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Sample records for ahr signaling pathway

  1. Microarray analysis of the AHR system: Tissue-specific flexibility in signal and target genes

    International Nuclear Information System (INIS)

    Data mining published microarray experiments require that expression profiles are directly comparable. We performed linear global normalization on the data of 1967 Affymetrix U74av2 microarrays, i.e. the transcriptomes of > 100 murine tissues or cell types. The mathematical transformation effectively nullifies inter-experimental or inter-laboratory differences between microarrays. The correctness of expression values was validated by quantitative RT-PCR. Using the database we analyze components of the aryl hydrocarbon receptor (AHR) signaling pathway in various tissues. We identified lineage and differentiation specific variant expression of AHR, ARNT, and HIF1α in the T-cell lineage and high expression of CYP1A1 in immature B cells and dendritic cells. Performing co-expression analysis we found unorthodox expression of the AHR in the absence of ARNT, particularly in stem cell populations, and can reject the hypothesis that ARNT2 takes over and is highly expressed when ARNT expression is low or absent. Furthermore the AHR shows no co-expression with any other transcript present on the chip. Analysis of differential gene expression under 308 conditions revealed 53 conditions under which the AHR is regulated, numerous conditions under which an intrinsic AHR action is modified as well as conditions activating the AHR even in the absence of known AHR ligands. Thus meta-analysis of published expression profiles is a powerful tool to gain novel insights into known and unknown systems

  2. Intersection of AHR and Wnt Signaling in Development, Health, and Disease

    Directory of Open Access Journals (Sweden)

    Andrew J. Schneider

    2014-10-01

    Full Text Available The AHR (aryl hydrocarbon receptor and Wnt (wingless-related MMTV integration site signaling pathways have been conserved throughout evolution. Appropriately regulated signaling through each pathway is necessary for normal development and health, while dysregulation can lead to developmental defects and disease. Though both pathways have been vigorously studied, there is relatively little research exploring the possibility of crosstalk between these pathways. In this review, we provide a brief background on (1 the roles of both AHR and Wnt signaling in development and disease, and (2 the molecular mechanisms that characterize activation of each pathway. We also discuss the need for careful and complete experimental evaluation of each pathway and describe existing research that explores the intersection of AHR and Wnt signaling. Lastly, to illustrate in detail the intersection of AHR and Wnt signaling, we summarize our recent findings which show that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD-induced disruption of Wnt signaling impairs fetal prostate development.

  3. A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC.

    Science.gov (United States)

    Occhi, Gianluca; Barollo, Susi; Regazzo, Daniela; Bertazza, Loris; Galuppini, Francesca; Guzzardo, Vincenza; Jaffrain-Rea, Marie Lise; Vianello, Federica; Ciato, Denis; Ceccato, Filippo; Watutantrige-Fernando, Sara; Bisognin, Andrea; Bortoluzzi, Stefania; Pennelli, Gianmaria; Boscaro, Marco; Scaroni, Carla; Mian, Caterina

    2015-10-13

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAFV600E may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice. PMID:26392334

  4. Potential protective mechanisms of aryl hydrocarbon receptor (AHR) signaling in benign prostatic hyperplasia.

    Science.gov (United States)

    Mehta, Vatsal; Vezina, Chad M

    2011-01-01

    The aryl hydrocarbon receptor (AHR) is an evolutionarily conserved ligand activated transcription factor best known for its role in mediating toxic responses to dioxin-like environmental contaminants. However, AHR signaling has also emerged as an active participant in processes of normal development and disease progression. Here, we review the role of AHR signaling in prostate development and disease processes, with a particular emphasis on benign prostatic hyperplasia (BPH). Inappropriate AHR activation has recently been associated with a decreased risk of symptomatic BPH in humans and has been shown to impair prostate development and disrupt endocrine signaling in rodents. We highlight known physiological responses to AHR activation in prostate and other tissues and discuss potential mechanisms by which it may act in adult human prostate to protect against symptomatic BPH. PMID:21684673

  5. The Effects of Chronic Lifelong Activation of the AHR Pathway by Industrial Chemical Pollutants on Female Human Reproduction

    Science.gov (United States)

    Vacca, Margherita; Nardelli, Claudia; Castegna, Alessandra; Arnesano, Fabio; Carella, Nicola; Depalo, Raffaella

    2016-01-01

    Environmental chemicals, such as heavy metals, affect female reproductive function. A biological sensor of the signals of many toxic chemical compounds seems to be the aryl hydrocarbon receptor (AHR). Previous studies demonstrated the environmental of heavy metals in Taranto city (Italy), an area that has been influenced by anthropogenic factors such as industrial activities and waste treatments since 1986. However, the impact of these elements on female fertility in this geographic area has never been analyzed. Thus, in the present study, we evaluated the AHR pathway, sex steroid receptor pattern and apoptotic process in granulosa cells (GCs) retrieved from 30 women, born and living in Taranto, and 30 women who are living in non-contaminated areas (control group), who were undergoing in vitro fertilization (IVF) protocol. In follicular fluids (FFs) of both groups the toxic and essential heavy metals, such as chromiun (Cr), Manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), cadmium (Cd) and lead (Pb), were also analyzed. Higher levels of Cr, Fe, Zn and Pb were found in the FFs of the women from Taranto as compared to the control group, as were the levels of AHR and AHR-dependent cytochrome P450 1A1 and 1B1; while CYP19A1 expression was decreased. The anti-apoptotic process found in the GCs of women fromTaranto was associated with the highest levels of progesterone receptor membrane component 1 (PGRMC1), a novel progesterone receptor, the expression of which is subjected to AHR activated by its highest affinity ligands (e.g., dioxins) or indirectly by other environmental pollutants, such as heavy metals. In conclusion, decreased production of estradiol and decreased number of retrieved mature oocytes found in women from Taranto could be due to chronic exposure to heavy metals, in particular to Cr and Pb. PMID:27008165

  6. Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells.

    Science.gov (United States)

    Rentas, Stefan; Holzapfel, Nicholas T; Belew, Muluken S; Pratt, Gabriel A; Voisin, Veronique; Wilhelm, Brian T; Bader, Gary D; Yeo, Gene W; Hope, Kristin J

    2016-04-28

    Umbilical cord blood-derived haematopoietic stem cells (HSCs) are essential for many life-saving regenerative therapies. However, despite their advantages for transplantation, their clinical use is restricted because HSCs in cord blood are found only in small numbers. Small molecules that enhance haematopoietic stem and progenitor cell (HSPC) expansion in culture have been identified, but in many cases their mechanisms of action or the nature of the pathways they impinge on are poorly understood. A greater understanding of the molecular circuitry that underpins the self-renewal of human HSCs will facilitate the development of targeted strategies that expand HSCs for regenerative therapies. Whereas transcription factor networks have been shown to influence the self-renewal and lineage decisions of human HSCs, the post-transcriptional mechanisms that guide HSC fate have not been closely investigated. Here we show that overexpression of the RNA-binding protein Musashi-2 (MSI2) induces multiple pro-self-renewal phenotypes, including a 17-fold increase in short-term repopulating cells and a net 23-fold ex vivo expansion of long-term repopulating HSCs. By performing a global analysis of MSI2-RNA interactions, we show that MSI2 directly attenuates aryl hydrocarbon receptor (AHR) signalling through post-transcriptional downregulation of canonical AHR pathway components in cord blood HSPCs. Our study gives mechanistic insight into RNA networks controlled by RNA-binding proteins that underlie self-renewal and provides evidence that manipulating such networks ex vivo can enhance the regenerative potential of human HSCs. PMID:27121842

  7. Interactions between polymorphisms in the aryl hydrocarbon receptor signalling pathway and exposure to persistent organochlorine pollutants affect human semen quality

    DEFF Research Database (Denmark)

    Brokken, L J S; Lundberg, P J; Spanò, M;

    2014-01-01

    Persistent organic pollutants (POPs) may affect male reproductive function. Many dioxin-like POPs exert their effects by activation of the aryl hydrocarbon receptor (AHR) signalling pathway. We analysed whether gene-environment interactions between polymorphisms in AHR (R554K) and AHR repressor (...

  8. Malformation of certain brain blood vessels caused by TCDD activation of Ahr2/Arnt1 signaling in developing zebrafish

    International Nuclear Information System (INIS)

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various signs of toxicity in early life stages of vertebrates through activation of the aryl hydrocarbon receptor (AHR). The AHR also plays important roles in normal development in mice, and AHR-/- mice show abnormal development of vascular structures in various blood vessels. Our previous studies revealed that Ahr type 2 (Ahr2) activation by TCDD and β-naphthoflavone (BNF) caused a significant decrease in blood flow in the dorsal midbrain of zebrafish embryos. Here we report effects of TCDD exposure on the morphology of some blood vessels in the head of developing zebrafish. TCDD caused concentration-dependent anatomical rearrangements in the shape of the prosencephalic artery in zebrafish larvae. In contrast, no major vascular defects were recognized in the trunk and tail regions following exposure to TCDD at least at the concentrations used. Essentially, the same observations were also confirmed in BNF-exposed larvae. Knock-down of either Ahr2 or Ahr nuclear translocator type 1 (Arnt1) by morpholino oligonucleotides (MOs) protected larvae against abnormal shape of the prosencephalic artery caused by TCDD and BNF. On the other hand, knock-down of Ahr2 or Arnt1 in vehicle-exposed zebrafish larvae had no clear effect on morphology of the prosencephalic artery or trunk vessels. Ascorbic acid, an antioxidant, protected against the TCDD-induced decrease in blood flow through the prosencephalic artery, but not the abnormal morphological changes in the shape of this artery. These results indicate that activation of Ahr2/Arnt1 pathway by TCDD and BNF affects the shape of certain blood vessels in the brain of developing zebrafish.

