed. Serum IGF-1/IGFBP-3 molar ratio in MCI patients was significantly lower than that in the control group (p = 0.003). Significant negative correlations were found between IGF-1/IGFBP-3 molar ratio and Trail Making Test A and B (TMT-A and TMT-B) scores (p = 0.003; p function. Further multiple step-wise regression analysis revealed that the TMT-A or TMT-B score was significantly associated only with serum IGF-1/IGFBP-3 molar ratio (p = 0.016; p IGF-1 rs972936 polymorphism between MCI and control groups. A low serum IGF-1/IGFBP-3 molar ratio is associated with the pathogenesis of MCI, particularly executive function in T2DM populations. Further investigation with a large population size should be conducted to confirm this observed association.

  15. Up-Regulation of MicroRNA-190b Plays a Role for Decreased IGF-1 That Induces Insulin Resistance in Human Hepatocellular Carcinoma

    Science.gov (United States)

    Hung, Tzu-Min; Ho, Cheng-Maw; Liu, Yen-Chun; Lee, Jia-Ling; Liao, Yow-Rong; Wu, Yao-Ming; Ho, Ming-Chih; Chen, Chien-Hung; Lai, Hong-Shiee; Lee, Po-Huang

    2014-01-01

    Background & Aims Insulin-like growth factor, (IGF)-1, is produced mainly by the liver and plays important roles in promoting growth and regulating metabolism. Previous study reported that development of hepatocellular carcinoma (HCC) was accompanied by a significant reduction in serum IGF-1 levels. Here, we hypothesized that dysregulation of microRNAs (miRNA) in HCC can modulate IGF-1 expression post-transcriptionally. Methods The miRNAs expression profiles in a dataset of 29 HCC patients were examined using illumina BeadArray. Specific miRNA (miR)-190b, which was significantly up-regulated in HCC tumor tissues when compared with paired non-tumor tissues, was among those predicted to interact with 3′-untranslated region (UTR) of IGF-1. In order to explore the regulatory effects of miR-190b on IGF-1 expression, luciferase reporter assay, quantitative real-time PCR, western blotting and immunofluorecence analysis were performed in HCC cells. Results Overexpression of miR-190b in Huh7 cells attenuated the expression of IGF-1, whereas inhibition of miR-190b resulted in up-regulation of IGF-1. Restoration of IGF-1 expression reversed miR-190b-mediated impaired insulin signaling in Huh7 cells, supporting that IGF-1 was a direct and functional target of miR-190b. Additionally, low serum IGF-1 level was associated with insulin resistance and poor overall survival in HCC patients. Conclusions Increased expression of miR-190 may cause decreased IGF-1 in HCC development. Insulin resistance appears to be a part of the physiopathologic significance of decreased IGF-1 levels in HCC progression. This study provides a novel miRNA-mediated regulatory mechanism for controlling IGF-1 expression in HCC and elucidates the biological relevance of this interaction in HCC. PMID:24586785

  16. Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.

    Science.gov (United States)

    Choi, Hee-Joo; Joo, Hyeong-Seok; Won, Hee-Young; Min, Kyueng-Whan; Kim, Hyung-Yong; Son, Taekwon; Oh, Young-Ha; Lee, Jeong-Yeon; Kong, Gu

    2018-04-01

    resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001). RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  17. Insulin-like growth factors (IGFs) as autocrine/paracrine regulators of granulosa cell differentiation and growth: Studies with a neutralizing monoclonal antibody to IGF-I

    International Nuclear Information System (INIS)

    Mondschein, J.S.; Canning, S.F.; Miller, D.Q.; Hammond, J.M.

    1989-01-01

    Evidence that granulosa cells secrete and respond to insulin-like growth factors (IGFs) suggests, but does not prove, the importance of IGFs as intraovarian regulators. To further assess the role of these peptides in ovarian function, a neutralizing monoclonal antibody to IGF-I was employed to block the actions of IGFs in porcine follicular fluid and in granulosa cell-conditioned medium. In one series of experiments, granulosa cells from immature porcine follicles were cultured in medium containing porcine follicular fluid that had been charcoal-treated to remove steroids. As noted before, fluid from large follicles (LFF) stimulated progesterone production in a dose-dependent manner. The stimulatory effect of LFF (30% v/v) could be inhibited by greater than 50% by the anti-IGF monoclonal antibody. This inhibitory action was specific for the anti-IGF antibody and could be overcome by the addition of excess exogenous IGFs. In another series of experiments, granulosa cells were made dependent on endogenously produced IGFs by culturing them in a serum-free medium without exogenous growth factors. The effects of follicle-stimulating hormone (FSH), estradiol (E2), growth hormone (GH), and combinations thereof on progesterone production were inhibited by approximately 50% by the anti-IGF antibody. The effects of IGFs on indices of cell growth (judged by the criterion of being inhibited by the anti-IGF antibody) were less dramatic. A modest 18% increase in cell number was observed with FSH and E2 treatment in serum-free medium; this effect was virtually abolished by the antibody

  18. Insulin-like growth factors (IGFs) as autocrine/paracrine regulators of granulosa cell differentiation and growth: Studies with a neutralizing monoclonal antibody to IGF-I

    Energy Technology Data Exchange (ETDEWEB)

    Mondschein, J.S.; Canning, S.F.; Miller, D.Q.; Hammond, J.M. (Pennsylvania State Univ., Hershey (USA))

    1989-07-01

    Evidence that granulosa cells secrete and respond to insulin-like growth factors (IGFs) suggests, but does not prove, the importance of IGFs as intraovarian regulators. To further assess the role of these peptides in ovarian function, a neutralizing monoclonal antibody to IGF-I was employed to block the actions of IGFs in porcine follicular fluid and in granulosa cell-conditioned medium. In one series of experiments, granulosa cells from immature porcine follicles were cultured in medium containing porcine follicular fluid that had been charcoal-treated to remove steroids. As noted before, fluid from large follicles (LFF) stimulated progesterone production in a dose-dependent manner. The stimulatory effect of LFF (30% v/v) could be inhibited by greater than 50% by the anti-IGF monoclonal antibody. This inhibitory action was specific for the anti-IGF antibody and could be overcome by the addition of excess exogenous IGFs. In another series of experiments, granulosa cells were made dependent on endogenously produced IGFs by culturing them in a serum-free medium without exogenous growth factors. The effects of follicle-stimulating hormone (FSH), estradiol (E2), growth hormone (GH), and combinations thereof on progesterone production were inhibited by approximately 50% by the anti-IGF antibody. The effects of IGFs on indices of cell growth (judged by the criterion of being inhibited by the anti-IGF antibody) were less dramatic. A modest 18% increase in cell number was observed with FSH and E2 treatment in serum-free medium; this effect was virtually abolished by the antibody.

  19. Insulin-like growth factors (IGFs) and IGF binding proteins in active Crohn’s disease treated with omega-3 or omega-6 fatty acids and corticosteroids

    DEFF Research Database (Denmark)

    Eivindson, Martin; Grønbæk, Henning; Nielsen, J.N.

    2005-01-01

    of the present study was to examine the effects of enteral nutrition, Impact Powder, as adjuvant therapy to corticosteroid treatment on changes in the GH/IGF-I axis in patients with Crohn's disease (CD). MATERIAL AND METHODS: The patients were randomized to 3-IP (omega-3-fatty acid (FA), 3 g/day) or 6-IP (omega...... with previously published studies and may be explained by corticosteroid treatment; however, we cannot exclude an additional effect of omega3-/omega6 FA as adjuvant enteral nutrition.......-6-FA, 9 g/day). Changes in total IGF-I (tIGF-I) and total IGF-II (tIGF-II), free IGF-I (fIGF-I), IGF binding proteins (IGFBP-1 and IGFBP-3), IGFBP-3 protease activity and insulin levels were examined in 31 patients with active CD (CDAI: 186-603) during treatment with prednisolone (40 mg for 1 week...

  20. Validation of serum IGF-I as a biomarker to monitor the bioactivity of exogenous growth hormone agonists and antagonists in rabbits

    Science.gov (United States)

    Bielohuby, Maximilian; Zarkesh-Esfahani, Sayyed Hamid; Manolopoulou, Jenny; Wirthgen, Elisa; Walpurgis, Katja; Toghiany Khorasgani, Mohaddeseh; Aghili, Zahra Sadat; Wilkinson, Ian Robert; Hoeflich, Andreas; Thevis, Mario; Ross, Richard J.; Bidlingmaier, Martin

    2014-01-01

    The development of new growth hormone (GH) agonists and growth hormone antagonists (GHAs) requires animal models for pre-clinical testing. Ideally, the effects of treatment are monitored using the same pharmacodynamic marker that is later used in clinical practice. However, intact rodents are of limited value for this purpose because serum IGF-I, the most sensitive pharmacodynamic marker for the action of GH in humans, shows no response to treatment with recombinant human GH and there is little evidence for the effects of GHAs, except when administered at very high doses or when overexpressed. As an alternative, more suitable model, we explored pharmacodynamic markers of GH action in intact rabbits. We performed the first validation of an IGF-I assay for the analysis of rabbit serum and tested precision, sensitivity, linearity and recovery using an automated human IGF-I assay (IDS-iSYS). Furthermore, IGF-I was measured in rabbits of different strains, age groups and sexes, and we monitored IGF-I response to treatment with recombinant human GH or the GHA Pegvisomant. For a subset of samples, we used LC-MS/MS to measure IGF-I, and quantitative western ligand blot to analyze IGF-binding proteins (IGFBPs). Although recovery of recombinant rabbit IGF-I was only 50% in the human IGF-I assay, our results show that the sensitivity, precision (1.7–3.3% coefficient of variation) and linearity (90.4–105.6%) were excellent in rabbit samples. As expected, sex, age and genetic background were major determinants of IGF-I concentration in rabbits. IGF-I and IGFBP-2 levels increased after single and multiple injections of recombinant human GH (IGF-I: 286±22 versus 434±26 ng/ml; PIGF-I levels from the fourth injection onwards (PIGF-I immunoassay can be used in rabbits. Similar to rodents, rabbits display variations in IGF-I depending on sex, age and genetic background. Unlike in rodents, the IGF-I response to treatment with recombinant human GH or a GHA closely mimics the

  1. Nutritional modulation of IGF-1 in relation to growth and body condition in Sceloporus lizards.

    Science.gov (United States)

    Duncan, Christine A; Jetzt, Amanda E; Cohick, Wendie S; John-Alder, Henry B

    2015-05-15

    of nutritional stress. Further studies on ecologically relevant variation in food intake are required to establish the importance of nutrition as an environmental regulator of the GH/IGF axis. Within the range of positive energy balance, the potential involvement of molecular signals in growth regulation requires further investigation. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Effect of Modified and accumulated decoction on serum ER, PR, sex hormone, IGF-I and IGF-I in patients with uterine fibroids

    Directory of Open Access Journals (Sweden)

    Yi-Sha Li

    2017-11-01

    Full Text Available Objective: To study the effect of Modified and accumulated Decoction on serum ER, PR, sex hormone, IGF-I and IGF-I in patients with uterine fibroids. Method: A total of 90 patients with uterine fibroids in our hospital from January 2015 to January 2017 were enrolled in this study. The subjects were divided into the control group (n=45 and the treatment group (n=45 randomly. The control group was treated with mifepristone, the treatment group was treated with Modified and accumulated Decoction combined with mifepristone, and both the two groups were treated for 3 months. The uterine fibroid volume and uterine volume of the two groups before and after treatment were compared. The serum ER, PR, P, E 2 , LH, FSH, IGF-I and IGF-IR of the two groups before and after treatment were compared. Result: There were no significantly differences of the uterine fibroid volume and uterine volume of the two groups before treatment. The uterine fibroid volume and uterine volume of the two groups after treatment were significantly less than before treatment, and that of the treatment group after treatment were significantly less than the control group. There were no significantly differences among the serum ER, PR, P, E 2 , LH, FSH, IGF-I and IGF-IR of the two groups before treatment. The serum ER, PR, P, E 2 , LH, FSH, IGF-I and IGF-IR of the two groups after treatment were significantly lower than before treatment, and that of the treatment group after treatment were significantly lower than the control group. Conclusion: Modified and accumulated Decoction combined with mifepristonecan significantly reduce the uterine fibroid volume, improve the serum ER, PR, sex hormone, IGF-I and IGF-I levels of the patients with uterine fibroids, and it was worthy clinical application.

  3. Circadian variation in serum free and total insulin-like growth factor (IGF)-I and IGF-II in untreated and treated acromegaly and growth hormone deficiency

    DEFF Research Database (Denmark)

    Skjaerbaek, Christian; Frystyk, Jan; Kaal, Andreas

    2000-01-01

    to the nocturnal increase in IGF binding protein-1. In this study we have investigated the circadian variation in circulating free IGF-I and IGF-II in patients with acromegaly and patients with adult onset growth hormone deficiency. PATIENTS: Seven acromegalic patients were studied with and without treatment...... no significant circadian variations in free IGF-I or free IGF-II in either of the two occasions. In contrast, there was a significant circadian variation of total IGF-I after adjustment for changes in plasma volume in both treated and untreated acromegaly and GH deficiency in all cases with a peak between 0300 h...

  4. Insulin-like growth factor 1 (IGF1) and its active peptide (1-3)IGF1 enhance the expression of synaptic markers in neuronal circuits through different cellular mechanisms.

    LENUS (Irish Health Repository)

    Corvin, Aiden P

    2012-06-27

    Insulin-like growth factor-1 (IGF1) and its active peptide (1-3)IGF1 modulate brain growth and plasticity and are candidate molecules for treatment of brain disorders. IGF1 N-terminal portion is naturally cleaved to generate the tri-peptide (1-3)IGF1 (glycine-praline-glutamate). IGF1 and (1-3)IGF have been proposed as treatment for neuropathologies, yet their effect on nerve cells has not been directly compared. In this study we examine the effects of IGF1 and (1-3)IGF1 in primary cortical cultures and measure the expression levels of markers for intracellular pathways and synaptic function. We find that both treatments activate the IGF1 receptor and enhance the expression of synaptic markers, however, they activate different intracellular pathways. Furthermore, (1-3)IGF1 administration increases the expression of endogenous IGF1, suggesting a direct interaction between the two molecules. The results show that the two molecules increase the expression of synaptic proteins through activating different cellular mechanisms.

  5. miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect.

    Science.gov (United States)

    Liu, Wenpeng; Kang, Lei; Han, Juqiang; Wang, Yadong; Shen, Chuan; Yan, Zhifeng; Tai, Yanhong; Zhao, Caiyan

    2018-01-01

    Insulin-like growth factor-1 receptor (IGF-1R) is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC). Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear. Cell proliferation was evaluated by cell counting Kit-8 and colony formation assay. Western blot and real-time PCR were accordingly used to detect the relevant proteins, miRNA and gene expression. Luciferase reporter assays were used to illustrate the interaction between miR-342-3p and IGF-1R. The effect of miR-342-3p on glycolysis was determined by glucose uptake, ATP concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. In vivo, subcutaneous tumor formation assay and PET were performed in nude mice. In this study, we demonstrate that by directly targeting the 3'-UTR (3'-untranslated regions) of IGF-1R, microRNA-342-3p (miR-342-3p) suppresses IGF-1R-mediated PI3K/AKT/GLUT1 signaling pathway both in vitro and in vivo. Through suppression of IGF-1R, miR-342-3p dampens glycolysis by decreasing glucose uptake, lactate generation, ATP production, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in hepatoma cells. Importantly, glycolysis regulated by miR-342-3p is critical for its regulating HCC growth both in vitro and in vivo. Our findings provide clues regarding the role of miR-342-3p as a tumor suppressor in liver cancer mainly through the inhibition of IGF-1R. Targeting IGF-1R by miR-342-3p could be a potential therapeutic strategy in liver cancer.

  6. The effects of milking frequency on insulin-like growth factor I signaling within the mammary gland of dairy cows.

    Science.gov (United States)

    Murney, R; Stelwagen, K; Wheeler, T T; Margerison, J K; Singh, K

    2015-08-01

    In dairy cows, short-term changes in milking frequency (MF) in early lactation have been shown to produce both an immediate and a long-term effect on milk yield. The effect of MF on milk yield is controlled locally within mammary glands and could be a function of changes in either number or activity of secretory mammary epithelial cells (MEC). Insulin-like growth factor I (IGF-I) signaling is one candidate factor that could mediate these effects, as it can be controlled locally within mammary glands. Both MEC number and activity can be affected by IGF-I signaling by activating the phosphoinositide 3-kinase (PI3K)/Akt and extracellular-signal-regulated kinase (ERK)1/2 pathways. To investigate the relationship between MF and IGF-I signaling, udder halves of 17 dairy cows were milked either 4 times a day (4×) or once a day (1×) for 14 d in early lactation. On d 14, between 3 and 5 h following milking, mammary biopsies were obtained from 10 cows from both udder halves, and changes in the expression of genes associated with IGF-I signaling and the activation of the PI3K/Akt and ERK1/2 pathways were measured. The mRNA abundance of IGF type I receptor, IGF binding protein (IGFBP)-3, and IGFBP-5 were lower following 4× milking relative to 1× milking. However, the mRNA abundance of IGF-I was not affected by MF. Both IGFBP3 and IGFBP5 are thought to inhibit IGF-I; therefore, decreases in their mRNA abundance may serve to stimulate the IGF-I signal in the 4×-milked mammary gland. The activation of PI3K/Akt pathway was lower in response to 4× milking relative to 1×, and the activation of the ERK1/2 was unaffected by MF, suggesting that they do not mediate the effects of MF. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  7. Adaptability of the Immature Ocular Motor Control System: Unilateral IGF-1 Medial Rectus Treatment.

    Science.gov (United States)

    Willoughby, Christy L; Fleuriet, Jérome; Walton, Mark M; Mustari, Michael J; McLoon, Linda K

    2015-06-01

    Unilateral treatment with sustained release IGF-1 to one medial rectus muscle in infant monkeys was performed to test the hypothesis that strabismus would develop as a result of changes in extraocular muscles during the critical period of development of binocularity. Sustained release IGF-1 pellets were implanted unilaterally on one medial rectus muscle in normal infant monkeys during the first 2 weeks of life. Eye position was monitored using standard photographic methods. After 3 months of treatment, myofiber and neuromuscular size, myosin composition, and innervation density were quantified in all rectus muscles and compared to those in age-matched controls. Sustained unilateral IGF-1 treatments resulted in strabismus for all treated subjects; 3 of the 4 subjects had a clinically significant strabismus of more than 10°. Both the treated medial rectus and the untreated ipsilateral antagonist lateral rectus muscles had significantly larger myofibers. No adaptation in myofiber size occurred in the contralateral functionally yoked lateral rectus or in myosin composition, neuromuscular junction size, or nerve density. Sustained unilateral IGF-1 treatment to extraocular muscles during the sensitive period of development of orthotropic eye alignment and binocularity was sufficient to disturb ocular motor development, resulting in strabismus in infant monkeys. This could be due to altering fusion of gaze during the early sensitive period. Serial measurements of eye alignment suggested the IGF-1-treated infants received insufficient coordinated binocular experience, preventing the establishment of normal eye alignment. Our results uniquely suggest that abnormal signaling by the extraocular muscles may be a cause of strabismus.

  8. PKC{eta} is a negative regulator of AKT inhibiting the IGF-I induced proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Shahaf, Galit; Rotem-Dai, Noa; Koifman, Gabriela; Raveh-Amit, Hadas; Frost, Sigal A.; Livneh, Etta, E-mail: etta@bgu.ac.il

    2012-04-15

    The PI3K-AKT pathway is frequently activated in human cancers, including breast cancer, and its activation appears to be critical for tumor maintenance. Some malignant cells are dependent on activated AKT for their survival; tumors exhibiting elevated AKT activity show sensitivity to its inhibition, providing an Achilles heel for their treatment. Here we show that the PKC{eta} isoform is a negative regulator of the AKT signaling pathway. The IGF-I induced phosphorylation on Ser473 of AKT was inhibited by the PKC{eta}-induced expression in MCF-7 breast adenocarcinoma cancer cells. This was further confirmed in shRNA PKC{eta}-knocked-down MCF-7 cells, demonstrating elevated phosphorylation on AKT Ser473. While PKC{eta} exhibited negative regulation on AKT phosphorylation it did not alter the IGF-I induced ERK phosphorylation. However, it enhanced ERK phosphorylation when stimulated by PDGF. Moreover, its effects on IGF-I/AKT and PDGF/ERK pathways were in correlation with cell proliferation. We further show that both PKC{eta} and IGF-I confer protection against UV-induced apoptosis and cell death having additive effects. Although the protective effect of IGF-I involved activation of AKT, it was not affected by PKC{eta} expression, suggesting that PKC{eta} acts through a different route to increase cell survival. Hence, our studies show that PKC{eta} provides negative control on AKT pathway leading to reduced cell proliferation, and further suggest that its presence/absence in breast cancer cells will affect cell death, which could be of therapeutic value.

  9. Regulation of Kisspeptin Synthesis and Release in the Preoptic/Anterior Hypothalamic Region of Prepubertal Female Rats: Actions of IGF-1 and Alcohol.

    Science.gov (United States)

    Hiney, Jill K; Srivastava, Vinod K; Vaden Anderson, Danielle N; Hartzoge, Nicole L; Dees, William L

    2018-01-01

    Alcohol (ALC) causes suppressed secretion of prepubertal luteinizing hormone-releasing hormone (LHRH). Insulin-like growth factor-1 (IGF-1) and kisspeptin (Kp) are major regulators of LHRH and are critical for puberty. IGF-1 may be an upstream mediator of Kp in the preoptic area and rostral hypothalamic area (POA/RHA) of the rat brain, a region containing both Kp and LHRH neurons. We investigated the ability of IGF-1 to stimulate prepubertal Kp synthesis and release in POA/RHA, and the potential inhibitory effects of ALC. Immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 0730 hours. At 0900 hours, both groups were subdivided where half received either saline or IGF-1 into the brain third ventricle. A second dose of ALC (2 g/kg) or water was administered at 1130 hours. Rats were killed 6 hours after injection and POA/RHA region collected. IGF-1 stimulated Kp, an action blocked by ALC. Upstream to Kp, IGF-1 receptor (IGF-1R) activation, as demonstrated by the increase in insulin receptor substrate 1, resulted in activation of Akt, tuberous sclerosis 2, ras homologue enriched in brain, and mammalian target of rapamycin (mTOR). ALC blocked the central action of IGF-1 to induce their respective phosphorylation. IGF-1 specificity and ALC specificity for the Akt-activated mTOR pathway were demonstrated by the absence of effects on PRAS40. Furthermore, IGF-1 stimulated Kp release from POA/RHA incubated in vitro. IGF-1 stimulates prepubertal Kp synthesis and release following activation of a mTOR signaling pathway, and ALC blocks this pathway at the level of IGF-1R. Copyright © 2017 by the Research Society on Alcoholism.

  10. Fetal programming of insulin-like growth factor (IGF)-I and IGF-binding protein-3: evidence for an altered response to undernutrition in late gestation following exposure to periconceptual undernutrition in the sheep.

    Science.gov (United States)

    Gallaher, B W; Breier, B H; Keven, C L; Harding, J E; Gluckman, P D

    1998-12-01

    It has been demonstrated in several animal models that undernutrition in utero has significant long lasting effects on subsequent fetal and postnatal development. To address the hypothesis that the insulin-like growth factors (IGFs) may mediate such effects, our study examined whether a period of periconceptual maternal undernutrition could have a lasting influence on the IGF axis in the fetal sheep. Ewes were either allowed to feed ad libitum or kept undernourished from day 60 prior to mating until day 30 after conception, and then both groups were allowed to feed ad libitum. These groups were further divided at day 105 of gestation, either being fed ad libitum or undernourished until day 115 of gestation. Fetal and maternal blood samples were obtained at both day 105 and 115 of gestation. We describe the development of a specific homologous RIA to measure ovine IGF-binding protein-3 (IGFBP-3) in fetal and maternal sheep plasma. Fetal plasma IGFBP-3 and IGF-I concentrations were significantly (Pfetal plasma IGFBP-2 levels were unchanged. The degree of reduction in fetal plasma IGFBP-3 and IGF-I between day 105 and 115 of gestation as a response to acute maternal undernutrition was significantly greater (Pfetal plasma IGFBP-3 concentrations were not the result of increased proteolytic activity. These results suggest that exposure to maternal periconceptual undernutrition reprograms IGFBP-3 and IGF-I regulation in the developing sheep fetus, altering its response to undernutrition in late gestation.