  9. Malformation of certain brain blood vessels caused by TCDD activation of Ahr2/Arnt1 signaling in developing zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Teraoka, Hiroki, E-mail: hteraoka@rakuno.ac.jp [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501 (Japan); Ogawa, Akira [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501 (Japan); Kubota, Akira [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501 (Japan); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA (United States); Stegeman, John J. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA (United States); Peterson, Richard E. [School of Pharmacy, University of Wisconsin, Madison, WI (United States); Hiraga, Takeo [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501 (Japan)

    2010-08-15

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes various signs of toxicity in early life stages of vertebrates through activation of the aryl hydrocarbon receptor (AHR). The AHR also plays important roles in normal development in mice, and AHR{sup -/-} mice show abnormal development of vascular structures in various blood vessels. Our previous studies revealed that Ahr type 2 (Ahr2) activation by TCDD and {beta}-naphthoflavone (BNF) caused a significant decrease in blood flow in the dorsal midbrain of zebrafish embryos. Here we report effects of TCDD exposure on the morphology of some blood vessels in the head of developing zebrafish. TCDD caused concentration-dependent anatomical rearrangements in the shape of the prosencephalic artery in zebrafish larvae. In contrast, no major vascular defects were recognized in the trunk and tail regions following exposure to TCDD at least at the concentrations used. Essentially, the same observations were also confirmed in BNF-exposed larvae. Knock-down of either Ahr2 or Ahr nuclear translocator type 1 (Arnt1) by morpholino oligonucleotides (MOs) protected larvae against abnormal shape of the prosencephalic artery caused by TCDD and BNF. On the other hand, knock-down of Ahr2 or Arnt1 in vehicle-exposed zebrafish larvae had no clear effect on morphology of the prosencephalic artery or trunk vessels. Ascorbic acid, an antioxidant, protected against the TCDD-induced decrease in blood flow through the prosencephalic artery, but not the abnormal morphological changes in the shape of this artery. These results indicate that activation of Ahr2/Arnt1 pathway by TCDD and BNF affects the shape of certain blood vessels in the brain of developing zebrafish.

  10. The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Haitao; Du, Yuxuan; Zhang, Xulong; Sun, Ying; Li, Shentao; Dou, Yunpeng [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China); Li, Zhanguo [Department of Rheumatology and Immunology, Clinical Immunology Center, Peking University People' s Hospital, No. 11 Xizhimen South Street, Beijing 100044 (China); Yuan, Huihui, E-mail: huihui_yuan@163.com [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China); Zhao, Wenming, E-mail: zhao-wenming@163.com [Department of Immunology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069 (China)

    2014-11-01

    Ahr activation is known to be associated with synovitis and exacerbated rheumatoid arthritis (RA), but its contributions to bone loss have not been completely elucidated. Osteoblast proliferation and differentiation are abnormal at the erosion site in RA. Here, we reported that the expression of Ahr was increased in the hind paws' bone upon collagen-induced arthritis (CIA) in mice, and the levels of Ahr were negatively correlated with bone mineral density (BMD). In addition, immunofluorescent staining showed that the high expression of Ahr was mainly localized in osteoblasts from the CIA mice compared to normal controls. Moreover, the luciferase intensity of Ahr in the nucleus increased by 12.5% in CIA osteoblasts compared to that in normal controls. In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activation of the Ahr inhibited pre-osteoblast MC3T3-E1 cellular proliferation and differentiation in a dose-dependent manner. Interestingly, the levels of alkaline phosphatase (ALP) mRNA expression in the osteoblasts of CIA mice were reduced compared to normal controls. In contrast, decreased ALP expression by activated Ahr was completely reversed after pretreatment with an Ahr inhibitor (CH-223191) in MC3T3-E1 cell lines and primary osteoblasts on day 5. Our data further showed that activation of Ahr promoted the phosphorylation of ERK after 5 days. Moreover, Ahr-dependent activation of the ERK signaling pathway decreased the levels of proliferation cells and inhibited ALP activity in MC3T3-E1 cells. These results demonstrated that the high expression of Ahr may suppress osteoblast proliferation and differentiation through activation of the ERK signaling pathway, further enabling bone erosion in CIA mice. - Highlights: • The upregulation of Ahr was localized in osteoblasts of CIA mice. • The overexpression of Ahr suppressed osteoblast development. • The Ahr activated ERK signaling pathway to exacerbate bone erosion.

  11. The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway

    International Nuclear Information System (INIS)

    Ahr activation is known to be associated with synovitis and exacerbated rheumatoid arthritis (RA), but its contributions to bone loss have not been completely elucidated. Osteoblast proliferation and differentiation are abnormal at the erosion site in RA. Here, we reported that the expression of Ahr was increased in the hind paws' bone upon collagen-induced arthritis (CIA) in mice, and the levels of Ahr were negatively correlated with bone mineral density (BMD). In addition, immunofluorescent staining showed that the high expression of Ahr was mainly localized in osteoblasts from the CIA mice compared to normal controls. Moreover, the luciferase intensity of Ahr in the nucleus increased by 12.5% in CIA osteoblasts compared to that in normal controls. In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activation of the Ahr inhibited pre-osteoblast MC3T3-E1 cellular proliferation and differentiation in a dose-dependent manner. Interestingly, the levels of alkaline phosphatase (ALP) mRNA expression in the osteoblasts of CIA mice were reduced compared to normal controls. In contrast, decreased ALP expression by activated Ahr was completely reversed after pretreatment with an Ahr inhibitor (CH-223191) in MC3T3-E1 cell lines and primary osteoblasts on day 5. Our data further showed that activation of Ahr promoted the phosphorylation of ERK after 5 days. Moreover, Ahr-dependent activation of the ERK signaling pathway decreased the levels of proliferation cells and inhibited ALP activity in MC3T3-E1 cells. These results demonstrated that the high expression of Ahr may suppress osteoblast proliferation and differentiation through activation of the ERK signaling pathway, further enabling bone erosion in CIA mice. - Highlights: • The upregulation of Ahr was localized in osteoblasts of CIA mice. • The overexpression of Ahr suppressed osteoblast development. • The Ahr activated ERK signaling pathway to exacerbate bone erosion

  12. Molecular and functional characterization of a novel aryl hydrocarbon receptor isoform, AHR1β, in the chicken (Gallus gallus).

    Science.gov (United States)

    Lee, Jin-Seon; Iwabuchi, Kohei; Nomaru, Koji; Nagahama, Nobumasa; Kim, Eun-Young; Iwata, Hisato

    2013-12-01

    Dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cause toxic effects through activation of the aryl hydrocarbon receptor (AHR)-mediated signaling pathway. Our previous studies have investigated the function of 2 AHR isoforms (AHR1 and AHR2) in avian species and identified a third AHR in the chicken (Gallus gallus) genome. Knowledge of multiple avian AHRs is indispensable to understand molecular mechanisms of AHR-mediated toxic effects and establish risk assessment framework for environmental AHR ligands in avian species. In this study, we successfully isolated a third novel AHR1-like cDNA from chicken and designated it as chicken AHR1 beta (ckAHR1β). The mRNA expression of ckAHR1β was primarily detected in the liver, and the hepatic protein expression was confirmed by Western blotting. Although mRNA expression of ckAHR1β was not altered by in ovo TCDD exposure, ckAHR1β exhibited specific binding to [(3)H]TCDD, TCDD-dependent nuclear translocation, and interaction with xenobiotic responsive elements (XREs) and AHR nuclear translocators (ARNTs). In vitro XRE-driven reporter gene assays revealed ckAHR1β-mediated transactivation of TCDD in a dose-dependent manner, showing a 10-fold reduced sensitivity (high EC50) compared with that mediated by ckAHR1. The mutation of Val(371) to Ser(371) in the ligand-binding domain of ckAHR1β shifted the TCDD-EC50 toward the value observed in ckAHR1, indicating the critical roles of the amino acid in sensitivity. Furthermore, ckAHR1β-mediated transactivation of TCDD was enhanced by 17β-estradiol (E2)-activated chicken estrogen receptor α (ckERα), suggesting a positive cross talk between ckERα and ckAHRsignaling pathway. Both TCDD-induced and its enhanced activities by E2 were suppressed by the ckAHR repressor in a manner similar to ckAHR1. Collectively, our findings discover the role of ckAHR1β in dioxin toxicity and give an insight into the evolutionary history of the AHR signaling pathway. PMID:23997109

  13. Plant polyphenols differentially modulate inflammatory responses of human keratinocytes by interfering with activation of transcription factors NFκB and AhR and EGFR-ERK pathway

    International Nuclear Information System (INIS)

    Molecular mechanisms underlying modulation of inflammatory responses in primary human keratinocytes by plant polyphenols (PPs), namely the glycosylated phenylpropanoid verbascoside, the stilbenoid resveratrol and its glycoside polydatin, and the flavonoid quercetin and its glycoside rutin were evaluated. As non-lethal stimuli, the prototypic ligand for epidermal growth factor receptor (EGFR) transforming growth factor alpha (TGFalpha), the combination of tumor necrosis factor (TNFalpha) and interferon (IFNgamma) (T/I), UVA + UVB irradiation, and bacterial lipopolysaccharide (LPS) were used. We demonstrated differential modulation of inflammatory responses in keratinocytes at signal transduction, gene transcription, and protein synthesis levels as a function of PP chemical structure, the pro-inflammatory trigger used, and PP interaction with intracellular detoxifying systems. The PPs remarkably inhibited constitutive, LPS- and T/I-induced but not TGFalpha-induced ERK phosphorylation. They also suppressed NFkappaB activation by LPS and T/I. Verbascoside and quercetin invariably impaired EGFR phosphorylation and UV-associated aryl hydrocarbon receptor (AhR)-mediated signaling, while rutin, polydatin and resveratrol did not affect EGFR phosphorylation and further activated AhR machinery in UV-exposed keratinocytes. In general, PPs down-regulated gene expression of pro-inflammatory cytokines/enzymes, except significant up-regulation of IL-8 observed under stimulation with TGFalpha. Both spontaneous and T/I-induced release of IL-8 and IP-10 was suppressed, although 50 μM resveratrol and polydatin up-regulated IL-8. At this concentration, resveratrol activated both gene expression and de novo synthesis of IL-8 and AhR-mediated mechanisms were involved. We conclude that PPs differentially modulate the inflammatory response of human keratinocytes through distinct signal transduction pathways, including AhR and EGFR. - Graphical abstract: Display Omitted Highlights:

  14. Hexachlorobenzene induces cell proliferation, and aryl hydrocarbon receptor expression (AhR) in rat liver preneoplastic foci, and in the human hepatoma cell line HepG2. AhR is a mediator of ERK1/2 signaling, and cell cycle regulation in HCB-treated HepG2 cells

    International Nuclear Information System (INIS)

    Highlights: • Hexachlorobenzene induces cell proliferation in HepG2 cells and preneoplastic foci. • Hexachlorobenzene promotes HepG2 cells accumulation in S and G2/M phase. • Hexachlorobenzene induces ERK1/2phosphorylation in HepG2 cells. • Hexachlorobenzene induces arylhydrocarbon receptor (AhR) protein overexpression. • Hexachlorobenzene-induced cell proliferation is mediated by AhR. - Abstract: Hexachlorobenzene (HCB) is a widespread environmental pollutant, and a liver tumor promoter in rodents. Depending on the particular cell lines studied, exposure to these compounds may lead to cell proliferation, terminal differentiation, or apoptosis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is involved in drug and xenobiotic metabolism. AhR can also modulate a variety of cellular and physiological processes that can affect cell proliferation and cell fate determination. The mechanisms by which AhR ligands, both exogenous and endogenous, affect these processes involve multiple interactions between AhR and other signaling pathways. In the present study, we examined the effect of HCB on cell proliferation and AhR expression, using an initiation-promotion hepatocarcinogenesis protocol in rat liver and in the human-derived hepatoma cell line, HepG2. Female Wistar rats were initiated with a single dose of 100 mg/kg of diethylnitrosamine (DEN) at the start of the experiment. Two weeks later, daily dosing of 100 mg/kg HCB was maintained for 10 weeks. Partial hepatectomy was performed 3 weeks after initiation. The number and area of glutathione S-transferase-P (GST-P)-positive foci, in the rat liver were used as biomarkers of liver precancerous lesions. Immunohistochemical staining showed an increase in proliferating cell nuclear antigen (PCNA)-positive cells, along with enhanced AhR protein expression in hepatocytes within GST-P-positive foci of (DEN HCB) group, when compared to DEN. In a similar manner, Western blot analysis

  15. Critical nodes in signalling pathways

    DEFF Research Database (Denmark)

    Taniguchi, Cullen M; Emanuelli, Brice; Kahn, C Ronald

    2006-01-01

    Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique ro...

  16. Aberrant Signaling Pathways in Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Nakada, Mitsutoshi, E-mail: nakada@ns.m.kanazawa-u.ac.jp; Kita, Daisuke; Watanabe, Takuya; Hayashi, Yutaka [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan); Teng, Lei [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan); Department of Neurosurgery, The First Clinical College of Harbin Medical University, Nangang, Harbin 150001 (China); Pyko, Ilya V.; Hamada, Jun-Ichiro [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan)

    2011-08-10

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies.

  17. Aberrant Signaling Pathways in Glioma

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies

  18. Signaling Pathways in Melanogenesis

    Directory of Open Access Journals (Sweden)

    Stacey A. N. D’Mello

    2016-07-01

    Full Text Available Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light absorption of melanin in skin and hair leads to photoreceptor shielding, thermoregulation, photoprotection, camouflage and display coloring. Melanins are also powerful cation chelators and may act as free radical sinks. Melanin formation is a product of complex biochemical events that starts from amino acid tyrosine and its metabolite, dopa. The types and amounts of melanin produced by melanocytes are determined genetically and are influenced by a variety of extrinsic and intrinsic factors such as hormonal changes, inflammation, age and exposure to UV light. These stimuli affect the different pathways in melanogenesis. In this review we will discuss the regulatory mechanisms involved in melanogenesis and explain how intrinsic and extrinsic factors regulate melanin production. We will also explain the regulatory roles of different proteins involved in melanogenesis.

  19. Signaling Pathways in Melanogenesis.

    Science.gov (United States)

    D'Mello, Stacey A N; Finlay, Graeme J; Baguley, Bruce C; Askarian-Amiri, Marjan E

    2016-01-01

    Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light absorption of melanin in skin and hair leads to photoreceptor shielding, thermoregulation, photoprotection, camouflage and display coloring. Melanins are also powerful cation chelators and may act as free radical sinks. Melanin formation is a product of complex biochemical events that starts from amino acid tyrosine and its metabolite, dopa. The types and amounts of melanin produced by melanocytes are determined genetically and are influenced by a variety of extrinsic and intrinsic factors such as hormonal changes, inflammation, age and exposure to UV light. These stimuli affect the different pathways in melanogenesis. In this review we will discuss the regulatory mechanisms involved in melanogenesis and explain how intrinsic and extrinsic factors regulate melanin production. We will also explain the regulatory roles of different proteins involved in melanogenesis. PMID:27428965

  20. Signalling pathways in endometrial cancer

    OpenAIRE

    Markowska, Anna; Pawałowska, Monika; Lubin, Jolanta; Markowska, Janina

    2014-01-01

    Carcinogenesis is a multistage process, during which the activity of signalling pathways responsible for cell cycle regulation and division is disrupted which leads to inhibition of apoptosis and enhanced proliferation. Improper activation of Wnt/β-catenin and PI3K. Akt pathways play essential role in endometrial cancers (EC), mainly type I. Mutations in APC, axin or CTNBB1 may lead to β-catenin overactivation leading to excessive gene expression. PTEN inactivation, mutations in the PIK3CA or...

  1. Selective Aryl Hydrocarbon Receptor Modulator 3,3'-Diindolylmethane Impairs AhR and ARNT Signaling and Protects Mouse Neuronal Cells Against Hypoxia.

    Science.gov (United States)

    Rzemieniec, J; Litwa, E; Wnuk, A; Lason, W; Krzeptowski, W; Kajta, M

    2016-10-01

    The neuroprotective potential of 3,3'-diindolylmethane (DIM), which is a selective aryl hydrocarbon receptor modulator, has recently been shown in cellular and animal models of Parkinson's disease and lipopolysaccharide-induced inflammation. However, there are no data concerning the protective capacity and mechanisms of DIM action in neuronal cells exposed to hypoxia. The aim of the present study was to investigate the neuroprotective potential of DIM against the hypoxia-induced damage in mouse hippocampal cells in primary cultures, with a particular focus on DIM interactions with the aryl hydrocarbon receptor (AhR), its nuclear translocator ARNT, and estrogen receptor β (ERβ). In the present study, 18 h of hypoxia induced apoptotic processes, in terms of the mitochondrial membrane potential, activation of caspase-3, and fragmentation of cell nuclei. These effects were accompanied by substantial lactate dehydrogenase release and neuronal cell death. The results of the present study demonstrated strong neuroprotective and anti-apoptotic actions of DIM in hippocampal cells exposed to hypoxia. In addition, DIM decreased the Ahr and Arnt mRNA expression and stimulated Erβ mRNA expression level. DIM-induced mRNA alterations were mirrored by changes in protein levels, except for ERβ, as detected by ELISA, Western blotting, and immunofluorescence labeling. We also demonstrated that DIM decreased the expression of AhR-regulated CYP1A1. Using specific siRNAs, we provided evidence that impairment of AhR and ARNT, but not ERβ plays a key role in the neuroprotective action of DIM against hypoxia-induced cell damage. This study may have implication for identifying new agents that could protect neurons against hypoxia by targeting AhR/ARNT signaling. PMID:26476840

  2. Signaling pathways in diabetic nephropathy.

    Science.gov (United States)

    Kawanami, Daiji; Matoba, Keiichiro; Utsunomiya, Kazunori

    2016-10-01

    Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), however, specific treatment for DN has not yet been elucidated. Therefore, it is critically important to understand the molecular mechanism underlying DN to develop cause-related therapeutic strategy. To date, various factors such as hemodynamic changes and metabolic pathways have been shown to be involved in the pathogenesis of DN. Excessive glucose influx activates cellular signaling pathways, including the diacylglycerol (DAG)-protein kinase C (PKC) pathway, advanced glycation end-products (AGE), polyol pathway, hexosamine pathway and oxidative stress. These factors interact with one another, thereby facilitating inflammatory processes, leading to the development of glomerulosclerosis under diabetic conditions. In addition to metabolic pathways, Rho-kinase, an effector of small-GTPase binding protein Rho, has been implicated as an important factor in the pathogenesis of DN. A number of studies have demonstrated that Rho-kinase plays key roles in the development of DN by inducing endothelial dysfunction, mesangial excessive extracellular matrix (ECM) production, podocyte abnormality, and tubulointerstitial fibrosis. In this review article, we describe our current understanding of the signaling pathways in DN. PMID:27094540