  11. IGF-1 has plaque-stabilizing effects in atherosclerosis by altering vascular smooth muscle cell phenotype

    NARCIS (Netherlands)

    von der Thüsen, Jan H.; Borensztajn, Keren S.; Moimas, Silvia; van Heiningen, Sandra; Teeling, Peter; van Berkel, Theo J. C.; Biessen, Erik A. L.

    2011-01-01

    Insulin-like growth factor-1 (IGF-1) signaling is important for the maintenance of plaque stability in atherosclerosis due to its effects on vascular smooth muscle cell (vSMC) phenotype. To investigate this hypothesis, we studied the effects of the highly inflammatory milieu of the atherosclerotic

  12. A mechanism of extreme growth and reliable signaling in sexually selected ornaments and weapons.

    Science.gov (United States)

    Emlen, Douglas J; Warren, Ian A; Johns, Annika; Dworkin, Ian; Lavine, Laura Corley

    2012-08-17

    Many male animals wield ornaments or weapons of exaggerated proportions. We propose that increased cellular sensitivity to signaling through the insulin/insulin-like growth factor (IGF) pathway may be responsible for the extreme growth of these structures. We document how rhinoceros beetle horns, a sexually selected weapon, are more sensitive to nutrition and more responsive to perturbation of the insulin/IGF pathway than other body structures. We then illustrate how enhanced sensitivity to insulin/IGF signaling in a growing ornament or weapon would cause heightened condition sensitivity and increased variability in expression among individuals--critical properties of reliable signals of male quality. The possibility that reliable signaling arises as a by-product of the growth mechanism may explain why trait exaggeration has evolved so many different times in the context of sexual selection.

  13. miR-598 acts as a tumor suppressor in human gastric cancer by targeting IGF-1R.

    Science.gov (United States)

    Liu, Na; Yang, Hua; Wang, Hong

    2018-01-01

    In recent years, the aberrant expression of miR-598 in tumorigenesis has been demonstrated, as well as the fact that the IGF-1R pathway is also involved in the development of human gastric cancer (GC). The present study aimed to investigate the molecular mechanisms underlying miR-598-regulated IGF-1R expression in human GC. We analyzed the expression of miR-598 and IGF-1R in GC samples and cells, and evaluated the clinical significance of miR-598 and IGF-1R in GC patients. Furthermore, in vitro and in vivo assays were used to investigate the molecular mechanisms of miR-598 and IGF-1R. miR-598 expression was frequently downregulated in GC tissues and cells, and significantly correlated with poor prognosis, vascular invasion, TNM stage, and lymph node metastases as well as IGF-1R expression. The overexpression of miR-598 obviously inhibited cell proliferation, migration, invasion, and induced cell cycle arrest in the G1/S phase, and increased the apoptosis of GC cells. The overexpression of miR-598 also significantly inhibited ERK1/2 and Akt phosphorylation level. In vivo assay validated the inhibitory effect of miR-598 on tumor growth. Further studies showed that miR-598 inhibited IGF-1R protein expression by directly targeting its 3'-UTR. Besides, over-expression of IGF-1R reversed the inhibitory effects of miR-598, while suppression of IGF-1R expression showed inverse effects. miR-598 suppresses GC cell proliferation, migration and invasion by directly targeting IGF-1R expression. Thus, miR-598 may be a useful target for GC patients.

  14. MMP-2 participates in the sclera of guinea pig with form-deprivation myopia via IGF-1/STAT3 pathway.

    Science.gov (United States)

    Liu, Y-X; Sun, Y

    2018-05-01

    To investigate the expression changes of MMP-2 (matrix metalloproteinases-2) mediated by IGF-1 (insulin-like growth factors-1) STAT3 (signal transducer and activator of transcription 3) pathway in the sclera of the form-deprivation myopia guinea pigs. Twenty-four three-week-old guinea pigs were randomly divided into 4 groups: group A (Control), B, C and D. Guinea pigs in group A were sacrificed after 21 days without any special treatment. Guinea pigs in group B were sacrificed 7 days after receiving stitch in the right eye. Guinea pigs in group C were sacrificed 14 days after receiving stitch in the right eye. Guinea pigs in group D were sacrificed 21 days after receiving stitch in the right eye. Eyeball refraction and axial length of guinea pigs were measured before sacrifice. Eyeballs of guinea pigs were enucleated after sacrifice. The expressions of IGF-1, STAT3 and MMP-2 in scleral tissue were detected by Western blot. Axial length extension and myopia appeared in the right eye of guinea pigs in group B. The expressions of IGF-1, STAT3 and MMP-2 in the sclera significantly increased after 7 days of occlusion compared with that in control group A (pIGF-1, STAT3 and MMP-2 in sclera significantly increased compared with that in group A (pIGF-1, STAT3 and MMP-2 in scleral significantly upregulated 21 days after occlusion (pIGF-1 in sclera were positively correlated (r = 0.962, pIGF-1, STAT3 and MMP-2 in the sclera and myopia of guinea pigs. The expressions of IGF-1, STAT3 and MMP-2 increased progressively over the time of deprivation. Additionally, overexpression of MMP-2 mediated by IGF-1/STAT3 pathway in sclera might promote the formation of myopia.

  15. The IGF1 small dog haplotype is derived from Middle Eastern grey wolves

    Directory of Open Access Journals (Sweden)

    Ostrander Elaine A

    2010-02-01

    Full Text Available Abstract Background A selective sweep containing the insulin-like growth factor 1 (IGF1 gene is associated with size variation in domestic dogs. Intron 2 of IGF1 contains a SINE element and single nucleotide polymorphism (SNP found in all small dog breeds that is almost entirely absent from large breeds. In this study, we surveyed a large sample of grey wolf populations to better understand the ancestral pattern of variation at IGF1 with a particular focus on the distribution of the small dog haplotype and its relationship to the origin of the dog. Results We present DNA sequence data that confirms the absence of the derived small SNP allele in the intron 2 region of IGF1 in a large sample of grey wolves and further establishes the absence of a small dog associated SINE element in all wild canids and most large dog breeds. Grey wolf haplotypes from the Middle East have higher nucleotide diversity suggesting an origin there. Additionally, PCA and phylogenetic analyses suggests a closer kinship of the small domestic dog IGF1 haplotype with those from Middle Eastern grey wolves. Conclusions The absence of both the SINE element and SNP allele in grey wolves suggests that the mutation for small body size post-dates the domestication of dogs. However, because all small dogs possess these diagnostic mutations, the mutations likely arose early in the history of domestic dogs. Our results show that the small dog haplotype is closely related to those in Middle Eastern wolves and is consistent with an ancient origin of the small dog haplotype there. Thus, in concordance with past archeological studies, our molecular analysis is consistent with the early evolution of small size in dogs from the Middle East. See associated opinion by Driscoll and Macdonald: http://jbiol.com/content/9/2/10

  16. INSULIN-LIKE GROWTH FACTOR (IGF-1 IN CNS AND CEREBROVASCULAR AGING

    Directory of Open Access Journals (Sweden)

    William E Sonntag

    2013-07-01

    Full Text Available Insulin-like growth factor-1 (IGF-1 is an important anabolic hormone that decreases with age. In the past two decades extensive research has determined that the reduction in IGF-1 is an important component of the age-related decline in cognitive function in multiple species including humans. Deficiency in circulating IGF-1 results in impairment in processing speed and deficiencies in both spatial and working memory. Replacement of IGF-1 or factors that increase IGF-1 to old animals and humans reverses many of these cognitive deficits. Despite the overwhelming evidence for IGF-1 as an important neurotrophic agent, the specific mechanisms through which IGF-1 acts have remained elusive. Recent evidence indicates that IGF-1 is both produced by and has important actions on the cerebrovasculature as well as neurons and glia. Nevertheless, the specific regulation and actions of brain- and vascular-derived IGF-1 is poorly understood. The diverse effects of IGF-1 discovered thus far reveal a complex endocrine and paracrine system essential for integrating many of the functions necessary for brain health. Identification of the mechanisms of IGF-1 actions will undoubtedly provide critical insight into regulation of brain function in general and the causes of cognitive decline with age.

  17. Bone Growth, Mechanical Stimulus and IGF-I

    National Research Council Canada - National Science Library

    Gilsanz, Vicente

    2002-01-01

    ... exercise intervention or no intervention. This study also examines the possible relations between the cross-sectional properties of bone and circulating levels of IGF-I, JGF-binding protein-3, and IGF-I genotypes in teenagers...

  18. IGF1-Dependent Synaptic Plasticity of Mitral Cells in Olfactory Memory during Social Learning.

    Science.gov (United States)

    Liu, Zhihui; Chen, Zijun; Shang, Congping; Yan, Fei; Shi, Yingchao; Zhang, Jiajing; Qu, Baole; Han, Hailin; Wang, Yanying; Li, Dapeng; Südhof, Thomas C; Cao, Peng

    2017-07-05

    During social transmission of food preference (STFP), mice form long-term memory of food odors presented by a social partner. How does the brain associate a social context with odor signals to promote memory encoding? Here we show that odor exposure during STFP, but not unconditioned odor exposure, induces glomerulus-specific long-term potentiation (LTP) of synaptic strength selectively at the GABAergic component of dendrodendritic synapses of granule and mitral cells in the olfactory bulb. Conditional deletion of synaptotagmin-10, the Ca 2+ sensor for IGF1 secretion from mitral cells, or deletion of IGF1 receptor in the olfactory bulb prevented the socially relevant GABAergic LTP and impaired memory formation after STFP. Conversely, the addition of IGF1 to acute olfactory bulb slices elicited the GABAergic LTP in mitral cells by enhancing postsynaptic GABA receptor responses. Thus, our data reveal a synaptic substrate for a socially conditioned long-term memory that operates at the level of the initial processing of sensory information. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis

    Directory of Open Access Journals (Sweden)

    Vittorio Locatelli

    2014-01-01

    Full Text Available Background. Growth hormone (GH and insulin-like growth factor (IGF-1 are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered.

  20. Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis

    Science.gov (United States)

    Locatelli, Vittorio; Bianchi, Vittorio E.

    2014-01-01

    Background. Growth hormone (GH) and insulin-like growth factor (IGF-1) are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered. PMID:25147565

  1. Insulin-Like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation.

    Science.gov (United States)

    Hughes, Amy; Mohanasundaram, Daisy; Kireta, Svjetlana; Jessup, Claire F; Drogemuller, Chris J; Coates, P Toby H

    2013-03-15

    The early loss of functional islet mass (50-70%) due to apoptosis after clinical transplantation contributes to islet allograft failure. Insulin-like growth factor (IGF)-II is an antiapoptotic protein that is highly expressed in β-cells during development but rapidly decreases in postnatal life. We used an adenoviral (Ad) vector to overexpress IGF-II in isolated rat islets and investigated its antiapoptotic action against exogenous cytokines interleukin-1β- and interferon-γ-induced islet cell death in vitro. Using an immunocompromised marginal mass islet transplant model, the ability of Ad-IGF-II-transduced rat islets to restore euglycemia in nonobese diabetic/severe combined immunodeficient diabetic recipients was assessed. Ad-IGF-II transduction did not affect islet viability or function. Ad-IGF-II cytokine-treated islets exhibited decreased cell death (40% ± 2.8%) versus Ad-GFP and untransduced control islets (63.2% ± 2.5% and 53.6% ± 2.3%, respectively). Ad-IGF-II overexpression during cytokine treatment resulted in a marked reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (8.3% ± 1.4%) versus Ad-GFP control (41% ± 4.2%) and untransduced control islets (46.5% ± 6.2%). Western blot analysis confirmed that IGF-II inhibits apoptosis via activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. Transplantation of IGF-II overexpressing islets under the kidney capsule of diabetic mice restored euglycemia in 77.8% of recipients compared with 18.2% and 47.5% of Ad-GFP and untransduced control islet recipients, respectively (Pislet transplant outcomes in vivo. Antiapoptotic gene transfer is a potentially powerful tool to improve islet survival after transplantation.

  2. IGF-I: A key growth factor that regulates neurogenesis and synaptogenesis from embryonic to adult stages of the brain

    Directory of Open Access Journals (Sweden)

    Vanesa eNieto-Estévez

    2016-02-01

    Full Text Available The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs. This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP and the subventricular zone-olfactory bulb (SVZ-OB. By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also, by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis and neuron integration in synaptic circuits.

  3. IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain

    Science.gov (United States)

    Nieto-Estévez, Vanesa; Defterali, Çağla; Vicario-Abejón, Carlos

    2016-01-01

    The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. PMID:26941597

  4. The relationship between maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGFBP-3 to gestational age and preterm delivery.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2012-02-01

    AIMS: To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2), and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational age at delivery. METHODS: Prospective cohort study of 1650 low-risk Caucasian women in a London University teaching hospital. Maternal IGF-1, IGF-2 and IGFBP-3 were measured in maternal blood at booking and analyzed with respect to gestational age at delivery. RESULTS: There was no significant association between maternal IGF-1 or IGF-2 and preterm birth (PTB). A significant reduction in mean IGFBP-3 levels was noted with delivery <32 completed weeks (P=0.02). CONCLUSION: Maternal mean IGFBP-3 levels are significantly reduced in cases complicated by delivery <32 completed weeks.

  5. Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells.

    Science.gov (United States)

    Lyons, Amy; Coleman, Michael; Riis, Sarah; Favre, Cedric; O'Flanagan, Ciara H; Zhdanov, Alexander V; Papkovsky, Dmitri B; Hursting, Stephen D; O'Connor, Rosemary

    2017-10-13

    Mitochondrial activity and metabolic reprogramming influence the phenotype of cancer cells and resistance to targeted therapy. We previously established that an insulin-like growth factor 1 (IGF-1)-inducible mitochondrial UTP carrier (PNC1/SLC25A33) promotes cell growth. This prompted us to investigate whether IGF signaling is essential for mitochondrial maintenance in cancer cells and whether this contributes to therapy resistance. Here we show that IGF-1 stimulates mitochondrial biogenesis in a range of cell lines. In MCF-7 and ZR75.1 breast cancer cells, IGF-1 induces peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) and PGC-1α-related coactivator (PRC). Suppression of PGC-1β and PRC with siRNA reverses the effects of IGF-1 and disrupts mitochondrial morphology and membrane potential. IGF-1 also induced expression of the redox regulator nuclear factor-erythroid-derived 2-like 2 (NFE2L2 alias NRF-2). Of note, MCF-7 cells with acquired resistance to an IGF-1 receptor (IGF-1R) tyrosine kinase inhibitor exhibited reduced expression of PGC-1β, PRC, and mitochondrial biogenesis. Interestingly, these cells exhibited mitochondrial dysfunction, indicated by reactive oxygen species expression, reduced expression of the mitophagy mediators BNIP3 and BNIP3L, and impaired mitophagy. In agreement with this, IGF-1 robustly induced BNIP3 accumulation in mitochondria. Other active receptor tyrosine kinases could not compensate for reduced IGF-1R activity in mitochondrial protection, and MCF-7 cells with suppressed IGF-1R activity became highly dependent on glycolysis for survival. We conclude that IGF-1 signaling is essential for sustaining cancer cell viability by stimulating both mitochondrial biogenesis and turnover through BNIP3 induction. This core mitochondrial protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Effects of High Intensity Interval Training on Plasma Levels of GH and IGF-I

    Directory of Open Access Journals (Sweden)

    Seyyed Mahmoud Hejazi

    2017-04-01

    Full Text Available Introduction: It is well-recognized that exercise has a significant impact on the GH/IGF system but less is known about the effects of HIIT on this axis. Aim of the present study was to evaluate the effect of ten weeks of HIIT on plasma levels of GH and IGF-I in healthy men. Methods: Twenty young men (age 23.34 ± 2.56 weight 72.47 ± 12.01 height 174.10 ± 5.75 recruited and randomly assigned into control (n=10 and HIIT (n=12 groups. HIIT protocol was started with 4 cycles. Then, every two weeks one cycle was added to the previous ones. Finally, it was to 8 cycles/ session in tenth weeks that lasted 16 minutes. Blood samples were collected prior to and after HIIT program for all subjects and IGF-I and GH levels were measured. Result: HIIT subjects showed a significant increase in IGF-I (P=0.002, F=12.38. However, no significant change was shown in GH levels (P=0.716, F=0.62. Discussion and conclusion: Our findings indicate that the HIIT caused increase in circulating levels of IGF-I independently from GH levels. Both hormones may contribute to positive effects of anabolic conditions.

  7. The Association between IGF-1 Polymorphisms, IGF-1 Serum Levels, and Cognitive Functions in Healthy Adults: The Amsterdam Growth and Health Longitudinal Study

    NARCIS (Netherlands)

    Licht, C.M.M.; van Turenhout, L.C.; Deijen, J.B.; Koppes, L.L.J.; van Mechelen, W.; Twisk, J.W.R.; Drent, M.L.

    2014-01-01

    Several studies have demonstrated an association between polymorphisms in the insulin-like growth factor-1 (IGF-1) gene and IGF-1 serum levels. IGF-1 levels have been associated with cognitive functioning in older persons and growth hormone deficient patients. The present study investigates whether

  8. The association between IGF-1 polymorphisms, IGF-1 serum levels, and cognitive functions in healthy adults: The amsterdam growth and health longitudinal study

    NARCIS (Netherlands)

    Licht, C.M.M.; Turenhout, L.C. van; Deijen, J.B.; Koppes, L.L.J.; Mechelen, W. van; Twisk, J.W.R.; Drent, M.L.

    2014-01-01

    Several studies have demonstrated an association between polymorphisms in the insulin-like growth factor-1 (IGF-1) gene and IGF-1 serum levels. IGF-1 levels have been associated with cognitive functioning in older persons and growth hormone deficient patients. The present study investigates whether

  9. The association between IGF-1 polymorphisms, IGF-1 serum levels, and cognitive functions in healthy adults: the Amsterdam Growth and Health longitudinal study.

    NARCIS (Netherlands)

    Licht, C.M.M.; Turenhout, L.C. van; Deijen, J.B.; Koppes, L.L.J.; Mechelen, W. van; Twisk, J.W.R.; Drent, M.L.

    2014-01-01

    Several studies have demonstrated an association between polymorphisms in the insulin-like growth factor-1 (IGF-1) gene and IGF-1 serum levels. IGF-1 levels have been associated with cognitive functioning in older persons and growth hormone deficient patients. The present study investigates whether

  10. Circulating IGF1 regulates hippocampal IGF1 levels and brain gene expression during adolescence

    OpenAIRE

    Yan, Han; Mitschelen, Matthew; Bixler, Georgina V; Brucklacher, Robert M; Farley, Julie A; Han, Song; Freeman, Willard M; Sonntag, William E

    2011-01-01

    GH and its anabolic mediator, IGF1, are important not only in somatic growth but also in the regulation of brain function. Even though GH treatment has been used clinically to improve body composition and exercise capacity in adults, its influence on central nervous system function has only recently been recognized. This is also the case for children with childhood-onset GH deficiency (GHD) where GH has been used to stimulate bone growth and enhance final adult height. Circulating IGF1 is tra...

  11. IGF-1, oxidative stress, and atheroprotection

    Science.gov (United States)

    Higashi, Yusuke; Sukhanov, Sergiy; Anwar, Asif; Shai, Shaw-Yung; Delafontaine, Patrice

    2009-01-01

    Atherosclerosis is a chronic inflammatory disease in which early endothelial dysfunction and subintimal modified lipoprotein deposition progress to complex, advanced lesions that are predisposed to erosion, rupture and thrombosis. Oxidative stress plays a critical role not only in initial lesion formation but also in lesion progression and destabilization. While growth factors are thought to promote vascular smooth muscle cell proliferation and migration, thereby increasing neointima, recent animal studies indicate that IGF-1 exerts pleiotropic anti-oxidant effects along with anti-inflammatory effects that together reduce atherosclerotic burden. This review discusses the effects of IGF-1 in vascular injury and atherosclerosis models, emphasizing the relationship between oxidative stress and potential atheroprotective actions of IGF-1. PMID:20071192

  12. The association between peripheral total IGF-1, IGFBP-3, and IGF-1/IGFBP-3 and functional and cognitive outcomes in the Mayo Clinic Study of Aging.

    Science.gov (United States)

    Wennberg, Alexandra M V; Hagen, Clinton E; Machulda, Mary M; Hollman, John H; Roberts, Rosebud O; Knopman, David S; Petersen, Ronald C; Mielke, Michelle M

    2018-06-01

    Levels of insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, and their ratio in the blood may be useful for monitoring those at risk of cognitive and functional decline. However, the association between IGF measures and functional and cognitive outcomes has been mixed, and the associations may vary by sex. The present study investigated the cross-sectional, sex-specific associations between serum measures total IGF-1, IGFBP-3, and the IGF-1/IGFBP-3 ratio, gait speed, and cognition in 1320 cognitively unimpaired participants aged 50-95 years enrolled in the Mayo Clinic Study of Aging. We used multivariable linear regression models to determine the association between IGF measures and gait speed or cognitive test performance by sex. IGF measures were not associated with cognitive or functional performance among men. Among women, higher levels of log total IGF-1 and IGFBP-3 were associated with better performance in attention, visuospatial, and global cognitive domains, independent of the gait speed. These findings suggest that among women, IGF measures are associated with cognition, and these associations are independent of function. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Liver-derived IGF-I contributes to GH-dependent increases in lean mass and bone mineral density in mice with comparable levels of circulating GH.

    Science.gov (United States)

    Nordstrom, Sarah M; Tran, Jennifer L; Sos, Brandon C; Wagner, Kay-Uwe; Weiss, Ethan J

    2011-07-01

    The relative contributions of circulating and locally produced IGF-I in growth remain controversial. The majority of circulating IGF-I is produced by the liver, and numerous mouse models have been developed to study the endocrine actions of IGF-I. A common drawback to these models is that the elimination of circulating IGF-I disrupts a negative feedback pathway, resulting in unregulated GH secretion. We generated a mouse with near total abrogation of circulating IGF-I by disrupting the GH signaling mediator, Janus kinase (JAK)2, in hepatocytes. We then crossed these mice, termed JAK2L, to GH-deficient little mice (Lit). Compound mutant (Lit-JAK2L) and control (Lit-Con) mice were treated with equal amounts of GH such that the only difference between the two groups was hepatic GH signaling. Both groups gained weight in response to GH but there was a reduction in the final weight of GH-treated Lit-JAK2L vs. Lit-Con mice. Similarly, lean mass increased in both groups, but there was a reduction in the final lean mass of Lit-JAK2L vs. Lit-Con mice. There was an equivalent increase in skeletal length in response to GH in Lit-Con and Lit-JAK2L mice. There was an increase in bone mineral density (BMD) in both groups, but Lit-JAK2L had lower BMD than Lit-Con mice. In addition, GH-mediated increases in spleen and kidney mass were absent in Lit-JAK2L mice. Taken together, hepatic GH-dependent production of IGF-I had a significant and nonredundant role in GH-mediated acquisition of lean mass, BMD, spleen mass, and kidney mass; however, skeletal length was dependent upon or compensated for by locally produced IGF-I.

  14. IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice.

    Science.gov (United States)

    Toth, Peter; Tucsek, Zsuzsanna; Tarantini, Stefano; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Koller, Akos; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2014-12-01

    Aging impairs autoregulatory protection in the brain, exacerbating hypertension-induced cerebromicrovascular injury, neuroinflammation, and development of vascular cognitive impairment. Despite the importance of the age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels in cerebrovascular aging, the effects of IGF-1 deficiency on functional adaptation of cerebral arteries to high blood pressure remain elusive. To determine whether IGF-1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF-1-deficient mice (Igf1(f/f)+TBG-iCre-AAV8) by chronic infusion of angiotensin-II. In hypertensive control mice, cerebral blood flow (CBF) autoregulation was extended to higher pressure values and the pressure-induced tone of middle cerebral arteries (MCAs) was increased. In hypertensive IGF-1-deficient mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice, the mechanism of adaptation to hypertension involved upregulation of TRPC channels in MCAs and this mechanism was impaired in hypertensive IGF-1-deficient mice. Likely downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF-1-deficient mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF-1 deficiency impairs autoregulatory protection in the brain of hypertensive mice, potentially exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype.