  3. Signalling pathways in endometrial cancer.

    Science.gov (United States)

    Markowska, Anna; Pawałowska, Monika; Lubin, Jolanta; Markowska, Janina

    2014-01-01

    Carcinogenesis is a multistage process, during which the activity of signalling pathways responsible for cell cycle regulation and division is disrupted which leads to inhibition of apoptosis and enhanced proliferation. Improper activation of Wnt/β-catenin and PI3K. Akt pathways play essential role in endometrial cancers (EC), mainly type I. Mutations in APC, axin or CTNBB1 may lead to β-catenin overactivation leading to excessive gene expression. PTEN inactivation, mutations in the PIK3CA or Akt result in increased transmission in the PI3K/Akt pathway, apoptosis inhibition, intensive cell division, mTOR excitation. In non-endometrioid cancers, key mutations include suppressor gene TP53 responsible for repairing damaged DNA or apoptosis initiation. Irregularities in gene P16, encoding a protein forming the p16-cyclinD/CDK-pRb have also been described. Understanding the complex relations between specific proteins taking part in signal transduction of the abovementioned pathways is key to research on drugs used in targeted therapy. PMID:25520571

  4. DMPD: Signal integration between IFNgamma and TLR signalling pathways in macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16920490 Signal integration between IFNgamma and TLR signalling pathways in macroph...ages. Schroder K, Sweet MJ, Hume DA. Immunobiology. 2006;211(6-8):511-24. Epub 2006 Jul 5. (.png) (.svg) (.html) (.csml) Show Signal... integration between IFNgamma and TLR signalling pathways in macrophages. PubmedID 16920490 Title Signal

  5. Leptin signalling pathways in hypothalamic neurons.

    Science.gov (United States)

    Kwon, Obin; Kim, Ki Woo; Kim, Min-Seon

    2016-04-01

    Leptin is the most critical hormone in the homeostatic regulation of energy balance among those so far discovered. Leptin primarily acts on the neurons of the mediobasal part of hypothalamus to regulate food intake, thermogenesis, and the blood glucose level. In the hypothalamic neurons, leptin binding to the long form leptin receptors on the plasma membrane initiates multiple signaling cascades. The signaling pathways known to mediate the actions of leptin include JAK-STAT signaling, PI3K-Akt-FoxO1 signaling, SHP2-ERK signaling, AMPK signaling, and mTOR-S6K signaling. Recent evidence suggests that leptin signaling in hypothalamic neurons is also linked to primary cilia function. On the other hand, signaling molecules/pathways mitigating leptin actions in hypothalamic neurons have been extensively investigated in an effort to treat leptin resistance observed in obesity. These include SOCS3, tyrosine phosphatase PTP1B, and inflammatory signaling pathways such as IKK-NFκB and JNK signaling, and ER stress-mitochondrial signaling. In this review, we discuss leptin signaling pathways in the hypothalamus, with a particular focus on the most recently discovered pathways. PMID:26786898

  6. Notch Signaling Pathway and Human Placenta

    OpenAIRE

    Wei-Xiu Zhao, Jian-Hua Lin

    2012-01-01

    Notch signaling was evolutionarily conserved and critical for cell-fate determination, differentiation and many other biological processes. Growing evidences suggested that Notch signaling pathway played an important role in the mammalian placental development. All of the mammalian Notch family proteins had been identified in human placenta except Delta-like 3, which appeared to affect the axial skeletal system. However the molecular mechanisms that regulated the Notch signaling pathway remai...

  7. AHR2 mutant reveals functional diversity of aryl hydrocarbon receptors in zebrafish.

    Directory of Open Access Journals (Sweden)

    Britton C Goodale

    Full Text Available The aryl hydrocarbon receptor (AHR is well known for mediating the toxic effects of TCDD and has been a subject of intense research for over 30 years. Current investigations continue to uncover its endogenous and regulatory roles in a wide variety of cellular and molecular signaling processes. A zebrafish line with a mutation in ahr2 (ahr2(hu3335, encoding the AHR paralogue responsible for mediating TCDD toxicity in zebrafish, was developed via Targeting Induced Local Lesions IN Genomes (TILLING and predicted to express a non-functional AHR2 protein. We characterized AHR activity in the mutant line using TCDD and leflunomide as toxicological probes to investigate function, ligand binding and CYP1A induction patterns of paralogues AHR2, AHR1A and AHR1B. By evaluating TCDD-induced developmental toxicity, mRNA expression changes and CYP1A protein in the AHR2 mutant line, we determined that ahr2(hu3335 zebrafish are functionally null. In silico modeling predicted differential binding of TCDD and leflunomide to the AHR paralogues. AHR1A is considered a non-functional pseudogene as it does not bind TCCD or mediate in vivo TCDD toxicity. Homology modeling, however, predicted a ligand binding conformation of AHR1A with leflunomide. AHR1A-dependent CYP1A immunohistochemical expression in the liver provided in vivo confirmation of the in silico docking studies. The ahr2(hu3335 functional knockout line expands the experimental power of zebrafish to unravel the role of the AHR during development, as well as highlights potential activity of the other AHR paralogues in ligand-specific toxicological responses.

  8. Clinical implications of hedgehog signaling pathway inhibitors

    Institute of Scientific and Technical Information of China (English)

    Hailan Liu; Dongsheng Gu; Jingwu Xie

    2011-01-01

    Hedgehog was first described in Drosophila melanogaster by the Nobel laureates Eric Wieschaus and Christiane Nusslein-Volhard. The hedgehog (Hh) pathway is a major regulator of cell differentiation,proliferation, tissue polarity, stem cell maintenance, and carcinogenesis. The first link of Hh signaling to cancer was established through studies of a rare familial disease, Gorlin syndrome, in 1996. Follow-up studies revealed activation of this pathway in basal cell carcinoma, medulloblastoma and, leukemia as well as in gastrointestinal, lung, ovarian, breast, and prostate cancer. Targeted inhibition of Hh signaling is now believed to be effective in the treatment and prevention of human cancer. The discovery and synthesis of specific inhibitors for this pathway are even more exciting. In this review, we summarize major advances in the understanding of Hh signaling pathway activation in human cancer, mouse models for studying Hhmediated carcinogenesis, the roles of Hh signaling in tumor development and metastasis, antagonists for Hh signaling and their clinical implications.

  9. AHR2 Mutant Reveals Functional Diversity of Aryl Hydrocarbon Receptors in Zebrafish

    OpenAIRE

    Goodale, Britton C.; La Du, Jane K; Bisson, William H.; Janszen, Derek B.; Waters, Katrina M.; Tanguay, Robert L.

    2012-01-01

    The aryl hydrocarbon receptor (AHR) is well known for mediating the toxic effects of TCDD and has been a subject of intense research for over 30 years. Current investigations continue to uncover its endogenous and regulatory roles in a wide variety of cellular and molecular signaling processes. A zebrafish line with a mutation in ahr2 (ahr2 hu3335), encoding the AHR paralogue responsible for mediating TCDD toxicity in zebrafish, was developed via Targeting Induced Local Lesions IN Genomes (TI...

  10. Signaling pathways regulating murine pancreatic development

    DEFF Research Database (Denmark)

    Serup, Palle

    2012-01-01

    The recent decades have seen a huge expansion in our knowledge about pancreatic development. Numerous lineage-restricted transcription factor genes have been identified and much has been learned about their function. Similarly, numerous signaling pathways important for pancreas development have...... been identified and the specific roles have been investigated by genetic and cell biological methods. The present review presents an overview of the principal signaling pathways involved in regulating murine pancreatic growth, morphogenesis, and cell differentiation....

  11. Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway

    International Nuclear Information System (INIS)

    Dioxins such as 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) are common environmental contaminants known to regulate several genes via activation of the transcription factor aryl hydrocarbon receptor (AhR) associated with the development of numerous adverse biological effects. However, comparatively little is known about the molecular mechanisms by which dioxins display their toxic effects in vertebrates. The 5' untranslated region of the hepatocellular Reduced folate carrier (Rfc1; Slc19a1) exhibits AhR binding sites termed dioxin responsive elements (DRE) that have as yet only been found in the promoter region of prototypical TCDD target genes. Rfc1 mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) plays an essential role in physiological folate homeostasis and MTX cancer chemotherapy. In order to determine whether this carrier represents a target gene of dioxins we have investigated the influence of TCDD on functional Rfc1 activity in rat liver. Pre-treatment of rats with TCDD significantly diminished hepatocellular Rfc1 uptake activity in a time- and dose-dependent manner. In further mechanistic studies we demonstrated that this reduction was due to TCDD-dependent activation of the AhR signalling pathway. We additionally showed that binding of the activated receptor to DRE motifs in the Rfc1 promoter resulted in downregulation of Rfc1 gene expression and reduced carrier protein levels. As downregulation of pivotal Rfc1 activity results in functional folate deficiency associated with an elevated risk of cardiovascular diseases or carcinogenesis, our results indicate that deregulation of this essential transport pathway represents a novel regulatory mechanism how dioxins display their toxic effects through the Ah receptor.

  12. Interleukin 4 signals through two related pathways.

    OpenAIRE

    Pernis, A; Witthuhn, B.; Keegan, A D; Nelms, K; Garfein, E; Ihle, J N; Paul, W. E.; Pierce, J H; Rothman, P.

    1995-01-01

    The interleukin 4 (IL-4) signaling pathway involves activation, by tyrosine phosphorylation, of two distinct substrates, a signal-transducing factor (STF-IL4) and the IL-4-induced phosphotyrosine substrate (4PS). It is not known whether the IL-4-mediated activation of these substrates occurs via related or distinct signaling pathways. We report that 32D cells, an IL-3-dependent myeloid progenitor cell line in which no phosphorylated 4PS is found, activate high levels of STF-IL4 in response to...

  13. The Hedgehog signalling pathway in bone formation

    Institute of Scientific and Technical Information of China (English)

    Jing Yang; Philipp Andre; Ling Ye; Ying-Zi Yang

    2015-01-01

    The Hedgehog (Hh) signalling pathway plays many important roles in development, homeostasis and tumorigenesis. The critical function of Hh signalling in bone formation has been identified in the past two decades. Here, we review the evolutionarily conserved Hh signalling mechanisms with an emphasis on the functions of the Hh signalling pathway in bone development, homeostasis and diseases. In the early stages of embryonic limb development, Sonic Hedgehog (Shh) acts as a major morphogen in patterning the limb buds. Indian Hedgehog (Ihh) has an essential function in endochondral ossification and induces osteoblast differentiation in the perichondrium. Hh signalling is also involved intramembrane ossification. Interactions between Hh and Wnt signalling regulate cartilage development, endochondral bone formation and synovial joint formation. Hh also plays an important role in bone homeostasis, and reducing Hh signalling protects against age-related bone loss. Disruption of Hh signalling regulation leads to multiple bone diseases, such as progressive osseous heteroplasia. Therefore, understanding the signalling mechanisms and functions of Hh signalling in bone development, homeostasis and diseases will provide important insights into bone disease prevention, diagnoses and therapeutics.

  14. Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1.

    Science.gov (United States)

    Moyer, Benjamin J; Rojas, Itzel Y; Kerley-Hamilton, Joanna S; Hazlett, Haley F; Nemani, Krishnamurthy V; Trask, Heidi W; West, Rachel J; Lupien, Leslie E; Collins, Alan J; Ringelberg, Carol S; Gimi, Barjor; Kinlaw, William B; Tomlinson, Craig R

    2016-06-01

    Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity

  15. Advances in Targeting Signal Transduction Pathways

    OpenAIRE

    McCubrey, James A.; Steelman, Linda S.; Chappell, William H.; Sun, Lin; Davis, Nicole M.; Abrams, Stephen L.; Franklin, Richard A.; Cocco, Lucio; Evangelisti, Camilla; Chiarini, Francesca; Martelli, Alberto M.; Libra, Massimo; Candido, Saverio; Ligresti, Giovanni; Malaponte, Grazia

    2012-01-01

    Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being ...

  16. Cellular Signaling Pathways and Their Clinical Reflections

    Directory of Open Access Journals (Sweden)

    N. Ceren Sumer-Turanligil

    2010-06-01

    Full Text Available Cellular signaling pathways have important roles in cellular growth, differentiation, inflammatory response and apoptosis and in regulation of cellular responses under various chemical stimulators. Different proteins which belong to these pathways may be exposed to loss-of-function or gain-of-function mutations; this may lead to many clinical phenotypes including primarily cancer. In this review information about basic working principles of these pathways and diseases related to them are included. [Archives Medical Review Journal 2010; 19(3.000: 180-191

  17. Wnt Signalling Pathway Parameters for Mammalian Cells

    OpenAIRE

    Tan, Chin Wee; Gardiner, Bruce S.; Hirokawa, Yumiko; Layton, Meredith J.; Smith, David W.; Burgess, Antony W.

    2012-01-01

    Wnt/β-catenin signalling regulates cell fate, survival, proliferation and differentiation at many stages of mammalian development and pathology. Mutations of two key proteins in the pathway, APC and β-catenin, have been implicated in a range of cancers, including colorectal cancer. Activation of Wnt signalling has been associated with the stabilization and nuclear accumulation of β-catenin and consequential up-regulation of β-catenin/TCF gene transcription. In 2003, Lee et al. constructed a c...

  18. Reciprocal regulation of metabolic and signaling pathways

    Directory of Open Access Journals (Sweden)

    Barth Andreas S

    2010-03-01

    Full Text Available Abstract Background By studying genome-wide expression patterns in healthy and diseased tissues across a wide range of pathophysiological conditions, DNA microarrays have revealed unique insights into complex diseases. However, the high-dimensionality of microarray data makes interpretation of heterogeneous gene expression studies inherently difficult. Results Using a large-scale analysis of more than 40 microarray studies encompassing ~2400 mammalian tissue samples, we identified a common theme across heterogeneous microarray studies evident by a robust genome-wide inverse regulation of metabolic and cell signaling pathways: We found that upregulation of cell signaling pathways was invariably accompanied by downregulation of cell metabolic transcriptional activity (and vice versa. Several findings suggest that this characteristic gene expression pattern represents a new principle of mammalian transcriptional regulation. First, this coordinated transcriptional pattern occurred in a wide variety of physiological and pathophysiological conditions and was identified across all 20 human and animal tissue types examined. Second, the differences in metabolic gene expression predicted the magnitude of differences for signaling and all other pathways, i.e. tissue samples with similar expression levels of metabolic transcripts did not show any differences in gene expression for all other pathways. Third, this transcriptional pattern predicted a profound effect on the proteome, evident by differences in structure, stability and post-translational modifications of proteins belonging to signaling and metabolic pathways, respectively. Conclusions Our data suggest that in a wide range of physiological and pathophysiological conditions, gene expression changes exhibit a recurring pattern along a transcriptional axis, characterized by an inverse regulation of major metabolic and cell signaling pathways. Given its widespread occurrence and its predicted effects

  19. Apoptosis signaling pathways and lymphocyte homeostasis

    Institute of Scientific and Technical Information of China (English)

    Guangwu Xu; Yufang Shi

    2007-01-01

    It has been almost three decades since the term "apoptosis" was first coined to describe a unique form of cell death that involves orderly, gene-dependent cell disintegration. It is now well accepted that apoptosis is an essential life process for metazoan animals and is critical for the formation and function of tissues and organs. In the adult mammalian body, apoptosis is especially important for proper functioning of the immune system. In recent years, along with the rapid advancement of molecular and cellular biology, great progress has been made in understanding the mechanisms leading to apoptosis. It is generally accepted that there are two major pathways of apoptotic cell death induction: extrinsic signaling through death receptors that leads to the formation of the death-inducing signaling complex (DISC), and intrinsic signaling mainly through mitochondria which leads to the formation of the apoptosome. Formation of the DISC or apoptosome, respectively, activates initiator and common effector caspases that execute the apoptosis process. In the immune system, both pathways operate; however, it is not known whether they are sufficient to maintain lymphocyte homeostasis. Recently, new apoptotic mechanisms including caspase-independent pathways and granzyme-initiated pathways have been shown to exist in lymphocytes. This review will summarize our understanding of the mechanisms that control the homeostasis of various lymphocyte populations.

  20. Wnt signalling pathway parameters for mammalian cells.

    Science.gov (United States)

    Tan, Chin Wee; Gardiner, Bruce S; Hirokawa, Yumiko; Layton, Meredith J; Smith, David W; Burgess, Antony W

    2012-01-01

    Wnt/β-catenin signalling regulates cell fate, survival, proliferation and differentiation at many stages of mammalian development and pathology. Mutations of two key proteins in the pathway, APC and β-catenin, have been implicated in a range of cancers, including colorectal cancer. Activation of Wnt signalling has been associated with the stabilization and nuclear accumulation of β-catenin and consequential up-regulation of β-catenin/TCF gene transcription. In 2003, Lee et al. constructed a computational model of Wnt signalling supported by experimental data from analysis of time-dependent concentration of Wnt signalling proteins in Xenopus egg extracts. Subsequent studies have used the Xenopus quantitative data to infer Wnt pathway dynamics in other systems. As a basis for understanding Wnt signalling in mammalian cells, a confocal live cell imaging measurement technique is developed to measure the cell and nuclear volumes of MDCK, HEK293T cells and 3 human colorectal cancer cell lines and the concentrations of Wnt signalling proteins β-catenin, Axin, APC, GSK3β and E-cadherin. These parameters provide the basis for formulating Wnt signalling models for kidney/intestinal epithelial mammalian cells. There are significant differences in concentrations of key proteins between Xenopus extracts and mammalian whole cell lysates. Higher concentrations of Axin and lower concentrations of APC are present in mammalian cells. Axin concentrations are greater than APC in kidney epithelial cells, whereas in intestinal epithelial cells the APC concentration is higher than Axin. Computational simulations based on Lee's model, with this new data, suggest a need for a recalibration of the model.A quantitative understanding of Wnt signalling in mammalian cells, in particular human colorectal cancers requires a detailed understanding of the concentrations of key protein complexes over time. Simulations of Wnt signalling in mammalian cells can be initiated with the parameters

  1. Wnt signalling pathway parameters for mammalian cells.

    Directory of Open Access Journals (Sweden)

    Chin Wee Tan

    Full Text Available Wnt/β-catenin signalling regulates cell fate, survival, proliferation and differentiation at many stages of mammalian development and pathology. Mutations of two key proteins in the pathway, APC and β-catenin, have been implicated in a range of cancers, including colorectal cancer. Activation of Wnt signalling has been associated with the stabilization and nuclear accumulation of β-catenin and consequential up-regulation of β-catenin/TCF gene transcription. In 2003, Lee et al. constructed a computational model of Wnt signalling supported by experimental data from analysis of time-dependent concentration of Wnt signalling proteins in Xenopus egg extracts. Subsequent studies have used the Xenopus quantitative data to infer Wnt pathway dynamics in other systems. As a basis for understanding Wnt signalling in mammalian cells, a confocal live cell imaging measurement technique is developed to measure the cell and nuclear volumes of MDCK, HEK293T cells and 3 human colorectal cancer cell lines and the concentrations of Wnt signalling proteins β-catenin, Axin, APC, GSK3β and E-cadherin. These parameters provide the basis for formulating Wnt signalling models for kidney/intestinal epithelial mammalian cells. There are significant differences in concentrations of key proteins between Xenopus extracts and mammalian whole cell lysates. Higher concentrations of Axin and lower concentrations of APC are present in mammalian cells. Axin concentrations are greater than APC in kidney epithelial cells, whereas in intestinal epithelial cells the APC concentration is higher than Axin. Computational simulations based on Lee's model, with this new data, suggest a need for a recalibration of the model.A quantitative understanding of Wnt signalling in mammalian cells, in particular human colorectal cancers requires a detailed understanding of the concentrations of key protein complexes over time. Simulations of Wnt signalling in mammalian cells can be initiated

  2. Analysis list: Ahr [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Ahr Blood + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Ahr.1.tsv htt...p://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Ahr.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Ahr....10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Ahr.Blood.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Blood.gml ...