  15. ERK phosphorylation is predictive of resistance to IGF-1R inhibition in small cell lung cancer.

    Science.gov (United States)

    Zinn, Rebekah L; Gardner, Eric E; Marchionni, Luigi; Murphy, Sara C; Dobromilskaya, Irina; Hann, Christine L; Rudin, Charles M

    2013-06-01

    New therapies are critically needed to improve the outcome for patients with small cell lung cancer (SCLC). Insulin-like growth factor 1 receptor (IGF-1R) inhibition is a potential treatment strategy for SCLC: the IGF-1R pathway is commonly upregulated in SCLC and has been associated with inhibition of apoptosis and stimulation of proliferation through downstream signaling pathways, including phosphatidylinositol-3-kinase-Akt and mitogen-activated protein kinase. To evaluate potential determinants of response to IGF-1R inhibition, we assessed the relative sensitivity of 19 SCLC cell lines to OSI-906, a small molecule inhibitor of IGF-1R, and the closely related insulin receptor. Approximately one third of these cell lines were sensitive to OSI-906, with an IC50 OSI-906. Interestingly, OSI-906 sensitive lines expressed significantly lower levels of baseline phospho-ERK relative to resistant lines (P = 0.006). OSI-906 treatment resulted in dose-dependent inhibition of phospho-IGF-1R and phospho-Akt in both sensitive and resistant cell lines, but induced apoptosis and cell-cycle arrest only in sensitive lines. We tested the in vivo efficacy of OSI-906 using an NCI-H187 xenograft model and two SCLC patient xenografts in mice. OSI-906 treatment resulted in 50% tumor growth inhibition in NCI-H187 and 30% inhibition in the primary patient xenograft models compared with mock-treated animals. Taken together our data support IGF-1R inhibition as a viable treatment strategy for a defined subset of SCLC and suggest that low pretreatment levels of phospho-ERK may be indicative of sensitivity to this therapeutic approach. ©2013 AACR

  16. Autophagy resolves early retinal inflammation in Igf1-deficient mice

    Directory of Open Access Journals (Sweden)

    Ana I. Arroba

    2016-09-01

    Full Text Available Insulin-like growth factor-1 (IGF-1 is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery, and anti-inflammatory properties in the nervous system. Mice that have mutations in the Igf1 gene, rendering the gene product inactive (Igf1−/−, present with age-related visual loss accompanied by structural alterations in the first synapses of the retinal pathway. Recent advances have revealed a crucial role of autophagy in immunity and inflammation. Keeping in mind this close relationship, we aimed to decipher these processes in the context of the defects that occur during ageing in the retina of Igf1−/− mice. Tnfa and Il1b mRNAs, and phosphorylation of JNK and p38 MAPK were elevated in the retinas of 6- and 12-month old Igf1−/− mice compared to those in age-matched Igf1+/+ controls. In 6-month-old Igf1−/− retinas, increased mRNA levels of the autophagy mediators Becn1, Atg9, Atg5 and Atg4, decreased p62 (also known as SQSTM1 protein expression together with an increased LC3-II:LC3-I ratio reflected active autophagic flux. However, in retinas from 12-month-old Igf1−/− mice, Nlrp3 mRNA, processing of the IL1β pro-form and immunostaining of active caspase-1 were elevated compared to those in age-matched Igf1+/+ controls, suggesting activation of the inflammasome. This effect concurred with accumulation of autophagosomes and decreased autophagic flux in the retina. Microglia localization and status of activation in the retinas of 12-month-old Igf1+/+ and Igf1−/− mice, analyzed by immunostaining of Cd11b and Iba-1, showed a specific distribution pattern in the outer plexiform layer (OPL, inner plexiform layer (IPL and inner nuclear layer (INL, and revealed an increased number of activated microglia cells in the retina of 12-month-old blind Igf1−/− mice. Moreover, reactive gliosis was exclusively detected in the retinas from 12-month-old blind Igf1−/− mice. In conclusion, this study

  17. Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington's disease knock-in striatal cells.

    Science.gov (United States)

    Ribeiro, Márcio; Rosenstock, Tatiana R; Oliveira, Ana M; Oliveira, Catarina R; Rego, A Cristina

    2014-09-01

    Oxidative stress and mitochondrial dysfunction have been described in Huntington's disease, a disorder caused by expression of mutant huntingtin (mHtt). IGF-1 was previously shown to protect HD cells, whereas insulin prevented neuronal oxidative stress. In this work we analyzed the role of insulin and IGF-1 in striatal cells derived from HD knock-in mice on mitochondrial production of reactive oxygen species (ROS) and related antioxidant and signaling pathways influencing mitochondrial function. Insulin and IGF-1 decreased mitochondrial ROS induced by mHtt and normalized mitochondrial SOD activity, without affecting intracellular glutathione levels. IGF-1 and insulin promoted Akt phosphorylation without changing the nuclear levels of phosphorylated Nrf2 or Nrf2/ARE activity. Insulin and IGF-1 treatment also decreased mitochondrial Drp1 phosphorylation, suggesting reduced mitochondrial fragmentation, and ameliorated mitochondrial function in HD cells in a PI-3K/Akt-dependent manner. This was accompanied by increased total and phosphorylated Akt, Tfam, and mitochondrial-encoded cytochrome c oxidase II, as well as Tom20 and Tom40 in mitochondria of insulin- and IGF-1-treated mutant striatal cells. Concomitantly, insulin/IGF-1-treated mutant cells showed reduced apoptotic features. Hence, insulin and IGF-1 improve mitochondrial function and reduce mitochondrial ROS caused by mHtt by activating the PI-3K/Akt signaling pathway, in a process independent of Nrf2 transcriptional activity, but involving enhanced mitochondrial levels of Akt and mitochondrial-encoded complex IV subunit. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Circulating levels of IGF-1 directly regulate bone growth and density

    Science.gov (United States)

    Yakar, Shoshana; Rosen, Clifford J.; Beamer, Wesley G.; Ackert-Bicknell, Cheryl L.; Wu, Yiping; Liu, Jun-Li; Ooi, Guck T.; Setser, Jennifer; Frystyk, Jan; Boisclair, Yves R.; LeRoith, Derek

    2002-01-01

    IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1–deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis. PMID:12235108

  19. Relationship between serum IGF-1 and skeletal muscle IGF-1 mRNA expression to phosphocreatine recovery after exercise in obese men with reduced GH.

    Science.gov (United States)

    Hamarneh, Sulaiman R; Murphy, Caitlin A; Shih, Cynthia W; Frontera, Walter; Torriani, Martin; Irazoqui, Javier E; Makimura, Hideo

    2015-02-01

    GH and IGF-1 are believed to be physiological regulators of skeletal muscle mitochondria. The objective of this study was to examine the relationship between GH/IGF-1 and skeletal muscle mitochondria in obese subjects with reduced GH secretion in more detail. Fifteen abdominally obese men with reduced GH secretion were treated for 12 weeks with recombinant human GH. Subjects underwent (31)P-magnetic resonance spectroscopy to assess phosphocreatine (PCr) recovery as an in vivo measure of skeletal muscle mitochondrial function and percutaneous muscle biopsies to assess mRNA expression of IGF-1 and mitochondrial-related genes at baseline and 12 weeks. At baseline, skeletal muscle IGF-1 mRNA expression was significantly associated with PCr recovery (r = 0.79; P = .01) and nuclear respiratory factor-1 (r = 0.87; P = .001), mitochondrial transcription factor A (r = 0.86; P = .001), peroxisome proliferator-activated receptor (PPAR)γ (r = 0.72; P = .02), and PPARα (r = 0.75; P = .01) mRNA expression, and trended to an association with PPARγ coactivator 1-α (r = 0.59; P = .07) mRNA expression. However, serum IGF-1 concentration was not associated with PCr recovery or any mitochondrial gene expression (all P > .10). Administration of recombinant human GH increased both serum IGF-1 (change, 218 ± 29 μg/L; P IGF-1 mRNA in muscle (fold change, 2.1 ± 0.3; P = .002). Increases in serum IGF-1 were associated with improvements in total body fat (r = -0.53; P = .04), trunk fat (r = -0.55; P = .03), and lean mass (r = 0.58; P = .02), but not with PCr recovery (P > .10). Conversely, increase in muscle IGF-1 mRNA was associated with improvements in PCr recovery (r = 0.74; P = .02), but not with body composition parameters (P > .10). These data demonstrate a novel association of skeletal muscle mitochondria with muscle IGF-1 mRNA expression, but independent of serum IGF-1 concentrations.

  20. Elevated Serum Levels of IGF-1 Are Sufficient to Establish Normal Body Size and Skeletal Properties Even in the Absence of Tissue IGF-1

    OpenAIRE

    Elis, Sebastien; Courtland, Hayden-William; Wu, Yingjie; Rosen, Clifford J; Sun, Hui; Jepsen, Karl J; Majeska, Robert J; Yakar, Shoshana

    2010-01-01

    Use of recombinant insulin-like growth factor 1 (IGF-1) as a treatment for primary IGF-1 deficiency in children has become increasingly common. When untreated, primary IGF-1 deficiency may lead to a range of metabolic disorders, including lipid abnormalities, insulin resistance, and decreased bone density. To date, results of this therapy are considered encouraging; however, our understanding of the role played by IGF-1 during development remains limited. Studies on long-term treatment with r...

  1. The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1).

    Science.gov (United States)

    Wolfe, Andrew; Divall, Sara; Wu, Sheng

    2014-10-01

    The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. The evaluation of central corneal thickness and intraocular pressure in conjunction with tear IGF-1 levels in patients with acromegaly.

    Science.gov (United States)

    Kan, Emrah; Kan, Elif K; Okuyucu, Ali

    2017-08-30

    To compare the central corneal thickness (CCT), intraocular pressure (IOP), and tear insulin-like growth factor 1 (IGF-1) levels between patients with acromegaly and a control group and to evaluate the possible effect of tear IGF-1 and duration of the disease on CCT and IOP. We included 31 patients with acromegaly (study group) and 40 age- and sex-matched controls in the study. Patients with acromegaly were divided into 2 subgroups based on disease status (active/inactive). All participants underwent complete ophthalmologic evaluation including CCT and IOP values. Basal tear samples were collected from both groups and tear IGF-1 levels were measured. The CCT, IOP, and tear IGF-1 levels were compared between groups and subgroups and the association between tear IGF-I levels and ocular parameters (CCT, IOP) and disease duration were also evaluated. Central corneal thickness, IOP, and tear IGF-1 levels did not show a significant difference between study and control groups. We also did not find a significant difference in terms of CCT, IOP, or tear IGF-1 levels between subgroups of patients. Correlation analysis did not show an association between the duration of disease and tear IGF-1 levels with CCT or IOP. There was no significant difference in tear IGF-1 levels between patients with acromegaly and controls. Additionally, there was no correlation between disease duration and tear IGF-1 levels with CCT or IOP levels. This lack of association may suggest that tear IGF-1 levels might not have an effect on CCT or IOP findings in patients with acromegaly.

  3. Serum tree IGF-I, total IGF-I, IGFBP-1 and IGFBP-3 levels in an elderly population : relation to age and sex steroid levels

    NARCIS (Netherlands)

    Janssen, JAMJL; Stolk, RP; Pols, HAP; Grobbee, DE; de Jong, FH; Lamberts, SWJ

    BACKGROUND Most previous studies concerning the relationship between IGF-I and age used assays measuring total IGF-I, Although free IGF-I is considered of greater biological relevance, little is known about its relationship with sex steroids levels in elderly healthy subjects, MEASUREMENTS In a

  4. Insulin and IGF-II, but not IGF-I, stimulate the in vitro regeneration of adult frog sciatic sensory axons

    DEFF Research Database (Denmark)

    Edbladh, M; Svenningsen, Åsa Fex; Ekström, P A

    1994-01-01

    We used the in vitro regenerating frog sciatic nerve to look for effects of insulin and insulin-like growth factors I and II (IGF-I, IGF-II) on regeneration of sensory axons and on injury induced support cell proliferation in the outgrowth region. In nerves cultured for 11 days, a physiological...... dose (10 ng/ml, approximately 2 nM) of insulin or IGF-II increased ganglionic protein synthesis (by 20% and 50%, respectively) as well as the level of newly formed, radiolabelled axonal material distal to a crush injury (both by 80%), compared to untreated, paired controls. In addition, insulin...... increased the outgrowth distance of the furthest regenerating sensory axons by 10%. The preparation was particularly sensitive to insulin during the first 5 days of culturing. Furthermore, both insulin and IGF-II were found to inhibit proliferation of support cells in the outgrowth region in a manner...

  5. A low-fat, whole-food vegan diet, as well as other strategies that down-regulate IGF-I activity, may slow the human aging process.

    Science.gov (United States)

    McCarty, Mark F

    2003-06-01

    A considerable amount of evidence is consistent with the proposition that systemic IGF-I activity acts as pacesetter in the aging process. A reduction in IGF-I activity is the common characteristic of rodents whose maximal lifespan has been increased by a wide range of genetic or dietary measures, including caloric restriction. The lifespans of breeds of dogs and strains of rats tend to be inversely proportional to their mature weight and IGF-I levels. The link between IGF-I and aging appears to be evolutionarily conserved; in worms and flies, lifespan is increased by reduction-of-function mutations in signaling intermediates homologous to those which mediate insulin/IGF-I activity in mammals. The fact that an increase in IGF-I activity plays a key role in the induction of sexual maturity, is consistent with a broader role for-IGF-I in aging regulation. If down-regulation of IGF-I activity could indeed slow aging in humans, a range of practical measures for achieving this may be at hand. These include a low-fat, whole-food, vegan diet, exercise training, soluble fiber, insulin sensitizers, appetite suppressants, and agents such as flax lignans, oral estrogen, or tamoxifen that decrease hepatic synthesis of IGF-I. Many of these measures would also be expected to decrease risk for common age-related diseases. Regimens combining several of these approaches might have a sufficient impact on IGF-I activity to achieve a useful retardation of the aging process. However, in light of the fact that IGF-I promotes endothelial production of nitric oxide and may be of especial importance to cerebrovascular health, additional measures for stroke prevention-most notably salt restriction-may be advisable when attempting to down-regulate IGF-I activity as a pro-longevity strategy.

  6. Plasma IGF-1 and IGFBP-3 may be imprecise surrogates for breast concentrations: an analysis of healthy women

    Science.gov (United States)

    Llanos, Adana A.; Brasky, Theodore M.; Dumitrescu, Ramona G.; Marian, Catalin; Makambi, Kepher H.; Kallakury, Bhaskar V. S.; Spear, Scott L.; Perry, David J.; Convit, Rafael J.; Platek, Mary E.; Adams-Campbell, Lucile L.; Freudenheim, Jo L.; Shields, Peter G.

    2013-01-01

    We investigated insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 concentrations in histologically normal breast tissues and assessed their association with plasma concentrations, and breast cancer risk factors. IGF-1 and IGFBP-3 were assessed in plasma and breast tissues of 90 women with no history of any cancer and undergoing reduction mammoplasty. Pearson correlations and ANOVAs were used to describe plasma-breast associations and biomarker differences by breast cancer risk factors, respectively. Multivariable regression models were used to determine associations between risk factors, and breast IGF-1 and IGFBP-3. The mean age of the study sample was 37.3 years, 58 % were white, and generally these women were obese (mean BMI = 30.8 kg/m2). We observed no plasma-breast correlation for IGF-1, IGFBP-3, or IGF-1/IGFBP-3 (r = −0.08, r = 0.14, and r = 0.03, respectively; p-values >0.05). Through age- and BMI-adjusted analysis, BMI and years of oral contraceptive (OC) use were inversely associated with breast IGF-1 (p-values = 0.02 and 0.003, respectively) and age was associated with breast IGFBP-3 (p = 0.01), while breast IGF-1/IGFBP-3 was higher in blacks than whites (1.08 vs. 0.68, p = 0.04) and associated with age and BMI (p-values = 0.03 and 0.002, respectively). In multivariable-adjusted models, some breast cancer risk factors studied herein explained 24, 10, and 15 % of the variation in breast IGF-1, IGFBP-3, and IGF-1/IGFBP-3, respectively. While reasons for the lack of plasma-breast hormone correlations in these cancer-free women are unknown, several factors were shown to be associated with breast concentrations. The lack of correlation between blood and tissue IGF-1 and IGFBP-3 suggests that studies of breast cancer risk assessing blood IGF-1 and IGFBP-3 may have important limitations in understanding their role in breast carcinogenesis. PMID:23456194

  7. Targeted Morphoproteomic Profiling of Ewing's Sarcoma Treated with Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors: Response/Resistance Signatures

    Science.gov (United States)

    Subbiah, Vivek; Naing, Aung; Brown, Robert E.; Chen, Helen; Doyle, Laurence; LoRusso, Patricia; Benjamin, Robert; Anderson, Pete; Kurzrock, Razelle

    2011-01-01

    Background Insulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewing's sarcoma. We performed morphoproteomic profiling to better understand response/resistance mechanisms of Ewing's sarcoma to IGF1R inhibitor-based therapy. Methodology/Principal Findings This pilot study assessed two patients with advanced Ewing's sarcoma treated with IGF1R antibody alone followed by combined IGF1R inhibitor plus mammalian target of rapamycin (mTOR) inhibitor treatment once resistance to single-agent IGF1R inhibitor developed. Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor. The initial remarkable radiographic responses to IGF1R-antibody therapy was followed by resistance and then response to combined IGF1R plus mTOR inhibitor therapy in both patients, and then resistance to the combination regimen in one patient. In patient 1, upregulation of p-Akt and p-mTOR in the tumor that relapsed after initial response to IGF1R antibody might explain the resistance that developed, and the subsequent response to combined IGF1R plus mTOR inhibitor therapy. In patient 2, upregulation of mTOR was seen in the primary tumor, perhaps explaining the initial response to the IGF1R and mTOR inhibitor combination, while the resistant tumor that emerged showed activation of the ERK pathway as well. Conclusion/Significance Morphoproteomic analysis revealed that the mTOR pathway was activated in these two patients with advanced Ewing's sarcoma who showed response to combined IGF1R and mTOR inhibition, and the ERK pathway in the patient in whom resistance to this combination emerged. Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewing's sarcoma merits further investigation as a guide to understanding response and resistance signatures. PMID

  8. The effect of growth hormone on bioactive IGF in overweight/obese women.

    Science.gov (United States)

    Dichtel, Laura E; Bjerre, Mette; Schorr, Melanie; Bredella, Miriam A; Gerweck, Anu V; Russell, Brian M; Frystyk, Jan; Miller, Karen K

    2018-03-10

    Overweight/obesity is characterized by decreased growth hormone (GH) secretion whereas circulating IGF-I levels are less severely reduced. Yet, the activity of the circulating IGF-system appears to be normal in overweight/obese subjects, as estimated by the ability of serum to activate the IGF-I receptor in vitro (bioactive IGF). We hypothesized that preservation of bioactive IGF in overweight/obese women is regulated by an insulin-mediated suppression of IGF-binding protein-1 (IGFBP-1) and IGFBP-2, and by suppression of IGFBP-3, mediated by low GH. We additionally hypothesized that increases in bioactive IGF would drive changes in body composition with low-dose GH administration. Cross-sectional analysis and 3-month interim analysis of a 6-month randomized, placebo-controlled study of GH administration in 50 overweight/obese women without diabetes mellitus. Bioactive IGF (kinase receptor activation assay) and body composition (DXA) were measured. Prior to treatment, IGFBP-3 (r = -0.33, p = 0.02), but neither IGFBP-1 nor IGFBP-2, associated inversely with bioactive IGF. In multivariate analysis, lower IGFBP-3 correlated with lower peak stimulated GH (r = 0.45, p = 0.05) and higher insulin sensitivity (r = -0.74, p = 0.003). GH administration resulted in an increase in mean serum IGF-I concentrations (144 ± 56 to 269 ± 66 μg/L, p IGF (1.29 ± 0.39 to 2.60 ± 1.12 μg/L, p IGF, but not total IGF-I concentration, predicted an increase in lean mass (r = 0.31, p = 0.03) and decrease in total adipose tissue/BMI (r = -0.43, p = 0.003). Our data suggest that in overweight/obesity, insulin sensitivity and GH have opposing effects on IGF bioactivity through effects on IGFBP-3. Furthermore, increases in bioactive IGF, rather than IGF-I concentration, predicted GH administration-related body composition changes. NCT00131378. Copyright © 2018. Published by Elsevier Ltd.

  9. The IGF-Axis and Diabetic Retinopathy Before and After Gastric Bypass Surgery

    DEFF Research Database (Denmark)

    Brynskov, Troels; Laugesen, Caroline Schmidt; Floyd, Andrea Karen

    2017-01-01

    at the two postoperative visits (p ≤ 0.001). Total IGF-I showed no significant changes. HbA1c, glucose, HOMA-IR and lipids improved after surgery. Two patients did not complete the 12-month visit. CONCLUSIONS: In obese T2D patients, bioactive IGF is a potential biomarker for DR and levels tended to increase....... We aimed to evaluate baseline imbalances in the circulating IGF-system and changes after LGB in patients with T2D. METHODS: Prospective ocular examinations and measurement of the IGF-axis before and 3 and 12 months after LGB. IGF-bioactivity was measured by cell-based IGF-I receptor (IGF-IR) kinase...

  10. PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma

    DEFF Research Database (Denmark)

    Thomsen, Jacob; Hjortebjerg, Rikke; Espelund, Ulrick

    2015-01-01

    Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared.......03). Ascites was more potent than serum in activating the IGF-I receptor (IGF-IR) in vitro (+31%, P IGF-I, and lower levels of IGF-II (P ... of IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P IGFs and these proteins...

  11. Differential binding of 125I-IGF-I preparations to human fibroblast monolayers

    International Nuclear Information System (INIS)

    Conover, C.A.; Misra, P.; Hintz, R.L.; Rosenfeld, R.G.

    1988-01-01

    Specific, high affinity binding of 125 I-IGF-I to the type IIGF receptor on human fibroblast monolyaers was not altered by varying feeding schedules, serum lots, washing procedures, or incubation times and temperatures. However, markedly different competitive binding curves were obtained when different iodinated IGF-I preparations were used. Five of six radioligands bound preferentially to the type IIGF receptor on human fibroblast monolayers, with 50% displacement at 4-8 μg/l unlabelled IGF-I; with one radioligand a paradoxical 20-200% increase in 125 I-IGF-I binding was observed at low concentrations of unlabelled IGF-I, while concentrations as high as 100 μg/l IGF-I failed to displace this radioligand. The latter binding pattern cannot be accounted for by 125 -I-IGF-I binding to the type II IGF receptor. These data indicate that various radioligands may have preferential affinities for different IGF-I binding sites on human fibroblast monolayers. (author)

  12. Serum IGF-1 concentrations change with soy and seaweed supplements in healthy postmenopausal American women.

    Science.gov (United States)

    Teas, Jane; Irhimeh, Mohammad R; Druker, Susan; Hurley, Thomas G; Hébert, James R; Savarese, Todd M; Kurzer, Mindy S

    2011-01-01

    Insulin-like growth factor 1 (IGF-1) is an anabolic hormone important for growth and development. However, high-circulating serum concentrations in adults are associated with increased risk of postmenopausal breast cancer. Nutritional status and specific foods influence serum IGF-1 concentrations. Breast cancer incidence is typically low in Asian countries where soy is commonly consumed. Paradoxically, soy supplement trials in American women have reported significant increases in IGF-1. Seaweed also is consumed regularly in Asian countries where breast cancer risk is low. We investigated the possibility that seaweed could modify soy-associated increases in IGF-1 in American women. Thirty healthy postmenopausal women (mean age 58 yr) participated in this 14-wk double-blinded, randomized, placebo-controlled crossover clinical trial. Participants consumed 5 g/day placebo or seaweed (Alaria esculenta) in capsules for 7 wk. During the 7th wk, a high-soy protein isolate powder was added (2 mg/kg body weight aglycone equivalent isoflavones). Overnight fasting blood samples were collected after each intervention period. Soy significantly increased serum IGF-1 concentrations compared to the placebo (21.2 nmol/L for soy vs. 16.9 nmol/L for placebo; P = 0.0001). The combination of seaweed and soy significantly reduced this increase by about 40% (21.2 nmol/L for soy alone vs. 19.4 nmol/L; P = 0.01). Concurrent seaweed and soy consumption may be important in modifying the effect of soy on IGF-1 serum concentrations.