  3. Lung carcinoma signaling pathways activated by smoking

    Institute of Scientific and Technical Information of China (English)

    Jing Wen; Jian-Hua Fu; Wei Zhang; Ming Guo

    2011-01-01

    Lung cancer is the leading cause of cancer death in men and women worldwide, with over a million deaths annually. Tobacco smoke is the major etiologic risk factor for lung cancer in current or previous smokers and has been strongly related to certain types of lung cancer, such as small cell lung carcinoma and squamous cell lung carcinoma. In recent years, there has been an increased incidence of lung adenocarcinoma. This change is strongly associated with changes in smoking behavior and cigarette design. Carcinogens present in tobacco products and their intermediate metabolites can activate multiple signaling pathways that contribute to lung cancer carcinogenesis. In this review, we summarize the smoking-activated signaling pathways involved in lung cancer.

  4. Obesity-Induced Hypertension: Brain Signaling Pathways.

    Science.gov (United States)

    do Carmo, Jussara M; da Silva, Alexandre A; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E P; Hall, John E

    2016-07-01

    Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review highlights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension. PMID:27262997

  5. Mathematics of the NFAT signalling pathway

    OpenAIRE

    Rendall, A.

    2012-01-01

    This paper is a mathematical study of some aspects of the signalling pathway leading to the activation of the transcription factor NFAT (nuclear factor of activated T cells). Activation takes place by dephosphorylation at multiple sites. This has been modelled by Salazar and H\\"ofer using a large system of ordinary differential equations depending on many parameters. With the help of chemical reaction network theory we show that for any choice of the parameters this system has a unique statio...

  6. Signaling Pathways Involved in Cardiac Hypertrophy

    Institute of Scientific and Technical Information of China (English)

    Tao Zewei; Li Longgui

    2006-01-01

    Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress.Traditionally, it has been considered a beneficial mechanism; however, sustained hypertrophy has been associated with a significant increase in the risk of cardiovascular disease and mortality. Delineating intracellular signaling pathways involved in the different aspects of cardiac hypertrophy will permit future improvements in potential targets for therapeutic intervention. Generally, there are two types of cardiac hypertrophies, adaptive hypertrophy, including eutrophy (normal growth) and physiological hypertrophy (growth induced by physical conditioning), and maladaptive hypertrophy, including pathologic or reactive hypertrophy (growth induced by pathologic stimuli) and hypertrophic growth caused by genetic mutations affecting sarcomeric or cytoskeletal proteins. Accumulating observations from animal models and human patients have identified a number of intracellular signaling pathways that characterized as important transducers of the hypertrophic response,including calcineurin/nuclear factor of activated Tcells, phosphoinositide 3-kinases/Akt (PI3Ks/Akt),G protein-coupled receptors, small G proteins,MAPK, PKCs, Gp130/STAT'3, Na+/H+ exchanger,peroxisome proliferator-activated receptors, myocyte enhancer factor 2/histone deacetylases, and many others. Furthermore, recent evidence suggests that adaptive cardiac hypertrophy is regulated in large part by the growth hormone/insulin-like growth factors axis via signaling through the PI3K/Akt pathway. In contrast, pathological or reactive hypertrophy is triggered by autocrine and paracrine neurohormonal factors released during biomechanical stress that signal through the Gq/phosphorlipase C pathway, leading to an increase in cytosolic calcium and activation of PKC.

  7. Insulin signaling pathways in lepidopteran steroidogenesis

    Directory of Open Access Journals (Sweden)

    WendySmith

    2014-02-01

    Full Text Available Molting and metamorphosis are stimulated by the secretion of ecdysteroid hormones from the prothoracic glands. Insulin-like hormones have been found to enhance prothoracic gland activity, providing a mechanism to link molting to nutritional state. In silk moths (Bombyx mori, the prothoracic glands are directly stimulated by insulin and the insulin-like hormone bombyxin. Further, in Bombyx , the neuropeptide prothoracicotropic hormone (PTTH appears to act at least in part through the insulin-signaling pathway. In the prothoracic glands of Manduca sexta, while insulin stimulates the phosphorylation of the insulin receptor and Akt, neither insulin nor bombyxin II stimulate ecdysone secretion. Involvement of the insulin-signaling pathway in Manduca prothoracic glands was explored using two inhibitors of phosphatidylinositol-3-kinase (PI3K, LY294002 and wortmannin. PI3K inhibitors block the phosphorylation of Akt and 4EBP but have no effect on ecdysone secretion, or on the phosphorylation of the MAPkinase, ERK. Inhibitors that block phosphorylation of ERK, including the MEK inhibitor U0126, and high doses of the RSK inhibitor SL0101, effectively inhibit ecdysone secretion. The results highlight differences between the two lepidopteran insects most commonly used to directly study ecdysteroid secretion. In Bombyx, the PTTH and insulin-signaling pathways intersect; both insulin and PTTH enhance the phosphorylation of Akt and stimulate ecdysteroid secretion, and inhibition of PI3K reduces ecdysteroid secretion. By contrast, in Manduca, the action of PTTH is distinct from insulin. The results highlight species differences in the roles of translational regulators such as 4EBP, and members of the MAPkinase pathway such as ERK and RSK, in the effects of nutritionally-sensitive hormones such as insulin on ecdysone secretion and molting.

  8. The immune signaling pathways of Manduca sexta.

    Science.gov (United States)

    Cao, Xiaolong; He, Yan; Hu, Yingxia; Wang, Yang; Chen, Yun-Ru; Bryant, Bart; Clem, Rollie J; Schwartz, Lawrence M; Blissard, Gary; Jiang, Haobo

    2015-07-01

    Signal transduction pathways and their coordination are critically important for proper functioning of animal immune systems. Our knowledge of the constituents of the intracellular signaling network in insects mainly comes from genetic analyses in Drosophila melanogaster. To facilitate future studies of similar systems in the tobacco hornworm and other lepidopteran insects, we have identified and examined the homologous genes in the genome of Manduca sexta. Based on 1:1 orthologous relationships in most cases, we hypothesize that the Toll, Imd, MAPK-JNK-p38 and JAK-STAT pathways are intact and operative in this species, as are most of the regulatory mechanisms. Similarly, cellular processes such as autophagy, apoptosis and RNA interference probably function in similar ways, because their mediators and modulators are mostly conserved in this lepidopteran species. We have annotated a total of 186 genes encoding 199 proteins, studied their domain structures and evolution, and examined their mRNA levels in tissues at different life stages. Such information provides a genomic perspective of the intricate signaling system in a non-drosophiline insect. PMID:25858029

  9. Modularized study of human calcium signalling pathway

    Indian Academy of Sciences (India)

    Losiana Nayak; Rajat K De

    2007-08-01

    Signalling pathways are complex biochemical networks responsible for reg ulation of numerous cellular functions. These networks function by serial and successive interactions among a large number of vital biomolecules and chemical compounds. For deciphering and analysing the underlying mechanism of such networks, a modularized study is quite helpful. Here we propose an algorithm for modularization of calcium signalling pathway of H. sapiens. The idea that ``a node whose function is dependant on maximum number of other nodes tends to be the center of a sub network” is used to divide a large signalling network into smaller sub networks. Inclusion of node(s) into sub networks(s) is dependant on the outdegree of the node(s). Here outdegree of a node refers to the number of re lations of the considered node lying outside the constructed sub network. Node(s) having more than c relations lying outside the expanding subnetwork have to be excluded from it. Here is a specified variable based on user preference, which is finally fixed during adjustments of created subnetworks, so that certain biological significance can be conferred on them.

  10. Signaling pathways in a Citrus EST database

    Directory of Open Access Journals (Sweden)

    Angela Mehta

    2007-01-01

    Full Text Available Citrus spp. are economically important crops, which in Brazil are grown mainly in the State of São Paulo. Citrus cultures are attacked by several pathogens, causing severe yield losses. In order to better understand this culture, the Millenium Project (IAC Cordeirópolis was launched in order to sequence Citrus ESTs (expressed sequence tags from different tissues, including leaf, bark, fruit, root and flower. Plants were submitted to biotic and abiotic stresses and investigated under different development stages (adult vs. juvenile. Several cDNA libraries were constructed and the sequences obtained formed the Citrus ESTs database with almost 200,000 sequences. Searches were performed in the Citrus database to investigate the presence of different signaling pathway components. Several of the genes involved in the signaling of sugar, calcium, cytokinin, plant hormones, inositol phosphate, MAPKinase and COP9 were found in the citrus genome and are discussed in this paper. The results obtained may indicate that similar mechanisms described in other plants, such as Arabidopsis, occur in citrus. Further experimental studies must be conducted in order to understand the different signaling pathways present.