  13. Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes

    Directory of Open Access Journals (Sweden)

    Sreemathi Logan

    2018-03-01

    Full Text Available Objective: A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1 that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory. Methods: Learning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-CreTAM/igfrf/f. The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfrf/f mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays. Results: Our results indicate that a reduction in IGF-1 receptor (IGFR expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte-specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30–50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to H2O2-induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and Aβ uptake, both critical functions of astrocytes in the brain. Conclusions: Regulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal

  14. PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma

    Science.gov (United States)

    Thomsen, Jacob; Hjortebjerg, Rikke; Espelund, Ulrick; Ørtoft, Gitte; Vestergaard, Poul; Magnusson, Nils E.; Conover, Cheryl A.; Tramm, Trine; Hager, Henrik; Høgdall, Claus; Høgdall, Estrid; Oxvig, Claus; Frystyk, Jan

    2015-01-01

    Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared serum and ascites from 22 women with ovarian carcinoma. We found that ascites contained 46-fold higher PAPP-A levels as compared to serum (P IGF-I receptor (IGF-IR) in vitro (+31%, P IGF-I, and lower levels of IGF-II (P IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P IGFs and these proteins are also present in ascites. We suggest that both soluble PAPP-A in ascites and tissue-associated PAPP-A serve to increase IGF bioactivity and, thereby, to stimulate IGF-IR-mediated tumor growth. PMID:26336825

  15. Emodin extends lifespan of Caenorhabditis elegans through insulin/IGF-1 signaling pathway depending on DAF-16 and SIR-2.1.

    Science.gov (United States)

    Zhao, Xuan; Lu, Lulu; Qi, Yonghao; Li, Miao; Zhou, Lijun

    2017-10-01

    The naturally occurring anthraquinone emodin has been serving primarily as an anti-bacterial and anti-inflammatory agent. However, little is known about its potential on anti-aging. This investigation examined the effect of emodin on lifespan and focused on its physiological molecular mechanisms in vivo. Using Caenorhabditis elegans (C. elegans) as an animal model, we found emodin could extend lifespan of worms and improve their antioxidant capacity. Our mechanistic studies revealed that emodin might function via insulin/IGF-1 signaling (IIS) pathway involving, specifically the core transcription factor DAF-16. Quantitative RT-PCR results illustrated that emodin up-regulated transcription of DAF-16 target genes which express antioxidants to promote antioxidant capacity and lifespan of worms. In addition, attenuated effect in sir-2.1 mutants suggests that emodin likely functioned in a SIR-2.1-dependent manner. Our study uncovers a novel role of emodin in prolonging lifespan and supports the understanding of emodin being a beneficial dietary supplement.

  16. Membrane-associated insulin-like growth factor (IGF binding structures in placental cells

    Directory of Open Access Journals (Sweden)

    ROMANA MASNIKOSA

    2003-11-01

    Full Text Available The biological activities of IGF-I and –II are mediated mainly by the type 1 IGF receptor (IGF 1R and controlled by their interaction with soluble proteins, the IGF binding proteins (IGFBPs. Although there is a growing body of evidence that some IGFBPs may be cell surface-bound, published data concerning cell association of IGFBP-1 are scarce and none of them concern placental cells. The cell membranes used in this study were isolated from term human placentae. Detergent-solubilized membranes were shown to contain two types of IGF binding structures that were separated by gel filtration on a Sephadex G-100 column. Proteins in the first peak were eluted at V0 (Mr > 100 kD and they bound IGF-I with greater specificity and affinity than IGF-II and insulin. Most likely, they represented the IGF 1R. Small proteins (Mr ~ 45 kD were eluted with the membrane proteins in the second maximum. They were able to bind IGF-I and IGF-II, but not insulin. The identity of these proteins was shown to be IGFBP-1 on the basis of their reaction with specific anti-IGFBP-1 antibodies. To the best of our knowledge, the existence of IGFBP-1 associated with human placental cell membranes has not been reported in the literature before. Colocalisation of IGFBP-1 with IGF 1R in cell membranes could provide efficient modulation of IGF 1R receptor-ligand interactions.

  17. Distribution of IGF receptors in the plasma membrane of proximal tubular cells

    International Nuclear Information System (INIS)

    Hammerman, M.R.; Rogers, S.

    1987-01-01

    To characterize the distribution of receptors for insulin-like growth factors I and II (IGF I and II) in the plasma membrane of the renal proximal tubular cell, the authors measured binding of 125 I-labeled IGF I and 125 I-labeled IGF II to proximal tubular basolateral and brush-border membranes and characterized IGF I-stimulated phosphorylation of detergent-solubilized membranes. 125 I-IGF bound primarily to a 135,000 relative molecular weight (M r ) protein and IGF II to a 260,000 M r protein in isolated membranes. Binding of 125 I-IGF I was severalfold greater in basolateral than in brush-border membranes. IGF I-stimulated phosphorylation of the 92,000 M r β-subunit of its receptors could be demonstrated only in basolateral membranes. These findings are consistent with an asymmetrical distribution of receptors for IGF I in the plasma membrane of the renal proximal tubular cell, localization being primary on the basolateral side. In contrast, binding of 125 I-IGF II to isolated basolateral and brush-border membranes was equivalent, suggesting that receptors for this peptide are distributed more symmetrically in the plasma membrane. The findings suggest that the action of IGF I in proximal tubule are mediated via interaction of circulating peptide with specific receptors in the basolateral membrane. However, the findings established the potential for actions of IGF II to be exerted in proximal tubule via interaction with both basolateral and/or brush-border membrane receptors

  18. IGF-1 promotes the development and cytotoxic activity of human NK cells

    Science.gov (United States)

    Ni, Fang; Sun, Rui; Fu, Binqing; Wang, Fuyan; Guo, Chuang; Tian, Zhigang; Wei, Haiming

    2013-01-01

    Insulin-like growth factor 1 (IGF-1) is a critical regulator of many physiological functions, ranging from longevity to immunity. However, little is known about the role of IGF-1 in natural killer cell development and function. Here, we identify an essential role for IGF-1 in the positive regulation of human natural killer cell development and cytotoxicity. Specifically, we show that human natural killer cells have the ability to produce IGF-1 and that differential endogenous IGF-1 expression leads to disparate cytotoxicity in human primary natural killer cells. Moreover, miR-483-3p is identified as a critical regulator of IGF-1 expression in natural killer cells. Overexpression of miR-483-3p has an effect similar to IGF-1 blockade and decreased natural killer cell cytotoxicity, whereas inhibition of miR-483-3p has the opposite effect, which is reversible with IGF-1 neutralizing antibody. These findings indicate that IGF-1 and miR-483-3p belong to a new class of natural killer cell functional modulators and strengthen the prominent role of IGF-1 in innate immunity. PMID:23403580

  19. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 levels are increased in central precocious puberty

    DEFF Research Database (Denmark)

    Juul, A; Scheike, Thomas Harder; Nielsen, C T

    1995-01-01

    Central precocious puberty (CPP) is characterized by early activation of the pituitary-gonadal axis, which leads to increased growth velocity and development of secondary sexual characteristics. It is generally believed that gonadal sex steroids stimulate pulsatile GH secretion, which, in turn......, stimulates insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) production. However, little is known about GH, IGF-I, and IGFBP-3 serum levels in children with precocious puberty. Treatment of CPP by GnRH agonists has become the treatment of choice. However, the effect of long term...

  20. Over-accumulation of nuclear IGF-1 receptor in tumor cells requires elevated expression of the receptor and the SUMO-conjugating enzyme Ubc9

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Hua; Lin, Yingbo; Badin, Margherita; Vasilcanu, Daiana; Stroemberg, Thomas [Department of Oncology and Pathology, The Karolinska Institute, Cancer Center Karolinska, SE-17176 Stockholm (Sweden); Jernberg-Wiklund, Helena [Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala (Sweden); Sehat, Bita [Department of Oncology and Pathology, The Karolinska Institute, Cancer Center Karolinska, SE-17176 Stockholm (Sweden); Larsson, Olle, E-mail: olle.larsson@ki.se [Department of Oncology and Pathology, The Karolinska Institute, Cancer Center Karolinska, SE-17176 Stockholm (Sweden)

    2011-01-14

    Research highlights: {yields} SUMOylation mediates nuclear translocation of IGF-1R which activates transcription. {yields} Here we show that nuclear IGF-1R over-accumulates in tumor cells. {yields} This requires overexpression of the receptor that is a common feature in tumor cells. {yields} An increased expression of the SUMO ligase Ubc9 seems to be an involved mechanism too. -- Abstract: The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in tumor cell growth and is overexpressed in many cancers. IGF-1R's trans-membrane kinase signaling pathways have been well characterized. Very recently, we showed that SUMOylation mediates nuclear translocation of the IGF-1R, and that nuclear IGF-1R (nIGF-1R) binds to enhancer regions and activates transcription. We identified three lysine residues in the {beta}-subunit of the receptor and that mutation of these blocks nuclear translocation and gene activation. Furthermore, accumulation of nIGF-1R was proven strongly dependent on the specific SUMO-conjugating enzyme Ubc9. Here we show that nIGF-1R originates solely from the cell membrane and that phosphorylation of the core tyrosine residues of the receptor kinase is crucial for nuclear accumulation. We also compared the levels of nIGF-1R, measured as nuclear/membrane ratios, in tumor and normal cells. We found that the breast cancer cell line MCF-7 has 13-fold higher amounts of nIGF-1R than breast epithelial cells (IME) which showed only a small amount of nIGF-1R. In comparison, the total expression of IGF-1R was only 3.7- higher in MCF-7. Comparison of several other tumor and normal cell lines showed similar tumor cell over-accumulation of nIGF-1R, exceeding the total receptor expression substantially. Ectopic overexpression (>10-fold) of the receptor increased nIGF-1R in IME cells but not to that high level as in wild type MCF-7. The levels of Ubc9 were higher in all tumor cell lines, compared to the normal cells, and this probably contributes to over

  1. Over-accumulation of nuclear IGF-1 receptor in tumor cells requires elevated expression of the receptor and the SUMO-conjugating enzyme Ubc9

    International Nuclear Information System (INIS)

    Deng, Hua; Lin, Yingbo; Badin, Margherita; Vasilcanu, Daiana; Stroemberg, Thomas; Jernberg-Wiklund, Helena; Sehat, Bita; Larsson, Olle

    2011-01-01

    Research highlights: → SUMOylation mediates nuclear translocation of IGF-1R which activates transcription. → Here we show that nuclear IGF-1R over-accumulates in tumor cells. → This requires overexpression of the receptor that is a common feature in tumor cells. → An increased expression of the SUMO ligase Ubc9 seems to be an involved mechanism too. -- Abstract: The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in tumor cell growth and is overexpressed in many cancers. IGF-1R's trans-membrane kinase signaling pathways have been well characterized. Very recently, we showed that SUMOylation mediates nuclear translocation of the IGF-1R, and that nuclear IGF-1R (nIGF-1R) binds to enhancer regions and activates transcription. We identified three lysine residues in the β-subunit of the receptor and that mutation of these blocks nuclear translocation and gene activation. Furthermore, accumulation of nIGF-1R was proven strongly dependent on the specific SUMO-conjugating enzyme Ubc9. Here we show that nIGF-1R originates solely from the cell membrane and that phosphorylation of the core tyrosine residues of the receptor kinase is crucial for nuclear accumulation. We also compared the levels of nIGF-1R, measured as nuclear/membrane ratios, in tumor and normal cells. We found that the breast cancer cell line MCF-7 has 13-fold higher amounts of nIGF-1R than breast epithelial cells (IME) which showed only a small amount of nIGF-1R. In comparison, the total expression of IGF-1R was only 3.7- higher in MCF-7. Comparison of several other tumor and normal cell lines showed similar tumor cell over-accumulation of nIGF-1R, exceeding the total receptor expression substantially. Ectopic overexpression (>10-fold) of the receptor increased nIGF-1R in IME cells but not to that high level as in wild type MCF-7. The levels of Ubc9 were higher in all tumor cell lines, compared to the normal cells, and this probably contributes to over-accumulation of nIGF-1R

  2. A chimeric receptor of the insulin-like growth factor receptor type 1 (IGFR1) and a single chain antibody specific to myelin oligodendrocyte glycoprotein activates the IGF1R signalling cascade in CG4 oligodendrocyte progenitors.

    Science.gov (United States)

    Annenkov, Alexander; Rigby, Anne; Amor, Sandra; Zhou, Dun; Yousaf, Nasim; Hemmer, Bernhard; Chernajovsky, Yuti

    2011-08-01

    In order to generate neural stem cells with increased ability to survive after transplantation in brain parenchyma we developed a chimeric receptor (ChR) that binds to myelin oligodendrocyte glycoprotein (MOG) via its ectodomain and activates the insulin-like growth factor receptor type 1 ‎‎(IGF1R) signalling cascade. Activation of this pro-survival pathway in response to ligand broadly available in the brain might increase neuroregenerative potential of transplanted precursors. The ChR was produced by fusing a MOG-specific single ‎chain antibody with the extracellular boundary of the IGF1R transmembrane segment. The ChR is expressed on the cellular surface, predominantly as a monomer, and is not N-glycosylated. To show MOG-dependent functionality of the ChR, neuroblastoma cells B104 expressing this ChR were stimulated with monolayers of cells expressing recombinant MOG. The ChR undergoes MOG-dependent tyrosine phosphorylation and homodimerisation. It promotes insulin and IGF-independent growth of the oligodendrocyte progenitor cell line CG4. The proposed mode of the ChR activation is by MOG-induced dimerisation which promotes kinase domain transphosphorylation, by-passing the requirement of conformation changes known to be important for IGF1R activation. Another ChR, which contains a segment of the β-chain ectodomain, was produced in an attempt to recapitulate some of these conformational changes, but proved non-functional. 2011 Elsevier B.V. All rights reserved.

  3. (igf1/igf1r) with milk production tr

    African Journals Online (AJOL)

    Gosia

    2016-06-15

    Jun 15, 2016 ... fragment length polymorphism (PCR-RFLP) (TaiI and MspI restriction enzymes) and amplification-created restriction site (ACRS) (SnaBI ... is the first association study based on polymorphisms of the primary genes encoding the IGF-1 system in a small herd of .... However, protein content was highest in milk ...

  4. IGF2BP3 as a potential tissue marker for the diagnosis of esophageal high-grade intraepithelial neoplasia

    Directory of Open Access Journals (Sweden)

    Zhang JJ

    2017-08-01

    Full Text Available Jingjing Zhang,1,* Qing Ji,2,* Chunhua Jiao,3,* Lihua Ren,4 Ye Zhao,4 Yanfang Chen,4 Ruihua Shi,4 Yadong Feng4 1State Key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, 2Department of Emergency, Jingjiang People’s Hospital, Jingjiang, 3Department of Gastroenterology, First Affiliated Hospital with Nanjing Medical University, 4Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China *These authors contributed equally to this work Background: The clinical significance of insulin-like growth factor-II mRNA-binding protein-3 (IGF2BP3 in esophageal high-grade intraepithelial neoplasia (HGIN is not clear. This study was designed to characterize the expression of IGF2BP3 in HGIN. Patients and methods: IGF2BP3 expression was evaluated by Western blot analyses in 12 cases and by immunohistochemistry (IHC in 112 cases. The associations between IGF2BP3 expression in HGIN and the clinicopathological parameters were examined. Results: Moderate to strong IGF2BP3 expression was present in HGIN samples. Using IHC, it was found that IGF2BP3 was positive in 68 (60.71% cases. Intense IHC of IGF2BP3 in HGIN was associated with a deeper lesion depth, and the lesion depth was the only predictor of the positive expression of IGF2BP3. Conclusion: Our results suggested that IGF2BP3 may be a supplementary tissue marker for preoperative diagnosis of HGIN. Keywords: esophageal squamous cell carcinoma, precancerous lesion, immunohistochemistry detection, early diagnosis

  5. Predicting refeeding hypophosphataemia: insulin growth factor 1 (IGF-1) as a diagnostic biochemical marker for clinical practice.

    Science.gov (United States)

    Goyale, Atul; Ashley, Sarah L; Taylor, David R; Elnenaei, Manal O; Alaghband-Zadeh, Jamshid; Sherwood, Roy A; le Roux, Carel W; Vincent, Royce P

    2015-01-01

    Refeeding syndrome (RS) is a potentially fatal condition that can occur following the re-introduction of nutrition after a period of starvation. Hypophosphataemia following the reintroduction of nutrition is often the only reliable biochemical marker of RS. Refeeding index (RI) generated from baseline insulin-like growth factor-1 (IGF-1) and leptin has been proposed as a useful biochemical marker for the identification of patients at risk of developing refeeding hypophosphataemia (RH). A prospective study included 52 patients referred for parenteral nutrition (PN). The sensitivity and specificity of IGF-1 measured using a sensitive assay was compared to the RI in predicting the development of RH (a ≥ 30% drop in PO4 during the first 36-h of PN administration). Leptin and IGF-1 were analysed on baseline samples using a quantitative enzyme-linked immunoassay. Daily blood samples were collected from all patients for routine biochemistry for the full duration of PN administration. High sensitivity IGF-1 measurement alone was comparable with the RI, using receiver-operating characteristic (ROC) curve analysis, with areas under the curve being 0.79 and 0.80, respectively, and superior to leptin alone (0.72) for predicting ≥ 30% drop in PO4. The cut-off value for IGF-1 that gave best sensitivity (91% [95% CI 75-98%]) and specificity (65% [95% CI 41-85%]) was 63.7 µg/L, with a likelihood ratio of 2.59. Baseline IGF-1 is an objective, sensitive and specific biochemical marker in identifying patients who are at high risk of developing RH prior to PN administration and therefore may have a role in clinical practice. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  6. Native and Complexed IGF-1: Biodistribution and Pharmacokinetics in Infantile Neuronal Ceroid Lipofuscinosis

    Directory of Open Access Journals (Sweden)

    Tuulia Huhtala

    2012-01-01

    Full Text Available Infantile neuronal ceroid lipofuscinosis (INCL is a severe neurodegenerative disorder of childhood characterized by selective death of cortical neurons. Insulin-like growth factor 1 (IGF-1 is important in embryonic development and is considered as a potential therapeutic agent for several disorders of peripheral and central nervous systems. In circulation IGF-1 is mainly bound to its carrier protein IGFBP-3. As a therapeutic agent IGF-1 has shown to be more active as free than complexed form. However, this may cause side effects during the prolonged treatment. In addition to IGFBP-3 the bioavailability of IGF-1 can be modulated by using mesoporous silicon nanoparticles (NPs which are optimal carriers for sustained release of unstable peptide hormones like IGF-1. In this study we compared biodistribution, pharmacokinetics, and bioavailability of radiolabeled free IGF-1, IGF-1/IGFBP-3, and IGF-1/NP complexes in a Cln1-/- knockout mouse model. IGF-1/NP was mainly accumulated in liver and spleen in all studied time points, whereas minor and more constant amounts were measured in other organs compared to free IGF-1 or IGF-1/IGFBP-3. Also concentration of IGF-1/NP in blood was relatively high and stable during studied time points suggesting continuous release of IGF-1 from the particles.

  7. Insulin-like Growth Factor 1 (IGF-1) Stabilizes Nascent Blood Vessels*

    Science.gov (United States)

    Jacobo, Sarah Melissa P.; Kazlauskas, Andrius

    2015-01-01

    Here we report that VEGF-A and IGF-1 differ in their ability to stabilize newly formed blood vessels and endothelial cell tubes. Although VEGF-A failed to support an enduring vascular response, IGF-1 stabilized neovessels generated from primary endothelial cells derived from various vascular beds and mouse retinal explants. In these experimental systems, destabilization/regression was driven by lysophosphatidic acid (LPA). Because previous studies have established that Erk antagonizes LPA-mediated regression, we considered whether Erk was an essential component of IGF-dependent stabilization. Indeed, IGF-1 lost its ability to stabilize neovessels when the Erk pathway was inhibited pharmacologically. Furthermore, stabilization was associated with prolonged Erk activity. In the presence of IGF-1, Erk activity persisted longer than in the presence of VEGF or LPA alone. These studies reveal that VEGF and IGF-1 can have distinct inputs in the angiogenic process. In contrast to VEGF, IGF-1 stabilizes neovessels, which is dependent on Erk activity and associated with prolonged activation. PMID:25564613

  8. IGF-I replacement therapy in children with congenital IGF-I deficiency (Laron syndrome) maintains heart dimension and function.

    Science.gov (United States)

    Scheinowitz, Mickey; Feinberg, Micha S; Laron, Zvi

    2009-06-01

    Untreated patients with congenital growth hormone deficiency (GHD) and IGF-I deficiency are characterized not only by dwarfism but also by acromicria and organomicria, such as the heart. We assessed cardiac dimensions and function in very young patients with Laron syndrome (LS) undergoing IGF-I replacement therapy. Two to seven echocardiographic measurements were performed during IGF-I replacement therapy on male (n=4) and female (n=4) LS -patients, mean+/-SD age of 7.1+/-3.6 years (range 1.6-11.6 years), weight 16.1+/-9.7 kg, and height 89.9+/-18.5 cm. As aged- and gender-matched controls served 44 healthy children, age: 8.7+/-5.5 years, weight: 36.1+/-22.4 kg, and height: 129.7+/-33.1cm. Data of LS patients were normalized to body surface area and compared to the control group as well as nomograms of normal echocardiographic parameters for this age group. Left ventricular diastolic and systolic dimensions (LVDD/ LVSD, mm) and LV mass (gr) were significantly smaller in boys and girls with IGF-I treated LS compared with controls while the shortening fraction (%) and intraventricular septum thickness (mm) were similar. When compared with standard values for this age group, all treated LS patients were within 1 standard deviation of the mean. IGF-I therapy of young patients with Laron syndrome maintain LV dimensions and function within the normal range of aged-matched controls.

  9. Endurance training-induced changes in the GH-IGF-I axis influence maximal muscle strength in previously untrained men.

    Science.gov (United States)

    Grandys, Marcin; Majerczak, Joanna; Kuczek, Piotr; Sztefko, Krystyna; Duda, Krzysztof; Zoladz, Jerzy A

    2017-02-01

    In this study we have determined the effects of 20weeks of endurance running training on the GH-IGF-I axis changes in the context of the skeletal muscle performance and physical capacity level. Before and after the endurance training program a maximal incremental exercise tests, a 1500m race and a muscle strength measurements were performed and the blood samples were taken to determine both resting as well as end-exercise serum growth hormone (GH), insulin-like growth hormone-I (IGF-I), insulin-like growth hormone binding protein-3 (IGFBP-3) and plasma interleukin-6 (IL-6) concentrations. 20weeks of endurance running training improved power output generated at the end of the maximal incremental test by 24% (P<0.012), 1500m running time by 13% (P<0.012) and maximal muscle strength by 9% (P<0.02). End-exercise IGF-I/IGFBP-3 ratio was decreased by 22% after the training (P<0.04) and the magnitude of IGF-I/IGFBP-3 ratio decrease (ΔIGF-I/IGFBP-3 ex ) was 2.3 times higher after the training (P<0.04). The magnitude of the exercise-induced changes in IGFBP-3 concentration was also significantly higher (P<0.04) and there was a trend toward lower end-exercise IGF-I concentration (P=0.08) after the training. These changes were accompanied by a significantly higher (30%) end-exercise IL-6 concentration (P<0.01) as well as by a 3.4 times higher magnitude of IL-6 increase (P<0.02) after the training. Moreover, there were strong positive correlations between changes in resting serum IGF-I concentration (ΔIGF-I res ) and IGF-I/IGFBP-3 ratio (ΔIGF-I/IGFBP-3 res ) and changes in muscle strength (ΔMVC) (r=0.95, P=0.0003 and r=0.90, P=0.002, respectively). The training-induced changes in the components of the GH-IGF-I axis may have additive effects on skeletal muscle performance and physical capacity improvement. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Human conditions of insulin-like growth factor-I (IGF-I) deficiency

    Science.gov (United States)

    2012-01-01

    Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range. PMID:23148873

  11. Human conditions of insulin-like growth factor-I (IGF-I deficiency

    Directory of Open Access Journals (Sweden)

    Puche Juan E

    2012-11-01

    Full Text Available Abstract Insulin-like growth factor I (IGF-I is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions. IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range.

  12. Differential basal and exercise-induced IGF-I system responses to resistance vs. calisthenic-based military readiness training programs.

    Science.gov (United States)

    Nindl, Bradley C; Alemany, Joseph A; Rarick, Kevin R; Eagle, Shawn R; Darnell, Mathew E; Allison, Katelyn F; Harman, Everett A

    2017-02-01

    The purpose of this study was to: 1) evaluate differential responses of the IGF-I system to either a calisthenic- or resistance exercise-based program and 2) determine if this chronic training altered the IGF-I system during an acute resistance exercise protocol. Thirty-two volunteers were randomly assigned into a resistance exercise-based training (RT) group (n=15, 27±5y, 174±6cm, 81±12kg) or a calisthenic-based training group (CT) (n=17, 29±5y, 179±8cm, 85±10kg) and all underwent 8weeks of exercise training (1.5h/d, 5d/wk). Basal blood was sampled pre- (Week 0), mid- (Week 4) and post-training (Week 8) and assayed for IGF-I system analytes. An acute resistance exercise protocol (AREP) was conducted preand post-training consisting of 6 sets of 10 repetitions in the squat with two minutes of rest in between sets and the IGF-I system analytes measured. A repeated measures ANOVA (p≤0.05) was used for statistical analysis. No interaction or within-subject effects were observed for basal total IGF-I, free IGF-I, or IGFBP-1. IGFBP-2 (pre; 578.6±295.7post-training; 14.3±1.9μg/mL; p=0.01). An interaction was observed for the RT group as IGFBP-3 increased from pre to mid (3462.4±216.4 vs. 3962.2±227.9ng/mL), but was not significant at the post-training time point (3770.3±228.7ng/mL). AREP caused all analytes except free IGF-I (40% decrease) to increase (17-27%; p=0.001) during exercise, returning to baseline concentration into recovery. Post-training, bioavailable IGF-I recovered more rapidly post-exercise. 8wks of chronic physical training resulted in increased basal IGFBP-2 and IGFBP-3, decreased ALS, increased pre-AREP free IGF-I and a more rapid free IGF-I recovery post-AREP. While total IGF-I was insensitive to chronic physical training, changes were observed with circulating IGFBPs and bioavailable IGF-I. To glean the most robust information on the effects of exercise training, studies must move beyond relying solely on total IGF-I measures and should

  13. Insulin and IGF-II, but not IGF-I, stimulate the in vitro regeneration of adult frog sciatic sensory axons

    DEFF Research Database (Denmark)

    Edbladh, M; Svenningsen, Åsa Fex; Ekström, P A

    1994-01-01

    We used the in vitro regenerating frog sciatic nerve to look for effects of insulin and insulin-like growth factors I and II (IGF-I, IGF-II) on regeneration of sensory axons and on injury induced support cell proliferation in the outgrowth region. In nerves cultured for 11 days, a physiological...

  14. Serum levels of bioactive IGF1 and physiological markers of ageing in healthy adults.

    Science.gov (United States)

    Vestergaard, Poul Frølund; Hansen, Mette; Frystyk, Jan; Espelund, Ulrick; Christiansen, Jens S; Jørgensen, Jens Otto Lunde; Fisker, Sanne

    2014-02-01

    Senescent changes in body composition and muscle strength are accompanied by reduced production of GH and IGF1, but the causal relationship remains elusive. We speculate that serum bioactive IGF1, measured by the IGF1 kinase receptor activation assay, is closer related to human physiological ageing than total IGF1 measured by immunoassay. We conducted a cross-sectional study in 150 adult males and females, between 20 and 70 years. After an overnight fasting, serum levels of bioactive IGF1, total IGF1 and IGF-binding protein 1 (IGFBP1) and IGFBP3 were assessed. Furthermore, body composition and muscle strength was measured. Total IGF1 levels were higher in females (P=0.048). Bioactive IGF1 were identical in males and females (P=0.31), decreasing with age. Total IGF1 tended to decrease more with age compared with bioactive IGF1 (-1.48 vs -0.89 percent/year, P=0.052). Total body fat (TBF) was lower and BMI was higher in males (Page. Knee extension and elbow flexion force were higher in males (P=0.001 and P=0.001), but decreased with age in both genders.  Total but not bioactive IGF1 was positively correlated to TBF, knee extension and muscle function in males. In multiple linear regression, only age predicted total IGF1, whereas age and IGFBP1 predicted bioactive IGF1. Bioactive IGF1 tends to decrease to a lesser extent than total IGF1 with age and was not correlated with measures of body composition or muscle strength. Therefore, levels of circulating bioactive IGF1 does not appear to be a better biomarker of physiological ageing than total IGF1.

  15. PLASMA INSULIN AND IGF-1 AND HEPATIC ACTIVITY IN SAANEN GOAT KIDS, AROUND WEANING

    Directory of Open Access Journals (Sweden)

    Damiano Magistrelli

    2009-02-01

    Full Text Available Weaning is a crucial event in the life of young ruminants. At weaning ruminal and digestive activity are still incomplete, so weaning may coincide with a period of growth stasis. Since insulin and insulin-like growth factor 1 (IGF-1 can play a fundamental role in post-natal development, the aim of the present study was to evaluate plasma variations of insulin and IGF-1 levels and their relationships with the hepatic activity, around weaning.For this purpose, eleven 3-days-old Saanen goat kids were randomly divided into MILK (6 animals and WMIX (5 animals groups. All kids were fed goat milk to age 29 days. After that, MILK kids continued to receive milk, while WMIX ones underwent weaning, based on the progressive replacement of milk with solid feed. WMIX kids were completely weaned on day 48. Blood samples were weekly analyzed for metabolic traits, insulin and IGF-1 levels, alanine aminotransferase (ALT and aspartate aminotransferase (AST activities. On day 50, all animals were slaughtered, liver weight was recorded and liver samples were analyzed for DNA, RNA, phospholipids, glicogen and soluble protein content, ALT and AST activity.On day 50, plasma insulin and IGF-1 were lower in WMIX group, as possible consequence of the lower plasma glucose and amino acids levels. Liver weight was not different between groups, but liver weight expressed as percentage of body weight was lower in WMIX kids and highly correlated to plasma IGF-1. Liver glycogen was also lower in WMIX kids, as possible consequence of the lower plasma glucose.Hepatic ALT and AST activities were not different between groups and both were strongly correlated to plasma insulin. Moreover, insulin was positively correlated to the proteosynthetic capability per cell (RNA/DNA of the liver.Our results indicate that the adopted livestock practice permitted the normal development of the animal used, avoiding growth stasis. Anyway, weaning altered plasma insulin and IGF-1, without affecting

  16. Potency of full-length MGF to induce maximal activation of the IGF-I R Is similar to recombinant human IGF-I at high equimolar concentrations

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); L.J. Hofland (Leo); C.J. Strasburger; E.S.R.D. Van Dungen (Elisabeth S.R. Den); M. Thevis (Mario)

    2016-01-01

    textabstractAims To compare full-length mechano growth factor (full-length MGF) with human recombinant insulin-like growth factor-I (IGF-I) and human recombinant insulin (HI) in their ability to activate the human IGF-I receptor (IGF-IR), the human insulin receptor (IR-A) and the human insulin

  17. Insulin, IGF-1, and GH Receptors Are Altered in an Adipose Tissue Depot-Specific Manner in Male Mice With Modified GH Action.

    Science.gov (United States)

    Hjortebjerg, Rikke; Berryman, Darlene E; Comisford, Ross; Frank, Stuart J; List, Edward O; Bjerre, Mette; Frystyk, Jan; Kopchick, John J

    2017-05-01

    Growth hormone (GH) is a determinant of glucose homeostasis and adipose tissue (AT) function. Using 7-month-old transgenic mice expressing the bovine growth hormone (bGH) gene and growth hormone receptor knockout (GHR-/-) mice, we examined whether changes in GH action affect glucose, insulin, and pyruvate tolerance and AT expression of proteins involved in the interrelated signaling pathways of GH, insulinlike growth factor 1 (IGF-1), and insulin. Furthermore, we searched for AT depot-specific differences in control mice. Glycated hemoglobin levels were reduced in bGH and GHR-/- mice, and bGH mice displayed impaired gluconeogenesis as judged by pyruvate tolerance testing. Serum IGF-1 was elevated by 90% in bGH mice, whereas IGF-1 and insulin were reduced by 97% and 61% in GHR-/- mice, respectively. Igf1 RNA was increased in subcutaneous, epididymal, retroperitoneal, and brown adipose tissue (BAT) depots in bGH mice (mean increase ± standard error of the mean in all five depots, 153% ± 27%) and decreased in all depots in GHR-/- mice (mean decrease, 62% ± 4%). IGF-1 receptor expression was decreased in all AT depots of bGH mice (mean decrease, 49% ± 6%) and increased in all AT depots of GHR-/- mice (mean increase, 94% ± 8%). Insulin receptor expression was reduced in retroperitoneal, mesenteric, and BAT depots in bGH mice (mean decrease in all depots, 56% ± 4%) and augmented in subcutaneous, retroperitoneal, mesenteric, and BAT depots in GHR-/- mice (mean increase: 51% ± 1%). Collectively, our findings indicate a role for GH in influencing hormone signaling in AT in a depot-dependent manner. Copyright © 2017 Endocrine Society.

  18. Birth weight, working memory and epigenetic signatures in IGF2 and related genes: a MZ twin study.

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    Aldo Córdova-Palomera

    Full Text Available Neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of several phenotypes associated with neuropsychiatric diseases and cognitive dysfunctions. Importantly, it has been noticed that epigenetic processes occurring early in life may mediate these associations. Here, DNA methylation signatures at IGF2 (insulin-like growth factor 2 and IGF2BP1-3 (IGF2-binding proteins 1-3 were examined in a sample consisting of 34 adult monozygotic (MZ twins informative for obstetric complications and cognitive performance. Multivariate linear regression analysis of twin data was implemented to test for associations between methylation levels and both birth weight (BW and adult working memory (WM performance. Familial and unique environmental factors underlying these potential relationships were evaluated. A link was detected between DNA methylation levels of two CpG sites in the IGF2BP1 gene and both BW and adult WM performance. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the WM-IGF2BP1 methylation relationship seemed mediated by both genes and environment. Our data is in agreement with previous evidence indicating that DNA methylation status may be related to prenatal stress and later neurocognitive phenotypes. While former reports independently detected associations between DNA methylation and either BW or WM, current results suggest that these relationships are not confounded by each other.

  19. Suckling induced insulin-like growth factor-1 (IGF-1) release in mother rats.

    Science.gov (United States)

    Lékó, András H; Cservenák, Melinda; Dobolyi, Árpád

    2017-12-01

    Lactation involves significant neuroendocrine changes. The elevated prolactin (PRL) release from the pituitary, induced markedly by suckling, is the most relevant example. Suckling also causes a significant and rapid elevation in growth hormone (GH) levels. GH is necessary for milk synthesis as milk yield is stopped completely in the absence of PRL and GH, while the absence of PRL alone causes only a 50% reduction. Insulin-like growth factor-1 (IGF-1) plays an important role in the GH axis. GH exerts its effects through IGF-1 in the periphery, for example in the mammary gland. In addition, IGF-1 is responsible for the long-loop feedback control of GH secretion. IGF-1 secretion has not been established yet in mothers. Therefore, in the present study, we investigated the effect of suckling on serum IGF-1 level in rat mothers and correlated it with serum PRL levels. We examined a potential mechanism of the regulation of IGF-1 level during suckling by administering IGF-1 into the lateral ventricle of rat mothers continuously for 12days, or acutely, right before the start of suckling. We described that suckling affected IGF-1 release based on one-way repeated measures ANOVA (F=10.8 and pIGF-1 level 30min after the start of suckling (pIGF-1 release. The prolonged central IGF-1 administration diminished the suckling-induced IGF-1 surge (F=9.19 and pIGF-1 release either by elevating PRL or GH. Long-loop feedback via IGF-1 in the GH axis can diminish this action. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Sustained IGF-1 Secretion by Adipose-Derived Stem Cells Improves Infarcted Heart Function.

    Science.gov (United States)

    Bagno, Luiza L; Carvalho, Deivid; Mesquita, Fernanda; Louzada, Ruy A; Andrade, Bruno; Kasai-Brunswick, Taís H; Lago, Vivian M; Suhet, Grazielle; Cipitelli, Debora; Werneck-de-Castro, João Pedro; Campos-de-Carvalho, Antonio C

    2016-01-01

    The mechanism by which stem cell-based therapy improves heart function is still unknown, but paracrine mechanisms seem to be involved. Adipose-derived stem cells (ADSCs) secrete several factors, including insulin-like growth factor-1 (IGF-1), which may contribute to myocardial regeneration. Our aim was to investigate whether the overexpression of IGF-1 in ADSCs (IGF-1-ADSCs) improves treatment of chronically infarcted rat hearts. ADSCs were transduced with a lentiviral vector to induce IGF-1 overexpression. IGF-1-ADSCs transcribe100- to 200-fold more IGF-1 mRNA levels compared to nontransduced ADSCs. IGF-1 transduction did not alter ADSC immunophenotypic characteristics even under hypoxic conditions. However, IGF-1-ADSCs proliferate at higher rates and release greater amounts of growth factors such as IGF-1, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) under normoxic and hypoxic conditions. Importantly, IGF-1 secreted by IGF-1-ADSCs is functional given that Akt-1 phosphorylation was remarkably induced in neonatal cardiomyocytes cocultured with IGF-1-ADSCs, and this increase was prevented with phosphatidylinositol 3-kinase (PI3K) inhibitor treatment. Next, we tested IGF-1-ADSCs in a rat myocardial infarction (MI) model. MI was performed by coronary ligation, and 4 weeks after MI, animals received intramyocardial injections of either ADSCs (n = 7), IGF-1-ADSCs (n = 7), or vehicle (n = 7) into the infarcted border zone. Left ventricular function was evaluated by echocardiography before and after 6 weeks of treatment, and left ventricular hemodynamics were assessed 7 weeks after cell injection. Notably, IGF-1-ADSCs improved left ventricular ejection fraction and cardiac contractility index, but did not reduce scar size when compared to the ADSC-treated group. In summary, transplantation of ADSCs transduced with IGF-1 is a superior therapeutic approach to treat MI compared to nontransduced ADSCs, suggesting that gene and cell

  1. IGF-I levels reflect hypopituitarism severity in adults with pituitary dysfunction.

    Science.gov (United States)

    Tirosh, Amit; Toledano, Yoel; Masri-Iraqi, Hiba; Eizenberg, Yoav; Tzvetov, Gloria; Hirsch, Dania; Benbassat, Carlos; Robenshtok, Eyal; Shimon, Ilan

    2016-08-01

    To evaluate the utility of Insulin-like growth factor I (IGF-I) standard deviation score (SDS) as a surrogate marker of severity of hypopituitarism in adults with pituitary pathology. We performed a retrospective data analysis, including 269 consecutive patients with pituitary disease attending a tertiary endocrine clinic in 1990-2015. The medical files were reviewed for the complete pituitary hormone profile, including IGF-I, and clinical data. Age-adjusted assay reference ranges of IGF-I were used to calculate IGF-I SDS for each patient. The main outcome measures were positive and negative predictive values of low and high IGF-I SDS, respectively, for the various pituitary hormone deficiencies. IGF-I SDS correlated negatively with the number of altered pituitary axes (p hypopituitarism in adults with pituitary disease, and thus can serve as a marker of hypopituitarism severity.

  2. IGF-1 promotes the development and cytotoxic activity of human NK cells

    OpenAIRE

    Ni, Fang; Sun, Rui; Fu, Binqing; Wang, Fuyan; Guo, Chuang; Tian, Zhigang; Wei, Haiming

    2013-01-01

    Insulin-like growth factor 1 (IGF-1) is a critical regulator of many physiological functions, ranging from longevity to immunity. However, little is known about the role of IGF-1 in natural killer cell development and function. Here, we identify an essential role for IGF-1 in the positive regulation of human natural killer cell development and cytotoxicity. Specifically, we show that human natural killer cells have the ability to produce IGF-1 and that differential endogenous IGF-1 expression...

  3. The Association Between IGF-I and Insulin Resistance

    DEFF Research Database (Denmark)

    Friedrich, Nele; Thuesen, Betina; Jørgensen, Torben

    2012-01-01

    OBJECTIVEIGF-I has an almost 50% amino acid sequence homology with insulin and elicits nearly the same hypoglycemic response. Studies showed that low and high IGF-I levels are related to impaired glucose tolerance and to a higher risk of type 2 diabetes. The aim of the current study was to evaluate...... the association between IGF-I level and insulin resistance in a Danish general population.RESEARCH DESIGN AND METHODSIncluded were 3,354 adults, aged 19-72 years, from the cross-sectional Health2006 study. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index to estimate insulin...... with intermediate (Q3) IGF-I levels. These associations remained statistically significant after the exclusion of subjects with type 2 diabetes and by using the updated computer HOMA2-IR model.CONCLUSIONSLow- and high-normal IGF-I levels are both related to insulin resistance. The biological mechanism...

  4. miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect

    Directory of Open Access Journals (Sweden)

    Liu W

    2018-03-01

    Full Text Available Wenpeng Liu,1,* Lei Kang,2,* Juqiang Han,3 Yadong Wang,1 Chuan Shen,1 Zhifeng Yan,4 Yanhong Tai,5 Caiyan Zhao1 1Department of Infectious Diseases, Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China; 2Department of Nuclear Medicine, Peking University First Hospital, Beijing, China; 3Institute of Liver Disease, Beijing Military General Hospital, Beijing, China; 4Department of Gynecology and Obstetrics, PLA General Hospital, Beijing, China; 5Department of Pathology, Hospital of PLA, Beijing, China *These authors contributed equally to this work Background: Insulin-like growth factor-1 receptor (IGF-1R is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC. Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear. Materials and methods: Cell proliferation was evaluated by cell counting Kit-8 and colony formation assay. Western blot and real-time PCR were accordingly used to detect the relevant proteins, miRNA and gene expression. Luciferase reporter assays were used to illustrate the interaction between miR-342-3p and IGF-1R. The effect of miR-342-3p on glycolysis was determined by glucose uptake, ATP concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. In vivo, subcutaneous tumor formation assay and PET were performed in nude mice. Results: In this study, we demonstrate that by directly targeting the 3’-UTR (3’-untranslated regions of IGF-1R, microRNA-342-3p (miR-342-3p suppresses IGF-1R-mediated PI3K/AKT/GLUT1 signaling pathway both in vitro and in vivo. Through suppression of IGF-1R, miR-342-3p dampens glycolysis by decreasing glucose uptake, lactate generation

  5. IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model

    International Nuclear Information System (INIS)

    Jia, Yanhan; Zhang, Yan; Qiao, Chunxia; Liu, Guijun; Zhao, Qing; Zhou, Tingting; Chen, Guojiang; Li, Yali; Feng, Jiannan; Li, Yan; Zhang, Qiuping; Peng, Hui

    2013-01-01

    Highlights: •We established trastuzumab-resistant cell line SKOV3/T. •SKOV3/T enhances proliferation and in vivo carcinogenesis. •IGF-1R and HER3 genes were up-regulated in SKOV3/T based on microarray analysis. •Targeting IGF-1R and/or HER3 inhibited the proliferation of SKOV3/T. •Therapies targeting IGF-1R and HER3 might be effective in ovarian cancer. -- Abstract: Trastuzumab (Herceptin®) has demonstrated clinical potential in several types of HER2-overexpressing human cancers. However, primary and acquired resistance occurs in many HER2-positive patients with regimens. To investigate the possible mechanism of acquired therapeutic resistance to trastuzumab, we have developed a preclinical model of human ovarian cancer cells, SKOV3/T, with the distinctive feature of stronger carcinogenesis. The differences in gene expression between parental and the resistant cells were explored by microarray analysis, of which IGF-1R and HER3 were detected to be key molecules in action. Their correctness was validated by follow-up experiments of RT-PCR, shRNA-mediated knockdown, downstream signal activation, cell cycle distribution and survival. These results suggest that IGF-1R and HER3 differentially regulate trastuzumab resistance and could be promising targets for trastuzumab therapy in ovarian cancer

  6. IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model

    Energy Technology Data Exchange (ETDEWEB)

    Jia, Yanhan [Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071 (China); Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Zhang, Yan [Department of Gynaecology and Obstetrics, PLA General Hospital, Beijing 100853 (China); Qiao, Chunxia; Liu, Guijun [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Zhao, Qing [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Department of Gynaecology and Obstetrics, PLA General Hospital, Beijing 100853 (China); Zhou, Tingting; Chen, Guojiang [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Li, Yali [Department of Gynaecology and Obstetrics, PLA General Hospital, Beijing 100853 (China); Feng, Jiannan; Li, Yan [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Zhang, Qiuping, E-mail: qpzhang@whu.edu.cn [Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071 (China); Peng, Hui, E-mail: p_h2002@hotmail.com [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Beijing 100850 (China)

    2013-07-12

    Highlights: •We established trastuzumab-resistant cell line SKOV3/T. •SKOV3/T enhances proliferation and in vivo carcinogenesis. •IGF-1R and HER3 genes were up-regulated in SKOV3/T based on microarray analysis. •Targeting IGF-1R and/or HER3 inhibited the proliferation of SKOV3/T. •Therapies targeting IGF-1R and HER3 might be effective in ovarian cancer. -- Abstract: Trastuzumab (Herceptin®) has demonstrated clinical potential in several types of HER2-overexpressing human cancers. However, primary and acquired resistance occurs in many HER2-positive patients with regimens. To investigate the possible mechanism of acquired therapeutic resistance to trastuzumab, we have developed a preclinical model of human ovarian cancer cells, SKOV3/T, with the distinctive feature of stronger carcinogenesis. The differences in gene expression between parental and the resistant cells were explored by microarray analysis, of which IGF-1R and HER3 were detected to be key molecules in action. Their correctness was validated by follow-up experiments of RT-PCR, shRNA-mediated knockdown, downstream signal activation, cell cycle distribution and survival. These results suggest that IGF-1R and HER3 differentially regulate trastuzumab resistance and could be promising targets for trastuzumab therapy in ovarian cancer.

  7. Hepatoprotection and neuroprotection induced by low doses of IGF-II in aging rats

    Directory of Open Access Journals (Sweden)

    Barhoum Rima

    2011-07-01

    Full Text Available Abstract Background GH and IGFs serum levels decline with age. Age-related changes appear to be associated to decreases in these anabolic hormones. We have previously demonstrated that IGF-I replacement therapy improves insulin resistance, lipid metabolism and reduces oxidative damage (in brain and liver in aging rats. Using the same experimental model, the aim of this work was to study whether the exogenous administration of IGF-II, at low doses, acts analogous to IGF-I in aging rats. Methods Three experimental groups were included in this study: young healthy controls (yCO, 17 weeks old; untreated old rats (O, 103 weeks old; and aging rats treated with IGF-II (O+IGF-II, 2 μg * 100 g body weight-1 * day-1 for 30 days. Analytical parameters were determined in serum by routine laboratory methods using an autoanalyzer (Cobas Mira; Roche Diagnostic System, Basel, Switzerland. Serum levels of hormones (testosterone, IGF-I and insulin were assessed by RIA. Serum Total Antioxidant Status was evaluated using a colorimetric assay. Mitochondrial membrane potential was evaluated using rhodamine 123 dye (adding different substrates to determine the different states. ATP synthesis in isolated mitochondria was determined by an enzymatic method. Results Compared with young controls, untreated old rats showed a reduction of IGF-I and testosterone levels with a decrease of serum total antioxidant status (TAS. IGF-II therapy improved serum antioxidant capability without modifying testosterone and IGF-I circulating concentrations. In addition, IGF-II treatment reduced oxidative damage in brain and liver, improving antioxidant enzyme activities and mitochondrial function. IGF-II was also able to reduce cholesterol and triglycerides levels increasing free fatty acids concentrations. Conclusions We demonstrate that low doses of IGF-II induce hepatoprotective, neuroprotective and metabolic effects, improving mitochondrial function, without affecting testosterone and

  8. Human IGF-I propeptide A promotes articular chondrocyte biosynthesis and employs glycosylation-dependent heparin binding.