  11. DMPD: When signaling pathways collide: positive and negative regulation of toll-likereceptor signal transduction. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18631453 When signaling pathways collide: positive and negative regulation of toll-likereceptor signal tran...l) Show When signaling pathways collide: positive and negative regulation of toll-likereceptor signal transd...ative regulation of toll-likereceptor signal transduction. Authors O'Neill LA. Publication Immunity. 2008 Ju

  12. Hedgehog signaling pathway and ovarian cancer

    Institute of Scientific and Technical Information of China (English)

    Qi Chen; Guolan Gao; Shiwen Luo

    2013-01-01

    Epithelial ovarian carcinoma (EOC) is the most common form of ovarian malignancies and the most lethal gynecologic malignancy in the United States.To date,in spite of treatment to it with the extensive surgical debulking and chemotherapy,the prognosis of EOC remains dismal.Recently,it has become increasingly clear that in many instances,the signaling and molecular players that control development are the same,and when inappropriately regulated,drive tumorigenesis and cancer development.Here,we discuss the possible involvement of Hedgehog (Hh) pathway in the cellular regulation and development of cancer in the ovaries.Using the in vitro and in vivo assays developed has facilitated the dissection of the mechanisms behind Hh-driven ovarian cancers formation and growth.Based on recent studies,we propose that the inhibition of Hh signaling may interfere with spheroid-like structures in ovarian cancers.The components of the Hh signaling may provide novel drug targets,which could be explored as crucial combinatorial strategies for the treatment of ovarian cancers.

  13. Effects of microgravity environment on intracellular signal transduction pathways

    Directory of Open Access Journals (Sweden)

    De CHANG

    2012-09-01

    Full Text Available Microgravity environment is a stress and extracellular signal that affects cellular morphology and function through signal transduction system, thus leading to certain biological effect. At present, many signaling pathways have been reported to be involved in the regulation of cell function under microgravity environment, such as NF-κB signaling pathway, Notch signaling pathway, MAPK signaling pathway, HSP signaling pathway and so on, and these reports have laid a foundation for the molecular studies of cytolergy under outer space environment. The recent progress in the researches on intracellular signaling pathways affected by microgravity is herewith reviewed in present paper in the hope of providing references for understanding the cell activity in space environment, and to find the ways to alleviate the harmful effects caused by the microgravity environment.

  14. DMPD: LPS/TLR4 signal transduction pathway. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18304834 LPS/TLR4 signal transduction pathway. Lu YC, Yeh WC, Ohashi PS. Cytokine. ...2008 May;42(2):145-51. Epub 2008 Mar 4. (.png) (.svg) (.html) (.csml) Show LPS/TLR4 signal transduction path...way. PubmedID 18304834 Title LPS/TLR4 signal transduction pathway. Authors Lu YC, Yeh WC, Ohashi PS. Publica

  15. DMPD: Regulation of mitochondrial antiviral signaling pathways. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18549796 Regulation of mitochondrial antiviral signaling pathways. Moore CB, Ting J...P. Immunity. 2008 Jun;28(6):735-9. (.png) (.svg) (.html) (.csml) Show Regulation of mitochondrial antiviral ...signaling pathways. PubmedID 18549796 Title Regulation of mitochondrial antiviral signaling pathways. Author

  16. DMPD: Signaling pathways activated by microorganisms. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17303405 Signaling pathways activated by microorganisms. Takeuchi O, Akira S. Curr ...Opin Cell Biol. 2007 Apr;19(2):185-91. Epub 2007 Feb 15. (.png) (.svg) (.html) (.csml) Show Signaling pathwa...ys activated by microorganisms. PubmedID 17303405 Title Signaling pathways activated by microorganisms. Auth

  17. A Study of the PDGF Signaling Pathway with PRISM

    OpenAIRE

    Qixia Yuan; Jun Pang; Sjouke Mauw; Panuwat Trairatphisan; Monique Wiesinger; Thomas Sauter

    2011-01-01

    In this paper, we apply the probabilistic model checker PRISM to the analysis of a biological system -- the Platelet-Derived Growth Factor (PDGF) signaling pathway, demonstrating in detail how this pathway can be analyzed in PRISM. We show that quantitative verification can yield a better understanding of the PDGF signaling pathway.

  18. [Sphingolipid-mediated apoptotic signaling pathways].

    Science.gov (United States)

    Cuvillier, Olivier; Andrieu-Abadie, Nathalie; Ségui, Bruno; Malagarie-Cazenave, Sophie; Tardy, Claudine; Bonhoure, Elisabeth; Levade, Thierry

    2003-01-01

    Various sphingolipids are being viewed as bioactive molecules and/or second messengers. Among them, ceramide (or N-acylsphingosine) and sphingosine generally behave as pro-apoptotic mediators. Indeed, ceramide mediates the death signal initiated by numerous stress agents which either stimulate its de novo synthesis or activate sphingomyelinases that release ceramide from sphingomyelin. For instance, the early generation of ceramide promoted by TNF is mediated by a neutral sphingomyelinase the activity of which is regulated by the FAN adaptor protein, thereby controlling caspase activation and the cell death programme. In addition, the activity of this neutral sphingomyelinase is negatively modulated by caveolin, a major constituent of some membrane microdomains. The enzyme sphingosine kinase also plays a crucial role in apoptosis signalling by regulating the intracellular levels of two sphingolipids having opposite effects, namely the pro-apoptotic sphingosine and the anti-apoptotic sphingosine 1-phosphate molecule. Ceramide and sphingosine metabolism therefore appears as a pivotal regulatory pathway in the determination of cell fate. PMID:14708343

  19. DMPD: Signalling pathways mediating type I interferon gene expression. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17904888 Signalling pathways mediating type I interferon gene expression. Edwards M...R, Slater L, Johnston SL. Microbes Infect. 2007 Sep;9(11):1245-51. Epub 2007 Jul 1. (.png) (.svg) (.html) (.csml) Show Signal...ling pathways mediating type I interferon gene expression. PubmedID 17904888 Title Signalli

  20. BowTieBuilder: modeling signal transduction pathways

    Directory of Open Access Journals (Sweden)

    Schröder Adrian

    2009-06-01

    Full Text Available Abstract Background Sensory proteins react to changing environmental conditions by transducing signals into the cell. These signals are integrated into core proteins that activate downstream target proteins such as transcription factors (TFs. This structure is referred to as a bow tie, and allows cells to respond appropriately to complex environmental conditions. Understanding this cellular processing of information, from sensory proteins (e.g., cell-surface proteins to target proteins (e.g., TFs is important, yet for many processes the signaling pathways remain unknown. Results Here, we present BowTieBuilder for inferring signal transduction pathways from multiple source and target proteins. Given protein-protein interaction (PPI data signaling pathways are assembled without knowledge of the intermediate signaling proteins while maximizing the overall probability of the pathway. To assess the inference quality, BowTieBuilder and three alternative heuristics are applied to several pathways, and the resulting pathways are compared to reference pathways taken from KEGG. In addition, BowTieBuilder is used to infer a signaling pathway of the innate immune response in humans and a signaling pathway that potentially regulates an underlying gene regulatory network. Conclusion We show that BowTieBuilder, given multiple source and/or target proteins, infers pathways with satisfactory recall and precision rates and detects the core proteins of each pathway.

  1. Interaction of fish aryl hydrocarbon receptor paralogs (AHR1 and AHR2) with the retinoblastoma protein

    Energy Technology Data Exchange (ETDEWEB)

    Merson, Rebeka R., E-mail: rmerson@ric.edu [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Biology Department, Rhode Island College, 500 Mt. Pleasant Ave., Providence, RI 02908 (United States); Karchner, Sibel I.; Hahn, Mark E. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States)

    2009-08-13

    The aryl hydrocarbon receptor (AHR) mediates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. In some mammalian cell lines, TCDD induces G1 cell cycle arrest, which depends on an interaction between the AHR and the retinoblastoma tumor suppressor (RB). Mammals possess one AHR, whereas fishes possess two or more AHR paralogs that differ in the domains important for AHR-RB interactions in mammals. To test the hypothesis that fish AHR paralogs differ in their ability to interact with RB, we cloned RB cDNA from Atlantic killifish, Fundulus heteroclitus, and studied the interactions of killifish RB protein with killifish AHR1 and AHR2. In coimmunoprecipitation experiments, in vitro-expressed killifish RB coprecipitated with both AHR1 and AHR2. Consistent with these results, both killifish AHR1 and AHR2 interacted with RB in mammalian two-hybrid assays. These results suggest that both fish AHR1 and AHR2 paralogs may have the potential to influence cell proliferation through interactions with RB.

  2. Interaction of fish aryl hydrocarbon receptor paralogs (AHR1 and AHR2) with the retinoblastoma protein

    International Nuclear Information System (INIS)

    The aryl hydrocarbon receptor (AHR) mediates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. In some mammalian cell lines, TCDD induces G1 cell cycle arrest, which depends on an interaction between the AHR and the retinoblastoma tumor suppressor (RB). Mammals possess one AHR, whereas fishes possess two or more AHR paralogs that differ in the domains important for AHR-RB interactions in mammals. To test the hypothesis that fish AHR paralogs differ in their ability to interact with RB, we cloned RB cDNA from Atlantic killifish, Fundulus heteroclitus, and studied the interactions of killifish RB protein with killifish AHR1 and AHR2. In coimmunoprecipitation experiments, in vitro-expressed killifish RB coprecipitated with both AHR1 and AHR2. Consistent with these results, both killifish AHR1 and AHR2 interacted with RB in mammalian two-hybrid assays. These results suggest that both fish AHR1 and AHR2 paralogs may have the potential to influence cell proliferation through interactions with RB.