    Science.gov (United States)

    Shi, Shuiliang; Kelly, Brian J; Wang, Congrong; Klingler, Ken; Chan, Albert; Eckert, George J; Trippel, Stephen B

    2018-03-01

    Insulin-like growth factor I (IGF-I) is a key regulator of chondrogenesis, but its therapeutic application to articular cartilage damage is limited by rapid elimination from the repair site. The human IGF-I gene gives rise to three IGF-I propeptides (proIGF-IA, proIGF-IB and proIGF-IC) that are cleaved to create mature IGF-I. In this study, we elucidate the processing of IGF-I precursors by articular chondrocytes, and test the hypotheses that proIGF-I isoforms bind to heparin and regulate articular chondrocyte biosynthesis. Human IGF-I propeptides and mutants were overexpressed in bovine articular chondrocytes. IGF-I products were characterized by ELISA, western blot and FPLC using a heparin column. The biosynthetic activity of IGF-I products on articular chondrocytes was assayed for DNA and glycosaminoglycan that the cells produced. Secreted IGF-I propeptides stimulated articular chondrocyte biosynthetic activity to the same degree as mature IGF-I. Of the three IGF-I propeptides, only one, proIGF-IA, strongly bound to heparin. Interestingly, heparin binding of proIGF-IA depended on N-glycosylation at Asn92 in the EA peptide. To our knowledge, this is the first demonstration that N-glycosylation determines the binding of a heparin-binding protein to heparin. The biosynthetic and heparin binding abilities of proIGF-IA, coupled with its generation of IGF-I, suggest that proIGF-IA may have therapeutic value for articular cartilage repair. These data identify human pro-insulin-like growth factor IA as a bifunctional protein. Its combined ability to bind heparin and augment chondrocyte biosynthesis makes it a promising therapeutic agent for cartilage damage due to trauma and osteoarthritis. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Serum insulin-like growth factor (IGF)-I and IGF binding protein-3 in relation to terminal duct lobular unit involution of the normal breast in Caucasian and African American women: The Susan G. Komen Tissue Bank.

    Science.gov (United States)

    Oh, Hannah; Pfeiffer, Ruth M; Falk, Roni T; Horne, Hisani N; Xiang, Jackie; Pollak, Michael; Brinton, Louise A; Storniolo, Anna Maria V; Sherman, Mark E; Gierach, Gretchen L; Figueroa, Jonine D

    2018-02-22

    Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin-like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 and 2012 (75% premenopausal), serum concentrations of IGF-I and binding protein (IGFBP)-3 were quantified using enzyme-linked immunosorbent assay. Hematoxilyn and eosin-stained tissue sections were assessed for numbers of TDLUs ("TDLU count"). Zero-inflated Poisson regression models with a robust variance estimator were used to estimate relative risks (RRs) for association of IGF measures (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. AA (vs. Caucasian) women had higher age-adjusted mean levels of serum IGF-I (137 vs. 131 ng/mL, p = 0.07) and lower levels of IGFBP-3 (4165 vs. 4684 ng/mL, p IGF-I:IGFBP-3 ratios were associated with higher TDLU count in Caucasian (RR T3vs.T1 =1.33, 95% CI = 1.02-1.75, p-trend = 0.04), but not in AA (RR T3vs.T1 =0.65, 95% CI = 0.42-1.00, p-trend = 0.05), women. Our data suggest a role of the IGF system, particularly IGFBP-3, in TDLU involution of the normal breast, a breast cancer risk factor, among Caucasian and AA women. © 2018 UICC.

  10. Insulin-like growth factor I (IGF-1) Ec/Mechano Growth factor--a splice variant of IGF-1 within the growth plate.

    Science.gov (United States)

    Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

    2013-01-01

    Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.

  11. Does adenotonsillectomy alter IGF-1 and ghrelin serum levels in children with adenotonsillar hypertrophy and failure to thrive? A prospective study.

    Science.gov (United States)

    Jabbari Moghaddam, Yalda; Golzari, Samad E J; Saboktakin, Lida; Seyedashrafi, Mir Hojjat; Sabermarouf, Babak; Gavgani, Heidar Ali Esmaeili; Haghjo, Amir Ghorbani; Lotfi, Alireza; Ghabili, Kamyar

    2013-09-01

    Adenotonsillar hypertrophy (ATH) contributes to upper airway obstruction and recurrent tonsillitis in children. The aim of this study was to evaluate the effect of adenotonsillectomy on serum IGF-1 and ghrelin levels in children with ATH failure to thrive. Forty pre-pubertal children with more than 5 years of age (6.57 ± 1.284 years) suffering from ATH, sleep disorder breathing, snoring, open mouth breathing and growth retardation were studied. Blood samples were taken eight hours after fasting and weight and height were measured by SECA instrument. Blood samples were centrifuged immediately and the extracted sera were stored at -70 °C in Eppendorf vials. IGF-1 and ghrelin were measured by ELISA kit. Patients with adenotonsillectomy indication underwent adenotonsillectomy and serum levels of IGF-1 and ghrelin were measured 12 months after operation. Weight, height and BMI were increased significantly after operation (P failure to thrive increases IGF-1 and Ghrelin serum levels which might contribute to the improvement in the growth pattern of the children. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Endocrine and Local IGF-I in the Bony Fish Immune System.

    Science.gov (United States)

    Franz, Anne-Constance; Faass, Oliver; Köllner, Bernd; Shved, Natallia; Link, Karl; Casanova, Ayako; Wenger, Michael; D'Cotta, Helena; Baroiller, Jean-François; Ullrich, Oliver; Reinecke, Manfred; Eppler, Elisabeth

    2016-01-26

    A role for GH and IGF-I in the modulation of the immune system has been under discussion for decades. Generally, GH is considered a stimulator of innate immune parameters in mammals and teleost fish. The stimulatory effects in humans as well as in bony fish often appear to be correlated with elevated endocrine IGF-I (liver-derived), which has also been shown to be suppressed during infection in some studies. Nevertheless, data are still fragmentary. Some studies point to an important role of GH and IGF-I particularly during immune organ development and constitution. Even less is known about the potential relevance of local (autocrine/paracrine) IGF-I within adult and developing immune organs, and the distinct localization of IGF-I in immune cells and tissues of mammals and fish has not been systematically defined. Thus far, IGF-I has been localized in different mammalian immune cell types, particularly macrophages and granulocytes, and in supporting cells, but not in T-lymphocytes. In the present study, we detected IGF-I in phagocytic cells isolated from rainbow trout head kidney and, in contrast to some findings in mammals, in T-cells of a channel catfish cell line. Thus, although numerous analogies among mammals and teleosts exist not only for the GH/IGF-system, but also for the immune system, there are differences that should be further investigated. For instance, it is unclear whether the primarily reported role of GH/IGF-I in the innate immune response is due to the lack of studies focusing on the adaptive immune system, or whether it truly preferentially concerns innate immune parameters. Infectious challenges in combination with GH/IGF-I manipulations are another important topic that has not been sufficiently addressed to date, particularly with respect to developmental and environmental influences on fish growth and health.

  13. Endocrine and Local IGF-I in the Bony Fish Immune System

    Directory of Open Access Journals (Sweden)

    Anne-Constance Franz

    2016-01-01

    Full Text Available A role for GH and IGF-I in the modulation of the immune system has been under discussion for decades. Generally, GH is considered a stimulator of innate immune parameters in mammals and teleost fish. The stimulatory effects in humans as well as in bony fish often appear to be correlated with elevated endocrine IGF-I (liver-derived, which has also been shown to be suppressed during infection in some studies. Nevertheless, data are still fragmentary. Some studies point to an important role of GH and IGF-I particularly during immune organ development and constitution. Even less is known about the potential relevance of local (autocrine/paracrine IGF-I within adult and developing immune organs, and the distinct localization of IGF-I in immune cells and tissues of mammals and fish has not been systematically defined. Thus far, IGF-I has been localized in different mammalian immune cell types, particularly macrophages and granulocytes, and in supporting cells, but not in T-lymphocytes. In the present study, we detected IGF-I in phagocytic cells isolated from rainbow trout head kidney and, in contrast to some findings in mammals, in T-cells of a channel catfish cell line. Thus, although numerous analogies among mammals and teleosts exist not only for the GH/IGF-system, but also for the immune system, there are differences that should be further investigated. For instance, it is unclear whether the primarily reported role of GH/IGF-I in the innate immune response is due to the lack of studies focusing on the adaptive immune system, or whether it truly preferentially concerns innate immune parameters. Infectious challenges in combination with GH/IGF-I manipulations are another important topic that has not been sufficiently addressed to date, particularly with respect to developmental and environmental influences on fish growth and health.

  14. IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3.

    Directory of Open Access Journals (Sweden)

    Alpa V Patel

    2008-07-01

    Full Text Available IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3. This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.

  15. MSM enhances GH signaling via the Jak2/STAT5b pathway in osteoblast-like cells and osteoblast differentiation through the activation of STAT5b in MSCs.

    Directory of Open Access Journals (Sweden)

    Youn Hee Joung

    Full Text Available Methylsulfonylmethane (MSM is a naturally occurring sulfur compound with well-known anti-oxidant properties and anti-inflammatory activities. But, its effects on bone are unknown. Growth hormone (GH is regulator of bone growth and bone metabolism. GH activates several signaling pathways such as the Janus kinase (Jak/signal transducers and activators of transcription (STAT pathway, thereby regulating expression of genes including insulin-like growth factor (IGF-1. GH exerts effects both directly and via IGF-1, which signals by activating the IGF-1 receptor (IGF-1R. In this study, we investigated the effects of MSM on the GH signaling via the Jak/STAT pathway in osteoblasts and the differentiation of primary bone marrow mesenchymal stem cells (MSCs. MSM was not toxic to osteoblastic cells and MSCs. MSM increased the expression of GH-related proteins including IGF-1R, p-IGF-1R, STAT5b, p-STAT5b, and Jak2 in osteoblastic cells and MSCs. MSM increased IGF-1R and GHR mRNA expression in osteoblastic cells. The expression of MSM-induced IGF-1R and GHR was inhibited by AG490, a Jak2 kinase inhibitor. MSM induced binding of STAT5 to the IGF-1R and increased IGF-1 and IGF-1R promoter activities. Analysis of cell extracts by immunoprecipitation and Western blot showed that MSM enhanced GH-induced activation of Jak2/STAT5b. We found that MSM and GH, separately or in combination, activated GH signaling via the Jak2/STAT5b pathway in UMR-106 cells. Using siRNA analysis, we found that STAT5b plays an essential role in GH signaling activation in C3H10T1/2 cells. Osteogenic marker genes (ALP, ON, OCN, BSP, OSX, and Runx2 were activated by MSM, and siRNA-mediated STAT5b knockdown inhibited MSM-induced expression of osteogenic markers. Furthermore, MSM increased ALP activity and the mineralization of MSCs. Taken together, these results indicated that MSM can promote osteogenic differentiation of MSCs through activation of STAT5b.

  16. Characterisation of adiponectin multimers and the IGF axis in humans with a heterozygote mutation in the tyrosine kinase domain of the insulin receptor gene

    DEFF Research Database (Denmark)

    Højlund, Kurt; Beck-Nielsen, Henning; Flyvbjerg, Allan

    2012-01-01

    Objective: Low levels of adiponectin, IGF-binding protein (IGFBP)-1, and IGFBP-2, and high levels of leptin correlate with several indices of insulin resistance and risk of type 2 diabetes. However, in insulin receptoropathies plasma adiponectin is paradoxically increased despite severe insulin...... resistance, whereas the IGF-axis is sparsely described. Here, we aimed to characterize the multimeric distribution of adiponectin and the IGF-axis in humans with a heterozygous INSR mutation (Arg1174Gln).Methods: Blood samples obtained in six Arg1174Gln-carriers and 10 lean, healthy controls before and after...... an euglycemic-hyperinsulinemic clamp were examined for plasma adiponectin multimers, leptin, total IGF-I, IGF-II, free IGF-I, IGFBP-1 and IGFBP-2.Results: Despite 10-fold elevated fasting insulin and marked insulin resistance in Arg1174Gln-carriers, the levels of total adiponectin, leptin, IGFBP-1 and IGFBP-2...

  17. A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production

    DEFF Research Database (Denmark)

    Marzec, Michal; Hawkes, Colin P; Eletto, Davide

    2016-01-01

    IGFs are critical for normal intrauterine and childhood growth and sustaining health throughout life. We showed previously that the production of IGF-1 and IGF-2 requires interaction with the chaperone glucose-regulated protein 94 (GRP94) and that the amount of secreted IGFs is proportional...... in a child with primary IGF deficiency and was later shown to be a noncommon single-nucleotide polymorphism with frequencies of 1%-4% in various populations. When tested in the grp94(-/-) cell-based complementation assay, P300L supported only approximately 58% of IGF secretion relative to wild-type GRP94....... Furthermore, recombinant P300L showed impaired nucleotide binding activity. These in vitro data strongly support a causal relationship between the GRP94 variant and the decreased concentration of circulating IGF-1, as observed in human carriers of P300L. Thus, mutations in GRP94 that affect its IGF chaperone...

  18. IGF1 stimulates greater muscle hypertrophy in the absence of myostatin in male mice.

    Science.gov (United States)

    Hennebry, Alexander; Oldham, Jenny; Shavlakadze, Tea; Grounds, Miranda D; Sheard, Philip; Fiorotto, Marta L; Falconer, Shelley; Smith, Heather K; Berry, Carole; Jeanplong, Ferenc; Bracegirdle, Jeremy; Matthews, Kenneth; Nicholas, Gina; Senna-Salerno, Mônica; Watson, Trevor; McMahon, Christopher D

    2017-08-01

    Insulin-like growth factors (IGFs) and myostatin have opposing roles in regulating the growth and size of skeletal muscle, with IGF1 stimulating, and myostatin inhibiting, growth. However, it remains unclear whether these proteins have mutually dependent, or independent, roles. To clarify this issue, we crossed myostatin null ( Mstn -/- ) mice with mice overexpressing Igf1 in skeletal muscle ( Igf1 + ) to generate six genotypes of male mice; wild type ( Mstn +/+ ), Mstn +/- , Mstn -/- , Mstn +/+ :Igf1 + , Mstn +/- :Igf1 + and Mstn -/- :Igf1 + Overexpression of Igf1 increased the mass of mixed fibre type muscles (e.g. Quadriceps femoris ) by 19% over Mstn +/+ , 33% over Mstn +/- and 49% over Mstn -/- ( P  Myostatin regulated the number, while IGF1 regulated the size of myofibres, and the deletion of Mstn and Igf1 + independently increased the proportion of fast type IIB myosin heavy chain isoforms in T. anterior (up to 10% each, P  myostatin is absent and IGF1 is in excess. Finally, we show that myostatin and IGF1 regulate skeletal muscle size, myofibre type and gonadal fat through distinct mechanisms that involve increasing the total abundance and phosphorylation status of AKT and rpS6. © 2017 Society for Endocrinology.

  19. Insulin-like growth factor 1 (IGF-1): a growth hormone

    Science.gov (United States)

    Laron, Z

    2001-01-01

    Aim—To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process. Methods—To describe growth in human and animal models of isolated IGF-1 deficiency (IGHD), such as in Laron syndrome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH receptor gene knockout (KO) mice. Results—Since the description of LS in 1966, 51 patients were followed, many since infancy. Newborns with LS are shorter (42–47 cm) than healthy babies (49–52 cm), suggesting that IGF-1 has some influence on intrauterine growth. Newborn mice with IGF-1 gene KO are 30% smaller. The postnatal growth rate of patients with LS is very slow, the distance from the lowest normal centile increasing progressively. If untreated, the final height is 100–136 cm for female and 109–138 cm for male patients. They have acromicia, organomicria including the brain, heart, gonads, genitalia, and retardation of skeletal maturation. The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS. It accelerated linear growth rates to 8–9 cm in the first year of treatment, compared with 10–12 cm/year during GH treatment of IGHD. The growth rate in following years was 5–6.5 cm/year. Conclusion—IGF-1 is an important growth hormone, mediating the protein anabolic and linear growth promoting effect of pituitary GH. It has a GH independent growth stimulating effect, which with respect to cartilage cells is possibly optimised by the synergistic action with GH. PMID:11577173

  20. IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging.

    Science.gov (United States)

    Toth, Peter; Tarantini, Stefano; Ashpole, Nicole M; Tucsek, Zsuzsanna; Milne, Ginger L; Valcarcel-Ares, Noa M; Menyhart, Akos; Farkas, Eszter; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2015-12-01

    Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1(f/f) -TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  1. IGF-I and GH: potential use in gene doping.

    Science.gov (United States)

    Harridge, Stephen D R; Velloso, Cristiana P

    2009-08-01

    Gene doping is the term given to the potential misuse of gene therapy for the purposes of enhancing athletic performance. Insulin like growth factor-I (IGF-I), the prime target of growth hormone action, is one candidate gene for improving performance. In recent years a number of transgenic and somatic gene transfer studies on animals have shown that upregulation of IGF-I stimulates muscle growth and improves function. This increase in muscle IGF-I is not reflected in measurable increases in circulating IGF-I. Whilst the responses obtained in the animal studies would appear to give clear benefits for performance, the transfer of such techniques to humans still presents many technical challenges. Further challenges will also be faced by the anti doping authorities in detecting the endogenously produced products of enhanced gene expression.

  2. Compressive Sampling of EEG Signals with Finite Rate of Innovation

    Directory of Open Access Journals (Sweden)

    Poh Kok-Kiong

    2010-01-01

    Full Text Available Analyses of electroencephalographic signals and subsequent diagnoses can only be done effectively on long term recordings that preserve the signals' morphologies. Currently, electroencephalographic signals are obtained at Nyquist rate or higher, thus introducing redundancies. Existing compression methods remove these redundancies, thereby achieving compression. We propose an alternative compression scheme based on a sampling theory developed for signals with a finite rate of innovation (FRI which compresses electroencephalographic signals during acquisition. We model the signals as FRI signals and then sample them at their rate of innovation. The signals are thus effectively represented by a small set of Fourier coefficients corresponding to the signals' rate of innovation. Using the FRI theory, original signals can be reconstructed using this set of coefficients. Seventy-two hours of electroencephalographic recording are tested and results based on metrices used in compression literature and morphological similarities of electroencephalographic signals are presented. The proposed method achieves results comparable to that of wavelet compression methods, achieving low reconstruction errors while preserving the morphologiies of the signals. More importantly, it introduces a new framework to acquire electroencephalographic signals at their rate of innovation, thus entailing a less costly low-rate sampling device that does not waste precious computational resources.

  3. IGF binding protein alterations on periplaque oligodendrocytes in multiple sclerosis : Implications for remyelination

    NARCIS (Netherlands)

    Wilczak, Nadine; Chesik, Daniel; Hoekstra, Dick; De Keyser, Jacques

    Why myelin repair greatly fails in multiple sclerosis (MS) is unclear. The insulin-like growth factor (IGF) system plays vital roles in oligodendrocyte development, survival, and myelin synthesis. We used immunohistochemistry to study IGF-I, IGF-I receptors and IGF binding proteins (IGFBPs) 1-6 on

  4. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline

    Science.gov (United States)

    Talbot, Konrad; Wang, Hoau-Yan; Kazi, Hala; Han, Li-Ying; Bakshi, Kalindi P.; Stucky, Andres; Fuino, Robert L.; Kawaguchi, Krista R.; Samoyedny, Andrew J.; Wilson, Robert S.; Arvanitakis, Zoe; Schneider, Julie A.; Wolf, Bryan A.; Bennett, David A.; Trojanowski, John Q.; Arnold, Steven E.

    2012-01-01

    While a potential causal factor in Alzheimer’s disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS616) and IRS-1 pS636/639. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS616 and IRS-1 pS636/639 and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology. PMID:22476197

  5. Effect of resistance exercise intensity on the expression of PGC-1α isoforms and the anabolic and catabolic signaling mediators, IGF-1 and myostatin, in human skeletal muscle.

    Science.gov (United States)

    Schwarz, Neil A; McKinley-Barnard, Sarah K; Spillane, Mike B; Andre, Thomas L; Gann, Joshua J; Willoughby, Darryn S

    2016-08-01

    The purpose of this study was to investigate the acute messenger (mRNA) expression of the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) isoforms, insulin-like growth factor-1Ea (IGF-1Ea), and myostatin in response to 2 resistance exercise intensities. In a uniform-balanced, crossover design, 10 participants performed 2 separate testing sessions involving a lower body resistance exercise component consisting of a lower intensity (50% of 1-repetition maximum; 1RM) protocol and a higher intensity (80% of 1RM) protocol of equal volumes. Muscle samples were obtained at before exercise, 45 min, 3 h, 24 h, and 48 h postexercise. Resistance exercise did not alter total PGC-1α mRNA expression; however, distinct responses of each PGC-1α isoform were observed. The response of each isoform was consistent between sessions, suggesting no effect of resistance exercise intensity on the complex transcriptional expression of the PGC-1α gene. IGF-1Ea mRNA expression significantly increased following the higher intensity session compared with pre-exercise and the lower intensity session. Myostatin mRNA expression was significantly reduced compared with pre-exercise values at all time points with no difference between exercise intensity. Further research is needed to determine the effects of the various isoforms of PGC-1α in human skeletal muscle on the translational level as well as their relation to the expression of IGF-1 and myostatin.

  6. Exercise Activates p53 and Negatively Regulates IGF-1 Pathway in Epidermis within a Skin Cancer Model.

    Science.gov (United States)

    Yu, Miao; King, Brenee; Ewert, Emily; Su, Xiaoyu; Mardiyati, Nur; Zhao, Zhihui; Wang, Weiqun

    2016-01-01

    Exercise has been previously reported to lower cancer risk through reducing circulating IGF-1 and IGF-1-dependent signaling in a mouse skin cancer model. This study aims to investigate the underlying mechanisms by which exercise may down-regulate the IGF-1 pathway via p53 and p53-related regulators in the skin epidermis. Female SENCAR mice were pair-fed an AIN-93 diet with or without 10-week treadmill exercise at 20 m/min, 60 min/day and 5 days/week. Animals were topically treated with TPA 2 hours before sacrifice and the target proteins in the epidermis were analyzed by both immunohistochemistry and Western blot. Under TPA or vehicle treatment, MDM2 expression was significantly reduced in exercised mice when compared with sedentary control. Meanwhile, p53 was significantly elevated. In addition, p53-transcriptioned proteins, i.e., p21, IGFBP-3, and PTEN, increased in response to exercise. There was a synergy effect between exercise and TPA on the decreased MDM2 and increased p53, but not p53-transcripted proteins. Taken together, exercise appeared to activate p53, resulting in enhanced expression of p21, IGFBP-3, and PTEN that might induce a negative regulation of IGF-1 pathway and thus contribute to the observed cancer prevention by exercise in this skin cancer model.

  7. Co-targeting the HER and IGF/insulin receptor axis in breast cancer, with triple targeting with endocrine therapy for hormone-sensitive disease.

    Science.gov (United States)

    Chakraborty, Ashok; Hatzis, Christos; DiGiovanna, Michael P

    2017-05-01

    Interactions between HER2, estrogen receptor (ER), and insulin-like growth factor I receptor (IGF1R) are implicated in resistance to monotherapies targeting these receptors. We have previously shown in pre-clinical studies synergistic anti-tumor effects for co-targeting each pairwise combination of HER2, IGF1R, and ER. Strikingly, synergy for HER2/IGF1R targeting occurred not only in a HER2+ model, but also in a HER2-normal model. The purpose of the current study was therefore to determine the generalizability of synergistic anti-tumor effects of co-targeting HER2/IGF1R, the anti-tumor activity of triple-targeting HER2/IGF1R/ER in hormone-dependent cell lines, and the effect of using the multi-targeting drugs neratinib (pan-HER) and BMS-754807 (dual IGF1R/insulin receptor). Proliferation and apoptosis assays were performed in a large panel of cell lines representing varying receptor expression levels. Mechanistic effects were studied using phospho-protein immunoblotting. Analyses of drug interaction effects were performed using linear mixed-effects regression models. Enhanced anti-proliferative effects of HER/IGF-insulin co-targeting were seen in most, though not all, cell lines, including HER2-normal lines. For ER+ lines, triple targeting with inclusion of anti-estrogen generally resulted in the greatest anti-tumor effects. Double or triple targeting generally resulted in marked increases in apoptosis in the sensitive lines. Mechanistic studies demonstrated that the synergy between drugs was correlated with maximal inhibition of Akt and ERK pathway signaling. Dual HER/IGF-insulin targeting, and triple targeting with inclusion of anti-estrogen drugs, shows striking anti-tumor activity across breast cancer types, and drugs with broader receptor specificity may be more effective than single receptor selective drugs, particularly for ER- cells.

  8. Early IGF-1 primes visual cortex maturation and accelerates developmental switch between NKCC1 and KCC2 chloride transporters in enriched animals.

    Science.gov (United States)

    Baroncelli, Laura; Cenni, Maria Cristina; Melani, Riccardo; Deidda, Gabriele; Landi, Silvia; Narducci, Roberta; Cancedda, Laura; Maffei, Lamberto; Berardi, Nicoletta

    2017-02-01

    Environmental enrichment (EE) has a remarkable impact on brain development. Continuous exposure to EE from birth determines a significant acceleration of visual system maturation both at retinal and cortical levels. A pre-weaning enriched experience is sufficient to trigger the accelerated maturation of the visual system, suggesting that factors affected by EE during the first days of life might prime visual circuits towards a faster development. The search for such factors is crucial not only to gain a better understanding of the molecular hierarchy of brain development but also to identify molecular pathways amenable to be targeted to correct atypical brain developmental trajectories. Here, we showed that IGF-1 levels are increased in the visual cortex of EE rats as early as P6 and this is a crucial event for setting in motion the developmental program induced by EE. Early intracerebroventricular (i.c.v.) infusion of IGF-1 in standard rats was sufficient to mimic the action of EE on visual acuity development, whereas blocking IGF-1 signaling by i.c.v. injections of the IGF-1 receptor antagonist JB1 prevented the deployment of EE effects. Early IGF-1 decreased the ratio between the expression of NKCC1 and KCC2 cation/chloride transporters, and the reversal potential for GABA A R-driven Cl - currents (E Cl ) was shifted toward more negative potentials, indicating that IGF-1 is a crucial factor in accelerating the maturation of GABAergic neurotransmission and promoting the developmental switch of GABA polarity from excitation to inhibition. In addition, early IGF-1 promoted a later occurring increase in its own expression, suggesting a priming effect of early IGF-1 in driving post-weaning cortical maturation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. [Association between IGF system and PAPP-A in coronary atherosclerosis].

    Science.gov (United States)

    Fierro-Macías, Alfonso Eduardo; Floriano-Sánchez, Esaú; Mena-Burciaga, Victoria Michelle; Gutiérrez-Leonard, Hugo; Lara-Padilla, Eleazar; Abarca-Rojano, Edgar; Fierro-Almanzán, Alfonso Edmundo

    2016-01-01

    Atherosclerosis is a condition that involves multiple pathophysiological mechanisms and whose knowledge has not been fully elucidated. Often, scientific advances on the atherogenic pathophysiology generate that molecules not previously considered in the scene of this disease, were attributed actions on the onset or progression of it. A representative example is the study of a new mechanism involved in the atherogenic process, consisting of the association between the insulin-like growth factor (IGF) system and pregnancy-associated plasma protein-A (PAPP-A). Insulin-like growth factor system is a family of peptides that include 3 peptide hormones, 4 transmembrane receptors and 6 binding proteins. Insulin-like growth factor-1 (IGF-1) is the main ligand of the IGF system involved in coronary atherosclerosis. IGF-1 exerts its effects via activation of the IGF-1R receptor on vascular smooth muscle cells or macrophages. In vascular smooth muscle cells promotes migration and prevents apoptosis which increases plaque stability while in macrophages reduces reverse cholesterol transport leading to the formation of foam cells. Regulation of IGF-1 endothelial bioavailability is carried out by IGFBP proteases, mainly by PAPP-A. In this review, we address the mechanisms between IGF system and PAPP-A in atherosclerosis with emphasis on molecular effects on vascular smooth muscle cells and macrophages. Copyright © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

  10. Power Spectrum Estimation of Randomly Sampled Signals

    DEFF Research Database (Denmark)

    Velte, C. M.; Buchhave, P.; K. George, W.

    algorithms; sample and-hold and the direct spectral estimator without residence time weighting. The computer generated signal is a Poisson process with a sample rate proportional to velocity magnitude that consist of well-defined frequency content, which makes bias easy to spot. The idea...

  11. Recombinant bovine growth hormone (rBGH) enhances somatic growth by regulating the GH-IGF axis in fingerlings of gilthead sea bream (Sparus aurata).

    Science.gov (United States)

    Vélez, Emilio J; Perelló, Miquel; Azizi, Sheida; Moya, Alberto; Lutfi, Esmail; Pérez-Sánchez, Jaume; Calduch-Giner, Josep A; Navarro, Isabel; Blasco, Josefina; Fernández-Borràs, Jaume; Capilla, Encarnación; Gutiérrez, Joaquim

    2018-02-01

    The growth hormone (GH)/insulin-like growth factors (IGFs) endocrine axis is the main growth-regulator system in vertebrates. Some authors have demonstrated the positive effects on growth of a sustained-release formulation of a recombinant bovine GH (rBGH) in different fish species. The aim of this work was to characterize the effects of a single injection of rBGH in fingerlings of gilthead sea bream on growth, GH-IGF axis, and both myogenic and osteogenic processes. Thus, body weight and specific growth rate were significantly increased in rBGH-treated fish respect to control fish at 6weeks post-injection, whereas the hepatosomatic index was decreased and the condition factor and mesenteric fat index were unchanged, altogether indicating enhanced somatic growth. Moreover, rBGH injection increased the plasma IGF-I levels in parallel with a rise of hepatic mRNA from total IGF-I, IGF-Ic and IGF-II, the binding proteins IGFBP-1a and IGFBP-2b, and also the receptors IGF-IRb, GHR-I and GHR-II. In skeletal muscle, the expression of IGF-Ib and GHR-I was significantly increased but that of IGF-IRb was reduced; the mRNA levels of myogenic regulatory factors, proliferation and differentiation markers (PCNA and MHC, respectively), or that of different molecules of the signaling pathway (TOR/AKT) were unaltered. Besides, the growth inhibitor myostatin (MSTN1 and MSTN2) and the hypertrophic marker (MLC2B) expression resulted significantly enhanced, suggesting altogether that the muscle is in a non-proliferative stage of development. Contrarily in bone, although the expression of most molecules of the GH/IGF axis was decreased, the mRNA levels of several osteogenic genes were increased. The histology analysis showed a GH induced lipolytic effect with a clear decrease in the subcutaneous fat layer. Overall, these results reveal that a better growth potential can be achieved on this species and supports the possibility to improve growth and quality through the optimization of its

  12. Effect of milk proteins on linear growth and IGF variables in overweight adolescents

    DEFF Research Database (Denmark)

    Larnkjær, Anni; Arnberg, Karina; Michaelsen, Kim F

    2014-01-01

    Milk may stimulate growth acting via insulin-like growth factor-I (IGF-I) secretion but the effect in adolescents is less examined. This study investigates the effect of milk proteins on linear growth, IGF-I, IGF binding protein-3 (IGFBP-3) and IGF-I/IGFBP-3 ratio in overweight adolescents....

  13. IGF-1 colocalizes with muscle satellite cells following acute exercise in humans.

    Science.gov (United States)

    Grubb, Amanda; Joanisse, Sophie; Moore, Daniel R; Bellamy, Leeann M; Mitchell, Cameron J; Phillips, Stuart M; Parise, Gianni

    2014-04-01

    Insulin-like growth factor-1 (IGF-1) regulates stem cell proliferation and differentiation in vitro. The aim of this study was to quantify the change in satellite cell (SC) specific IGF-1 colocalization following exercise. We observed a significant increase (p IGF-1 colocalization from baseline to 72 h after a bout of resistance exercise. This strongly supports a role for IGF-1 in human SC function following exercise.

  14. Correction factor to determine total hydrogen+deuterium concentration obtained by inert gas fusion-thermal conductivity detection (IGF- TCD) technique

    International Nuclear Information System (INIS)

    Ramakumar, K.L.; Sesha Sayi, Y.; Shankaran, P.S.; Chhapru, G.C; Yadav, C.S.; Venugopal, V.

    2004-01-01

    The limitation of commercially available dedicated equipment based on Inert Gas Fusion- Thermal Conductivity Detection (IGF - TCD) for the determination of hydrogen+deuterium is described. For a given molar concentration, deuterium is underestimated vis a vis hydrogen because of lower thermal conductivity and not considering its molecular weight in calculations. An empirical correction factor based on the differences between the thermal conductivities of hydrogen, deuterium and the carrier gas argon, and the mole fraction of deuterium in the sample has been derived to correct the observed hydrogen+deuterium concentration. The corrected results obtained by IGF - TCD technique have been validated by determining hydrogen and deuterium contents in a few samples using an independent method based on hot vacuum extraction-quadrupole mass spectrometry (HVE-QMS). Knowledge of mole fraction of deuterium (XD) is necessary to effect the correction. The correction becomes insignificant at low X D values (XD < 0.2) as the precision in the IGF measurements is comparable with the extent of correction. (author)

  15. Postprandial hyperglycemia corrected by IGF-I (Increlex®) in Laron syndrome.

    Science.gov (United States)

    Latrech, Hanane; Simon, Albane; Beltrand, Jacques; Souberbielle, Jean-Claude; Belmejdoub, Ghizlane; Polak, Michel

    2012-01-01

    Laron syndrome is caused by a mutation in the growth hormone (GH) receptor and manifests as insulin-like growth factor-I (IGF-I) deficiency, severe short stature, and early hypoglycemia. We report a case with postprandial hyperglycemia, an abnormality not reported previously. Postprandial hyperglycemia was due to chronic IGF-I deficiency, and was reversed by IGF-I replacement therapy. A Moroccan girl referred for short stature at 7 years and 8 months of age had dwarfism [height, 78 cm (-9 SDs); weight, 10 kg (-4 SDs)], hypoglycemia, and truncal obesity. Her serum IGF-I level was very low, and her baseline serum GH level was elevated to 47 mIU/l. Molecular analysis showed a homozygous mutation in the GH receptor gene. Continuous glucose monitoring before treatment showed asymptomatic hypoglycemia with postprandial hyperglycemia (2.5 g/l, 13.75 mmol/l). Treatment with recombinant human IGF-I (mecasermin, Increlex®) was started. The blood glucose profile improved with 0.04 µg/kg/day and returned to normal with 0.12 µg/kg/day. Postprandial hyperglycemia is a metabolic consequence of chronic IGF-I deficiency. The beneficial effect of IGF-I replacement therapy may be ascribable to improved postprandial transfer of glucose. Copyright © 2012 S. Karger AG, Basel.

  16. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    International Nuclear Information System (INIS)

    Sun Yunguang; Zheng Siyuan; Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J.; Carbone, David P.; Zhao Zhongming; Lu Bo

    2012-01-01

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non–small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  17. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Sun Yunguang [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zheng Siyuan [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J. [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Carbone, David P. [Department of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zhao Zhongming, E-mail: zhongming.zhao@vanderbilt.edu [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Lu Bo, E-mail: bo.lu@vanderbilt.edu [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States)

    2012-03-01

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  18. Serum insulin-like growth factor II (IGF-II) in chronic heart failure

    International Nuclear Information System (INIS)

    Tong Lijun; Chen Donghai; Ji Naijun; Fan Bifu; Wang Chengyao; Mei Yibin; Li Fuyuan; Kao Yan

    2004-01-01

    Objective: To investigate the clinical significance of changes of serum insulin-like growth factor II (IGF-II) levels in patients with chronic heart failure. Methods: Serum IGF-II levels were measured with RIA in 132 cases of chronic heart failure and 45 controls. Results: Serum IGF-II levels were significantly higher in patients with chronic heart failure than those in the controls (t=0.033, P<0.001). IGF-II levels were highest in grade IV CHF patients (vs grade II t=3.963, P<0.01; vs grade III, t=3.578, P<0.01). In the twelve patients died in hospital, the serum IGF-II levels were significantly higher than those patients recovered (t=7.141, P<0.01). Conclusion: Serum IGF-II levels were increased in CHF patients and were highest in the most severe cases. (authors)

  19. Investigation of the 5' flanking region and exon 3 polymorphisms of IGF-1 gene showed moderate association with semen quality in Sanjabi breed rams.

    Science.gov (United States)

    Bakhtiar, R; Abdolmohammadi, A; Hajarian, H; Nikousefat, Z; Kalantar-Neyestanaki, D

    2017-12-01

    In this study, semen samples were collected from 96 Sanjabi rams in order to investigate the IGF-1 gene polymorphisms and their relationship with the characteristics of semen quality and testicular size. The dimensions of scrotal length, width and circumference were measured during autumn and spring over two years. Blood samples were simultaneously collected from jugular vein to extract DNA. PCR was performed using specific primers to amplify 294 and 272bp fragments including 5' regulatory region and exon 3 of IGF-1 gene, respectively. PCR products were digested by BFOI and Eco88l restriction enzymes, respectively. Two genotypes including AA (194 and 100bp), AB (294, 194 and 100bp) and all possible genotypes including CC (182 and 90bp), CT (272, 182, and 90bp) and TT (272bp) were observed for 5' flanking region and exon 3 of IGF-1 gene, respectively. The significant differences among IGF-1 genotypes for testicular dimensions were not observed. However, the polymorphism of 5' flanking region in the studied population had significant effect on individual motility and percent morphology traits. Animals with AB genotype had significantly higher individual motility compared with AA genotype (P IGF-1 gene had significant effect on individual motility, concentration, morphology and water test traits. Animals with CT genotype had the highest sperm concentration (P IGF-1 genotypes. It might be concluded that polymorphisms in IGF-1gene can be considered to develop male fertility in future and for using in selection process of better animals under masker assisted selection programs. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Changes in insulin-like growth factor signaling alter phenotypes in Fragile X Mice.

    Science.gov (United States)

    Wise, T L

    2017-02-01

    Fragile X syndrome (FXS) is an inherited form of intellectual disability that is usually caused by expansion of a polymorphic CGG repeat in the 5' untranslated region of the X-linked FMR1 gene, which leads to hypermethylation and transcriptional silencing. Two non-neurological phenotypes of FXS are enlarged testes and connective tissue dysplasia, which could be caused by alterations in a growth factor signaling pathway. FXS patients also frequently have autistic-like symptoms, suggesting that the signaling pathways affected in FXS may overlap with those affected in autism. Identifying these pathways is important for both understanding the effects of FMR1 inactivation and developing treatments for both FXS and autism. Here we show that decreasing the levels of the insulin-like growth factor (Igf) receptor 1 corrects a number of phenotypes in the mouse model of FXS, including macro-orchidism, and that increasing the levels of IGF2 exacerbates the seizure susceptibility phenotype. These results suggest that the pathways altered by the loss of the FMR1-encoded protein (FMRP) may overlap with the pathways affected by changes in Igf signaling or that one or more of the proteins that play a role in Igf signaling could interact with FMRP. They also indicate a new set of potential targets for drug treatment of FXS and autism spectrum disorders. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  1. MicroRNA-133a Inhibits Osteosarcoma Cells Proliferation and Invasion via Targeting IGF-1R

    Directory of Open Access Journals (Sweden)

    Guangnan Chen

    2016-02-01

    Full Text Available Background/Aims: MicroRNAs (miRNAs are a class of small noncoding RNAs that regulate gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. Downregulated microRNAs and their roles in cancer development have attracted much attention. A growing body of evidence showed that microRNA-133a (miR-133a has inhibitory effects on cell proliferation, migration, invasion, and metastasis of osteosarcoma. Methods: MiR-133a expression in human osteosarcoma cell lines and human normal osteoblastic cell line hFOB was investigated by real-time PCR (RT-PCR. The role of miR-133a in human osteosarcoma growth and invasion was assessed in cell lines in vitro and in vivo. Then, luciferase reporter assay validated IGF-1R as a downstream and functional target of miR-133a, and functional studies revealed that the anti-tumor effect of miR-133a was probably due to targeting and repressing of IGF-1R expression. Results: MiR-133a was lower expressed in human osteosarcoma cell lines than human normal osteoblastic cell line hFOB and its effect on inhibiting proliferation, invasion and metastasis is mediated by its direct interaction with the IGF-1R. Furthermore, the tumour-suppressive function of miR-133a probably contributed to inhibiting the activation AKT and ERK signaling pathway. Conclusion: MiR-133a suppresses osteosarcoma progression and metastasis by targeting IGF-1R in human osteosarcoma cells, providing a novel candidate prognostic factor and a potential anti-metastasis therapeutic target in osteosarcoma.

  2. Importance of circulating IGF-1 for normal cardiac morphology, function and post infarction remodeling.

    Science.gov (United States)

    Scharin Täng, M; Redfors, B; Lindbom, M; Svensson, J; Ramunddal, T; Ohlsson, C; Shao, Y; Omerovic, E

    2012-12-01

    IGF-1 plays an important role in cardiovascular homeostasis, and plasma levels of IGF-1 correlate inversely with systolic function in heart failure. It is not known to what extent circulating IGF-1 secreted by the liver and local autocrine/paracrine IGF-1 expressed in the myocardium contribute to these beneficial effects on cardiac function and morphology. In the present study, we used a mouse model of liver-specific inducible deletion of the IGF-1 gene (LI-IGF-1 -/- mouse) in an attempt to evaluate the importance of circulating IGF-I on cardiac morphology and function under normal and pathological conditions, with an emphasis on its regulatory role in myocardial phosphocreatine metabolism. Echocardiography was performed in LI-IGF-1 -/- and control mice at rest and during dobutamine stress, both at baseline and post myocardial infarction (MI). High-energy phosphate metabolites were compared between LI-IGF-1 -/- and control mice at 4 weeks post MI. We found that LI-IGF-1 -/- mice had significantly greater left ventricular dimensions at baseline and showed a greater relative increase in cardiac dimensions, as well as deterioration of cardiac function, post MI. Myocardial creatine content was 17.9% lower in LI-IGF-1 -/- mice, whereas there was no detectable difference in high-energy nucleotides. These findings indicate an important role of circulating IGF-1 in preserving cardiac structure and function both in physiological settings and post MI. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. IGF-1 levels are significantly correlated with patient-reported measures of sexual function.

    Science.gov (United States)

    Pastuszak, A W; Liu, J S; Vij, A; Mohamed, O; Sathyamoorthy, K; Lipshultz, L I; Khera, M

    2011-01-01

    Growth hormone (GH) supplementation may help to preserve erectile function. We assessed whether serum insulin-like growth factor 1 (IGF-1) levels, a surrogate for GH levels, correlate with sexual function scores in 65 men who completed the Sexual Health Inventory for Men (SHIM) and Expanded Prostate Cancer Index Composite (EPIC) questionnaires, and had serum IGF-1 and testosterone levels determined. Median±s.d. IGF-1 level, SHIM and EPIC scores were 235.0±86.4, 19.5±8.7 and 56.4±28.3 mg ml(-1), respectively. IGF-1 levels and total SHIM score correlate significantly (r=0.31, P=0.02), as do IGF-1 levels and all individual SHIM question scores, and IGF-1 levels and the sexual domain of the EPIC questionnaire (r=0.30, P=0.02). No correlation was observed between IGF-1 levels and Gleason score, IGF-1 and testosterone level or SHIM score and testosterone level. These data support a potential role for the GH axis in erectile function.

  4. Role of androgen receptor on cyclic mechanical stretch-regulated proliferation of C2C12 myoblasts and its upstream signals: IGF-1-mediated PI3K/Akt and MAPKs pathways.

    Science.gov (United States)

    Ma, Yiming; Fu, Shaoting; Lu, Lin; Wang, Xiaohui

    2017-07-15

    To detect the effects of androgen receptor (AR) on cyclic mechanical stretch-modulated proliferation of C2C12 myoblasts and its pathways: roles of IGF-1, PI3K and MAPK. C2C12 were randomly divided into five groups: un-stretched control, six or 8 h of fifteen percent stretch, and six or 8 h of twenty percent stretch. Cyclic mechanical stretch of C2C12 were completed using a computer-controlled FlexCell Strain Unit. Cell proliferation and IGF-1 concentration in medium were detected by CCK8 and ELISA, respectively. Expressions of AR and IGF-1R, and expressions and activities of PI3K, p38 and ERK1/2 in stretched C2C12 cells were determined by Western blot. ①The proliferation of C2C12 cells, IGF-1 concentration in medium, expressions of AR and IGF-1R, and activities of PI3K, p38 and ERK1/2 were increased by 6 h of fifteen percent stretch, while decreased by twenty percent stretch for six or 8 h ②The fifteen percent stretch-increased proliferation of C2C12 cells was reversed by AR inhibitor, Flutamide. ③The increases of AR expression, activities of PI3K, p38 and ERK1/2 resulted from fifteen percent stretch were attenuated by IGF-1 neutralizing antibody, while twenty percent stretch-induced decreases of the above indicators were enhanced by recombinant IGF-1. ④Specific inhibitors of p38, ERK1/2 and PI3K all decreased the expression of AR in fifteen percent and twenty percent of stretched C2C12 cells. Cyclic mechanical stretch modulated the proliferation of C2C12 cells, which may be attributed to the alterations of AR via IGF-1-PI3K/Akt and IGF-1-MAPK (p38, ERK1/2) pathways in C2C12 cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Targeting both IGF-1R and mTOR synergistically inhibits growth of renal cell carcinoma in vitro

    International Nuclear Information System (INIS)

    Cardillo, Thomas M; Trisal, Preeti; Arrojo, Roberto; Goldenberg, David M; Chang, Chien-Hsing

    2013-01-01

    Advanced or metastatic renal cell carcinoma (RCC) has a poor prognosis, because it is relatively resistant to conventional chemotherapy or radiotherapy. Treatments with human interferon-α2b alone or in combination with mammalian target of rapamycin (mTOR) inhibitors have led to only a modest improvement in clinical outcome. One observation made with mTOR inhibitors is that carcinomas can overcome these inhibitory effects by activating the insulin-like growth factor-I (IGF-I) signaling pathway. Clinically, there is an association of IGF-I receptor (IGF-IR) expression in RCC and poor long-term patient survival. We have developed a humanized anti-IGF-IR monoclonal antibody, hR1, which binds to RCC, resulting in effective down-regulation of IGF-IR and moderate inhibition of cell proliferation in vitro. In this work, we evaluate the anti-tumor activity of two novel IGF-1R-targeting agents against renal cell carcinoma given alone or in combination with an mTOR inhibitor. hR1 was linked by the DOCK-AND-LOCK™ (DNL™) method to four Fabs of hR1, generating Hex-hR1, or to four molecules of interferon-α2b, generating 1R-2b. Eight human RCC cell lines were screened for IGF-1R expression and sensitivity to treatment with hR1 in vitro. Synergy with an mTOR inhibitor, temsirolimus, was tested in a cell line (ACHN) with low sensitivity to hR1. Hex-hR1 induced the down-regulation of IGF-IR at 10-fold lower concentrations compared to the parental hR1. Sensitivity to growth inhibition mediated by hR1 and Hex-hR1 treatments correlated with IGF-1R expression (higher expression was more sensitive). The potency of 1R-2b to inhibit the in vitro growth of RCC was also demonstrated in two human cell lines, ACHN and 786-O, with EC 50 –values of 63 and 48 pM, respectively. When combined with temsirolimus, a synergistic growth-inhibition with hR1, Hex-hR1, and 1R-2b was observed in ACHN cells at concentrations as low as 10 nM for hR1, 1 nM for Hex-hR1, and 2.6 nM for 1R-2b. Both Hex-hR1

  6. Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways

    NARCIS (Netherlands)

    van der Meel, Roy; Oliveira, Sabrina; Altintas, Isil; Heukers, R.; Pieters, Ebel H.E.; van Bergen en Henegouwen, Paul M.P.; Storm, Gerrit; Hennink, Wim E.; Kok, Robbert J.; Schiffelers, Raymond M.

    2013-01-01

    The clinical efficacy of epidermal growth factor receptor (EGFR)-targeted inhibitors is limited due to resistance mechanisms of the tumor such as activation of compensatory pathways. Crosstalk between EGFR and insulin-like growth factor 1 (IGF-1R) signaling has been frequently described to be

  7. Factor de crecimiento semejante a la insulina tipo I (IGF-I y cirrosis hepática Insulin-like growth factor I (IGF-I and liver cirrhosis

    Directory of Open Access Journals (Sweden)

    M. Conchillo

    2007-03-01

    Full Text Available El factor de crecimiento semejante a la insulina tipo I (IGF-I es una hormona polipeptídica segregada en múltiples tejidos por efecto de la hormona de crecimiento (GH. Es responsable de parte de las acciones de la GH y además tiene efecto hipoglucemiante y anabolizante. El 90% del IGF-I circulante es de origen hepático y ejerce efectos autocrinos, paracrinos y endocrinos, estos últimos en múltiples tejidos. En la cirrosis hepática se produce una disminución progresiva de la producción hepática de IGF-I que llega a ser indetectable en la enfermedad avanzada. Algunas de las complicaciones de la cirrosis, fundamentalmente nutricionales y metabólicas (resistencia a insulina, desnutrición, osteopenia, hipogonadismo, alteraciones intestinales podrían estar, al menos en parte, relacionadas con esta carencia de IGF-I dado que algunas acciones de IGF-I representan la imagen inversa de las complicaciones de la cirrosis. A pesar de ello, nunca se había propuesto tratamiento sustitutivo con IGF-I en la cirrosis. En una serie de estudios experimentales realizados en ratas cirróticas se demostró que el tratamiento con dosis bajas de IGF-I recombinante produce dos tipos de efectos en la cirrosis experimental: a mejoría del hígado, dado que mejora la función hepatocelular, la hipertensión portal y la fibrosis hepática; y b mejoría de las alteraciones extrahepáticas de la cirrosis dado que mejora la eficiencia del alimento ingerido, la masa muscular, la masa ósea, la función y estructura gonadales y la función y estructura intestinales con normalización de la malabsorción de azúcares y aminoácidos y la mejoría de la función intestinal de barrera manifestada por disminución de la endotoxemia y la translocación bacteriana. Posteriormente el primer ensayo clínico piloto, aleatorizado, doble ciego y controlado con placebo llevado a cabo en un número reducido de pacientes cirróticos demostró aumento de la albúmina sérica y

  8. Higher Maternal Protein Intake during Pregnancy Is Associated with Lower Cord Blood Concentrations of Insulin-like Growth Factor (IGF)-II, IGF Binding Protein 3, and Insulin, but Not IGF-I, in a Cohort of Women with High Protein Intake.

    Science.gov (United States)

    Switkowski, Karen M; Jacques, Paul F; Must, Aviva; Hivert, Marie-France; Fleisch, Abby; Gillman, Matthew W; Rifas-Shiman, Sheryl; Oken, Emily

    2017-07-01

    Background: Prenatal exposure to dietary protein may program growth-regulating hormones, consequently influencing early-life growth patterns and later risk of associated chronic diseases. The insulin-like growth factor (IGF) axis is of particular interest in this context given its influence on pre- and postnatal growth and its sensitivity to the early nutritional environment. Objective: Our objective was to examine associations of maternal protein intake during pregnancy with cord blood concentrations of IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3), and insulin. Methods: We studied 938 mother-child pairs from early pregnancy through delivery in the Project Viva cohort. Using multivariable linear regression models adjusted for maternal race/ethnicity, education, income, smoking, parity, height, and gestational weight gain and for child sex, we examined associations of second-trimester maternal protein intake [grams per kilogram (weight before pregnancy) per day], as reported on a food frequency questionnaire, with IGF-I, IGF-II, IGFBP-3, and insulin concentrations in cord blood. We also examined how these associations may differ by child sex and parity. Results: Mothers were predominantly white (71%), college-educated (64%), and nonsmokers (67%). Mean ± SD protein intake was 1.35 ± 0.35 g ⋅ kg -1 ⋅ d -1 Each 1-SD increment in second-trimester protein intake corresponded to a change of -0.50 ng/mL (95% CI: -2.26, 1.26 ng/mL) in IGF-I and -0.91 μU/mL (95% CI: -1.45, -0.37 μU/mL) in insulin. Child sex and parity modified associations of maternal protein intake with IGF-II and IGFBP-3: protein intake was inversely associated with IGF-II in girls ( P -interaction = 0.04) and multiparous mothers ( P -interaction = 0.05), and with IGFBP-3 in multiparous mothers ( P -interaction = 0.04). Conclusions: In a cohort of pregnant women with relatively high mean protein intakes, higher intake was associated with lower concentrations of growth-promoting hormones in cord

  9. Impact of IGF-I release kinetics on bone healing: a preliminary study in sheep.

    Science.gov (United States)

    Luginbuehl, Vera; Zoidis, Evangelos; Meinel, Lorenz; von Rechenberg, Brigitte; Gander, Bruno; Merkle, Hans P

    2013-09-01

    Spatiotemporal release of growth factors from a delivery device can profoundly affect the efficacy of bone growth induction. Here, we report on a delivery platform based on the encapsulation of insulin-like growth factor I (IGF-I) in different poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) microsphere (MS) formulations to control IGF-I release kinetics. In vitro IGF-I release profiles generally exhibited an initial burst (14-36% of total IGF-I content), which was followed by a more or less pronounced dormant phase with little release (2 to 34 days), and finally, a third phase of re-increased IGF-I release. The osteoinductive potential of these different IGF-I PL(G)A MS formulations was tested in studies using 8-mm metaphyseal drill hole bone defects in sheep. Histomorphometric analysis at 3 and 6 weeks after surgery showed that new bone formation was improved in the defects locally treated with IGF-I PL(G)A MS (n=5) as compared to defects filled with IGF-I-free PL(G)A MS (n=4). The extent of new bone formation was affected by the particular release kinetics, although a definitive relationship was not evident. Local administration of IGF-I resulted in down-regulation of inflammatory marker genes in all IGF-I treated defects. The over-expression of growth factor genes in response to IGF-I delivery was restricted to formulations that produced osteogenic responses. These experiments demonstrate the osteoinductive potential of sustained IGF-I delivery and show the importance of delivery kinetics for successful IGF-I-based therapies. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Secondhand Smoke Exposure Reduced the Compensatory Effects of IGF-I Growth Signaling in the Aging Rat Hearts.

    Science.gov (United States)

    Wu, Jia-Ping; Hsieh, Dennis Jine-Yuan; Kuo, Wei-Wen; Han, Chien-Kuo; Pai, Peiying; Yeh, Yu-Lan; Lin, Chien-Chung; Padma, V Vijaya; Day, Cecilia Hsuan; Huang, Chih-Yang

    2015-01-01

    Secondhand smoke (SHS) exposure is associated with increased risk of cardiovascular disease. Aging is a physiological process that involves progressive impairment of normal heart functions due to increased vulnerability to damage. This study examines secondhand smoke exposure in aging rats to determine the age-related death-survival balance. Rats were placed into a SHS exposure chamber and exposed to smog. Old age male Sprague-Dawley rats were exposed to 10 cigarettes for 30 min, day and night, continuing for one week. After 4 weeks the rats underwent morphological and functional studies. Left ventricular sections were stained with hematoxylin-eosin for histopathological examination. TUNEL detected apoptosis cells and protein expression related death and survival pathway were analyzed using western blot. Death receptor-dependent apoptosis upregulation pathways and the mitochondria apoptosis proteins were apparent in young SHS exposure and old age rats. These biological markers were enhanced in aging SHS-exposed rats. The survival pathway was found to exhibit compensation only in young SHS-exposed rats, but not in the aging rats. Further decrease in the activity of this pathway was observed in aging SHS-exposed rats. TUNEL apoptotic positive cells were increased in young SHS-exposed rats, and in aging rats with or without SHS-exposure. Aging reduces IGF-I compensated signaling with accelerated cardiac apoptotic effects from second-hand smoke.

  11. Nuclear targeting of IGF-1 receptor in orbital fibroblasts from Graves' disease: apparent role of ADAM17.

    Directory of Open Access Journals (Sweden)

    Neil Hoa

    Full Text Available Insulin-like growth factor-1 receptor (IGF-1R comprises two subunits, including a ligand binding domain on extra- cellular IGF-1Rα and a tyrosine phosphorylation site located on IGF-1Rβ. IGF-1R is over-expressed by orbital fibroblasts in the autoimmune syndrome, Graves' disease (GD. When activated by IGF-1 or GD-derived IgG (GD-IgG, these fibroblasts produce RANTES and IL-16, while those from healthy donors do not. We now report that IGF-1 and GD-IgG provoke IGF-1R accumulation in the cell nucleus of GD fibroblasts where it co-localizes with chromatin. Nuclear IGF-1R is detected with anti-IGF-1Rα-specific mAb and migrates to approximately 110 kDa, consistent with its identity as an IGF-1R fragment. Nuclear IGF-1R migrating as a 200 kDa protein and consistent with an intact receptor was undetectable when probed with either anti-IGF-1Rα or anti-IGF-1Rβ mAbs. Nuclear redistribution of IGF-1R is absent in control orbital fibroblasts. In GD fibroblasts, it can be abolished by an IGF-1R-blocking mAb, 1H7 and by physiological concentrations of glucocorticoids. When cell-surface IGF-1R is cross-linked with (125I IGF-1, (125I-IGF-1/IGF-1R complexes accumulate in the nuclei of GD fibroblasts. This requires active ADAM17, a membrane associated metalloproteinase, and the phosphorylation of IGF-1R. In contrast, virally encoded IGF-1Rα/GFP fusion protein localizes equivalently in nuclei in both control and GD fibroblasts. This result suggests that generation of IGF-1R fragments may limit the accumulation of nuclear IGF-1R. We thus identify a heretofore-unrecognized behavior of IGF-1R that appears limited to GD-derived fibroblasts. Nuclear IGF-1R may play a role in disease pathogenesis.

  12. Sleep extension increases IGF-I concentrations before and during sleep deprivation in healthy young men.

    Science.gov (United States)

    Chennaoui, Mounir; Arnal, Pierrick J; Drogou, Catherine; Sauvet, Fabien; Gomez-Merino, Danielle

    2016-09-01

    Sleep deprivation is known to suppress circulating trophic factors such as insulin-like growth factor (IGF)-I and brain-derived neurotrophic factor (BDNF). This experiment examined the effect of an intervention involving 6 nights of extended sleep before total sleep deprivation on this catabolic profile. In a randomized crossover design, 14 young men (age range: 26-37 years) were either in an extended (EXT; time in bed: 2100-0700 h) or habitual (HAB: 2230-0700 h) sleep condition, followed by 3 days in the laboratory with blood sampling at baseline (B), after 24 h of sleep deprivation (24h-SD), and after 1 night of recovery sleep (R). In the EXT condition compared with the HAB condition, free IGF-I levels were significantly higher at B, 24h-SD, and R (P sleep deprivation was for insulin levels, which were significantly higher after R compared with B. In a healthy adult, additional sleep over 1 week increased blood concentrations of the anabolic factor IGF-I before and during 24 h of sleep deprivation and after the subsequent recovery night without effects on BDNF. With further research, these findings may prove to be important in guiding effective lifestyle modifications to limit physical or cognitive deficits associated with IGF-I decrease with age.

  13. Saw palmetto extract suppresses insulin-like growth factor-I signaling and induces stress-activated protein kinase/c-Jun N-terminal kinase phosphorylation in human prostate epithelial cells.

    Science.gov (United States)

    Wadsworth, Teri L; Carroll, Julie M; Mallinson, Rebecca A; Roberts, Charles T; Roselli, Charles E

    2004-07-01

    A common alternative therapy for benign prostatic hyperplasia (BPH) is the extract from the fruit of saw palmetto (SPE). BPH is caused by nonmalignant growth of epithelial and stromal elements of the prostate. IGF action is important for prostate growth and development, and changes in the IGF system have been documented in BPH tissues. The main signaling pathways activated by the binding of IGF-I to the IGF-I receptor (IGF-IR) are the ERK arm of the MAPK cascade and the phosphoinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt) cascade. We tested the hypothesis that SPE suppresses growth and induces apoptosis in the P69 prostate epithelial cell line by inhibiting IGF-I signaling. Treatment with 150 microg/ml SPE for 24 h decreased IGF-I-induced proliferation of P69 cells and induced cleavage of the enzyme poly(ADP-ribose)polymerase (PARP), an index of apoptosis. Treatment of serum-starved P69 cells with 150 microg/ml SPE for 6 h reduced IGF-I-induced phosphorylation of Akt (assessed by Western blot) and Akt activity (assessed by an Akt kinase assay). Western blot analysis showed that SPE reduced IGF-I-induced phosphorylation of the adapter protein insulin receptor substrate-1 and decreased downstream effects of Akt activation, including increased cyclin D1 levels and phosphorylation of glycogen synthase kinase-3 and p70(s6k). There was no effect on IGF-I-induced phosphorylation of MAPK, IGF-IR, or Shc. Treatment of starved cells with SPE alone induced phosphorylation the proapoptotic protein JNK. SPE treatment may relieve symptoms of BPH, in part, by inhibiting specific components of the IGF-I signaling pathway and inducing JNK activation, thus mediating antiproliferative and proapoptotic effects on prostate epithelia.

  14. SERUM IGF-I AND HORMONAL RESPONSES TO INCREMENTAL EXERCISE IN ATHLETES WITH AND WITHOUT LEFT VENTRICULAR HYPERTROPHY

    Directory of Open Access Journals (Sweden)

    Aleksandra Zebrowska

    2009-03-01

    Full Text Available We investigated the response of insulin-like growth factor (IGF- I, insulin-like growth factor binding protein-3 (IGFBP-3 and some hormones, i.e., testosterone (T, growth hormone (GH, cortisol (C, and insulin (I, to maximal exercise in road cyclists with and without diagnosed left ventricular hypertrophy. M-mode and two-dimensional Doppler echocardiography was performed in 30 professional male endurance athletes and a group of 14 healthy untrained subjects using a Hewlett-Packard Image Point HX ultrasound system with standard imaging transducers. Echocardiography and an incremental physical exercise test were performed during the competitive season. Venous blood samples were drawn before and immediately after the maximal cycling exercise test for determination of somatomedin and hormonal concentrations. The basal concentration of IGF-I was statistically higher (p < 0.05 in athletes with left ventricular muscle hypertrophy (LVH when compared to athletes with a normal upper limit of the left ventricular wall (LVN (p < 0.05 and to the control group (CG (p < 0.01. The IGF-I level increased significantly at maximal intensity of incremental exercise in CG (p < 0.01, LVN (p < 0.05 and LVH (p < 0.05 compared to respective values at rest. Long-term endurance training induced an increase in resting (p < 0.01 and post-exercise (p < 0.05 IGF-I/IGFBP-3 ratio in athletes with LVH compared to LVN. The testosterone (T level was lower in LVH at rest compared to LVN and CG groups (p < 0.05. These results indicate that resting serum IGF-I concentration were higher in trained subjects with LVH compared to athletes without LVH. Serum IGF- I/IGFBP-3 elevation at rest and after exercise might suggest that IGF-I act as a potent stimulant of left ventricular hypertrophy in chronically trained endurance athletes

  15. The glycogen metabolism via Akt signaling is important for the secretion of enamel matrix in tooth development.

    Science.gov (United States)

    Ida-Yonemochi, Hiroko; Otsu, Keishi; Ohshima, Hayato; Harada, Hidemitsu

    2016-02-01

    Cells alter their energy metabolism depending on the stage of differentiation or various environments. In the ameloblast differentiation of continuous growing mouse incisors, we found temporary glycogen storage in preameloblasts before the start of enamel matrix secretion and investigated the relationship between enamel matrix secretion and glycogen metabolism. Immunohistochemistry showed that in the transitional stage from preameloblasts to secretory ameloblasts, the glycogen synthase changed from the inactive form to the active form, the expression of glycogen phosphorylase increased, and further, the levels of IGF-1, IGF-1 receptor and activated Akt increased. These results suggested that the activation of Akt signaling via IGF is linked to the onset of both glycogen metabolism and enamel matrix deposition. In the experiments using organ culture and ameloblast cell line, the activation of Akt signaling by IGF-1 stimulated glycogen metabolism through the up-regulation of Glut-1,-4 and Gsk-3β and the dephosphorylation of glycogen synthase. Subsequently, they resulted in increased enamel matrix secretion. In contrast, some inhibitors of Akt signals and glycogen synthesis/degradation down-regulated enamel matrix secretion. Taking these findings together, glycogen metabolism via Akt signaling is an essential system for the secretion of enamel matrix in ameloblast differentiation. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. IGF-1, IGFBP-3 and ALS in adult patients with chronic kidney disease.

    Science.gov (United States)

    Lepenies, Julia; Wu, Zida; Stewart, Paul M; Strasburger, Christian J; Quinkler, Marcus

    2010-04-01

    Insulin-like growth factor I (IGF-1) is for the most part bound in a ternary complex with IGF-binding protein-3 (IGFBP-3) and acid-labile subunit (ALS). This ternary complex is a storage form of IGF-1 in blood and passes not through the renal glomerulus. Little information is available in regard to the components of the ternary complex in adult renal disease. To investigate levels of serum IGF-1, IGFBP-3 and ALS in relation to renal function and extent of proteinuria. We measured IGF-1, IGFBP-3 and ALS concentrations in 137 patients who were investigated due to proteinuria and/or haematuria and/or renal impairment. The patients received renal biopsies and the histological diagnosis was documented. Urinary albumin excretion and relevant clinical parameter were evaluated. IGF-1 showed a highly positive correlation to IGFBP-3 and ALS, and the latter to IGFBP-3. IGF-1, IGFBP-3 and ALS decreased with increasing age. IGF-1 and IGFBP-3 showed no significant change depending on the creatinine clearance. However, ALS decreased with decreasing renal function. In patients with heavy proteinuria ALS levels, but not IGF-1 and IGFBP-3 levels, decreased significantly. Patients with chronic ischaemic renal damage and diabetic glomerulopathy showed higher IGF-1 and IGFBP-3 levels compared to patients with thin glomerular basement membrane disease despite their older age. IGF-1 and IGFBP-3 levels seem to be independent of renal function and severity of proteinuria. However, ALS levels are altered in renal failure and nephrotic syndrome, which may be due to increased renal loss or diminished hepatic production or both. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

  17. IGF-1 levels may increase paradoxically with dopamine agonist treatment for prolactinomas.

    Science.gov (United States)

    Akirov, Amit; Greenman, Yona; Glaser, Benjamin; S'chigol, Irena; Mansiterski, Yossi; Eizenberg, Yoav; Shraga-Slutzky, Ilana; Shimon, Ilan

    2018-05-04

    Hyperprolactinemia is common in acromegaly and in these patients, insulin-like growth factor (IGF)-1 level may decrease with dopamine agonist. We report a series of patients with prolactinoma and a paradoxical increase of IGF-1 levels during cabergoline treatment. Clinical characteristics and response to treatment of patients with prolactinomas, in whom normal or slightly elevated baseline IGF-1 levels increased with cabergoline. The cohort consisted of ten prolactinoma patients (nine males, mean age 48 ± 14 years). Mean adenoma size was 23.8 ± 16.2 mm, with cavernous sinus invasion in eight. In five patients baseline IGF-1 levels were normal and in four levels were 1.2-1.5-fold the upper limit of the normal (ULN). One patient had IGF-1 measured shortly after initiating cabergoline and it was 1.4 × ULN. During cabergoline treatment (dose range 0.5-2 mg/week) PRL normalization was achieved in all and tumor shrinkage occurred in seven patients. The mean IGF-1 increase on cabergoline was 1.7 ± 0.4 × ULN. Cabergoline dose reduction or interruption was attempted in five patients and resulted in decreased IGF-1 levels in all, including normalization in two patients. Three patients were eventually diagnosed with acromegaly, one was referred for pituitary surgery followed by complete remission, another patient was switched to somatostatin analogue, and the third was treated by combination of somatostatin analogues with pegvisomant, with reduction of IGF-1 in all these patients. IGF-1 levels may increase to clinically significant levels during cabergoline treatment for PRL-adenoma. We suggest IGF-1 monitoring in all patients treated with dopamine agonists and not only in those presenting symptoms of acromegaly.

  18. IGF-I and IGFBP2 in peripheral artery disease

    DEFF Research Database (Denmark)

    Urbonaviciene, Grazina; Frystyk, Jan; Urbonavicius, Sigitas

    2014-01-01

    BACKGROUND AND OBJECTIVES: The search for novel risk factors of cardiovascular disease (CVD) has provided valuable clinical data concerning underlying mechanism of disease. Increasing evidence indicates a possible involvement of insulin-like growth factor-I (IGF-I) and its binding protein 2 (IGFBP......-2) in the pathogenesis of CVD disorders. The aim of this study was to examine the relationship between levels of IGF-I and IGFBP-2 with all-cause and CVD mortality in a prospective study of patients with lower-extremity peripheral artery disease (PAD). METHODS AND MATERIAL: Serum IGF-I and IGFBP-2...... levels were obtained in 440 patients (257 males) with symptomatic PAD. Patients were followed for a median of 6.1 (IQ 5.1-7.2) years. The relationship between times to lethal outcome and baseline serum IGF-I and IFGBP-2 levels were examined by Cox proportional hazard analysis. The role of IFGBP-2...

  19. Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2.

    Directory of Open Access Journals (Sweden)

    Cécile Pierre-Eugene

    Full Text Available BACKGROUND: In diabetic patients, the pharmacokinetics of injected human insulin does not permit optimal control of glycemia. Fast and slow acting insulin analogues have been developed, but they may have adverse properties, such as increased mitogenic or anti-apoptotic signaling. Insulin/IGF1 hybrid receptors (IR/IGF1R, present in most tissues, have been proposed to transmit biological effects close to those of IGF1R. However, the study of hybrid receptors is difficult because of the presence of IR and IGF1R homodimers. Our objective was to perform the first study on the pharmacological properties of the five marketed insulin analogues towards IR/IGF1R hybrids. METHODOLOGY: To study the effect of insulin analogues on IR/IGF1R hybrids, we used our previously developed Bioluminescence Resonance Energy Transfer (BRET assay that permits specific analysis of the pharmacological properties of hybrid receptors. Moreover, we have developed a new, highly sensitive BRET-based assay to monitor phophatidylinositol-3 phosphate (PIP(3 production in living cells. Using this assay, we performed a detailed pharmacological analysis of PIP(3 production induced by IGF1, insulin and insulin analogues in living breast cancer-derived MCF-7 and MDA-MB231 cells. RESULTS: Among the five insulin analogues tested, only glargine stimulated IR/IGF1R hybrids with an EC50 that was significantly lower than insulin and close to that of IGF1. Glargine more efficiently stimulated PIP(3 production in MCF-7 cells but not in MDA-MB231 cells as compared to insulin. In contrast, glargine metabolites M1 and M2 showed lower potency for hybrid receptors stimulation, PIP(3 production, Akt and Erk1/2 phosphorylation and DNA synthesis in MCF-7 cells, compared to insulin. CONCLUSION: Glargine, possibly acting through IR/IGF1R hybrids, displays higher potency, whereas its metabolites M1 and M2 display lower potency than insulin for the stimulation of proliferative/anti-apoptotic pathways in

  20. IGF-I bioactivity might reflect different aspects of quality of life than total IGF-I in gh-deficient patients during GH treatment

    NARCIS (Netherlands)

    A.J. Varewijck (Aimee); S.W.J. Lamberts (Steven); S.J.C.M.M. Neggers (Bas); L.J. Hofland (Leo); J.A.M.J.L. Janssen (Joseph)

    2013-01-01

    textabstractContext: No relationship has been found between improvement in quality of life (QOL) and total IGF-I during GH therapy. Aim: Our aim was to investigate the relationship between IGF-I bioactivity and QOL in GH-deficient (GHD) patients receiving GH for 12 months. Methods: Of 106 GHD