  3. Characterization of MCF mammary epithelial cells overexpressing the Arylhydrocarbon receptor (AhR

    Directory of Open Access Journals (Sweden)

    Matsumura Fumio

    2009-07-01

    Full Text Available Abstract Background Recent reports indicate the existence of breast cancer cells expressing very high levels of the Arylhydrocarbon receptor (AhR, a ubiquitous intracellular receptor best known for mediating toxic action of dioxin and related pollutants. Positive correlation between the degree of AhR overexpression and states of increasing transformation of mammary epithelial cells appears to occur in the absence of any exogenous AhR ligands. These observations have raised many questions such as why and how AhR is overexpressed in breast cancer and its physiological roles in the progression to advanced carcinogenic transformation. To address those questions, we hypothesized that AhR overexpression occurs in cells experiencing deficiencies in normally required estrogen receptor (ER signaling, and the basic role of AhR in such cases is to guide the affected cells to develop orchestrated cellular changes aimed at substituting the normal functions of ER. At the same time, the AhR serves as the mediator of the cell survival program in the absence of ER signaling. Methods We subjected two lines of Michigan Cancer Foundation (MCF mammary epithelial cells to 3 different types ER interacting agents for a number of passages and followed the changes in the expression of AhR mRNA. The resulting sublines were analyzed for phenotypical changes and unique molecular characteristics. Results MCF10AT1 cells continuously exposed to 17-beta-estradiol (E2 developed sub-lines that show AhR overexpression with the characteristic phenotype of increased proliferation, and distinct resistance to apoptosis. When these chemically selected cell lines were treated with a specific AhR antagonist, 3-methoxy-4-nitroflavone (MNF, both of the above abnormal cellular characteristics disappeared, indicating the pivotal role of AhR in expressing those cellular phenotypes. The most prominent molecular characteristics of these AhR overexpressing MCF cells were found to be

  4. Canonical WNT signaling pathway and human AREG.

    Science.gov (United States)

    Katoh, Yuriko; Katoh, Masaru

    2006-06-01

    AREG (Amphiregulin), BTC (beta-cellulin), EGF, EPGN (Epigen), EREG (Epiregulin), HBEGF, NRG1, NRG2, NRG3, NRG4 and TGFA (TGFalpha) constitute EGF family ligands for ERBB family receptors. Cetuximab (Erbitux), Pertuzumab (Omnitarg) and Trastuzumab (Herceptin) are anti-cancer drugs targeted to EGF family ligands, while Gefitinib (Iressa), Erlotinib (Tarceva) and Lapatinib (GW572016) are anti-cancer drugs targeted to ERBB family receptors. AREG and TGFA are biomarkers for Gefitinib non-responders. The TCF/LEF binding sites within the promoter region of human EGF family members were searched for by using bioinformatics and human intelligence (Humint). Because three TCF/LEF-binding sites were identified within the 5'-promoter region of human AREG gene, comparative genomics analyses on AREG orthologs were further performed. The EPGN-EREG-AREG-BTC cluster at human chromosome 4q13.3 was linked to the PPBP-CXCL segmental duplicons. AREG was the paralog of HBEGF at human chromosome 5q31.2. Chimpanzee AREG gene, consisting of six exons, was located within NW_105918.1 genome sequence. Chimpanzee AREG was a type I transmembrane protein showing 98.0% and 71.4% total amino-acid identity with human AREG and mouse Areg, respectively. Three TCF/LEF-binding sites within human AREG promoter were conserved in chimpanzee AREG promoter, but not in rodent Areg promoters. Primate AREG promoters were significantly divergent from rodent Areg promoters. AREG mRNA was expressed in a variety of human tumors, such as colorectal cancer, liver cancer, gastric cancer, breast cancer, prostate cancer, esophageal cancer and myeloma. Because human AREG was characterized as potent target gene of WNT/beta-catenin signaling pathway, WNT signaling activation could lead to Gefitinib resistance through AREG upregulation. AREG is a target of systems medicine in the field of oncology. PMID:16685431

  5. Notch -- a goldilocks signaling pathway in disease and cancer therapy.

    Science.gov (United States)

    Braune, Eike-Benjamin; Lendahl, Urban

    2016-03-01

    The Notch signaling pathway is a fundamental signaling mechanism operating in most, if not all, multicellular organisms and in most cell types in the body. Like other "ivy league" pathways such as Wnt, PI3K, Sonic Hedgehog, Receptor Tyrosine Kinases (RTKs), and JAK/STAT signaling, the Notch pathway is a linear signaling mechanism, i.e., an extracellular ligand activates a receptor, which ultimately leads to transcriptional alterations in the cell nucleus, but Notch signaling is a strict cell-cell communication mechanism and lacks built-in amplification steps in the signaling pathway. Dysregulated Notch signaling, either by direct mutations in the pathway or by altered signaling output, is increasingly linked to disease, and Notch can act as an oncogene or tumor suppressor depending on the cellular context. This underscores that appropriate level of Notch signaling is important for differentiation and tissue homeostasis, a notion supported also by genetic data indicating that Notch signaling is very gene dosage-sensitive. Thus, too much or too little signaling can lead to disease and Notch can therefore be considered a Goldilocks signaling pathway. Given the emerging role of dysregulated Notch signaling in disease, there is increasing interest in developing therapeutic approaches to modulate Notch signaling. In this review we discuss recent findings on how signal transduction is tuned in the Notch pathway and how Notch signaling is dysregulated in disease. We also discuss different strategies to modulate Notch signaling for clinical use, for example by novel antibody-based tools and by taking advantage of the cross-talk between Notch and other signaling mechanisms. PMID:27115169

  6. Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions

    Energy Technology Data Exchange (ETDEWEB)

    Wincent, Emma [Department of Environmental Toxicology, Uppsala University, 75236 Uppsala (Sweden); Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm (Sweden); Stegeman, John J. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543-1050 (United States); Jönsson, Maria E., E-mail: maria.jonsson@ebc.uu.se [Department of Environmental Toxicology, Uppsala University, 75236 Uppsala (Sweden)

    2015-04-15

    Wnt/β-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between β-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the β-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with β-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of β-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a β-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in the presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholino-oligonucleotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of β-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of β-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating β-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes.

  7. Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions

    International Nuclear Information System (INIS)

    Wnt/β-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between β-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the β-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with β-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of β-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a β-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in the presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholino-oligonucleotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of β-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of β-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating β-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes

  8. Unravelling the molecular mechanisms of the canonical Wnt signalling pathway

    OpenAIRE

    Ng, S. S.

    2010-01-01

    The Canonical Wnt signaling pathway (Wnt/beta-catenin pathway) is required during embryonic development and maintenance of adult-renewing tissue homeostasis. Deregulation of this pathway is found associated with cancer and other diseases. The main goal of this thesis is to discern the regulation mechanisms of canonical Wnt signaling and thereby identify potential drug targets. We found that, neither the dissembled of Axin1, APC or GSK3 from the destruction complex nor inactivation of GSK3 and...

  9. Singapore signalling: the 2012 hedgehog pathway cocktail

    OpenAIRE

    Briscoe, James; Rohatgi, Rajat

    2012-01-01

    The ‘Hedgehog Signalling in Development Evolution and Disease' conference took place in Singapore in March 2012. It brought leading researchers together to discuss the latest findings, and exchange ideas, on every aspect of Hedgehog signalling.

  10. Temporal and Evolutionary Dynamics of Two-Component Signaling Pathways

    OpenAIRE

    Salazar, Michael E.; Laub, Michael T.

    2015-01-01

    Bacteria sense and respond to numerous environmental signals through two-component signaling pathways. Typically, a given stimulus will activate a sensor histidine kinase to autophosphorylate and then phosphotransfer to a cognate response regulator, which can mount an appropriate response. Although these signaling pathways often appear to be simple switches, they can also orchestrate surprisingly sophisticated and complex responses. These temporal dynamics arise from several key regulatory fe...

  11. Dissection of the insulin signaling pathway via quantitative phosphoproteomics

    DEFF Research Database (Denmark)

    Krüger, Marcus; Kratchmarova, Irina; Blagoev, Blagoy;

    2008-01-01

    spectrum of the tyrosine phosphorylation cascade, we have defined the tyrosine-phosphoproteome of the insulin signaling pathway, using high resolution mass spectrometry in combination with phosphotyrosine immunoprecipitation and stable isotope labeling by amino acids in cell culture (SILAC) in...... calcium transporting ATPase SERCA2, supporting a connection to calcium signaling. The combination of quantitative phosphoproteomics with cell culture models provides a powerful strategy to dissect the insulin signaling pathways in intact cells....

  12. Death and dessert: Nutrient signalling pathways and ageing

    OpenAIRE

    Alic, Nazif; Partridge, Linda

    2011-01-01

    Reduction in nutrient intake without malnutrition can delay ageing and extend healthy life in diverse organisms from yeast to primates. This effect can be recapitulated by genetic or pharmacological dampening of the signal through nutrient signalling pathways, making them a promising target for intervention into human ageing and age-related diseases. Here we review the current knowledge of the interactions between nutrient signalling pathways and ageing, focusing on the findings emerged in th...

  13. Radioresistance-related signaling pathways in nasopharyngeal carcinoma cells

    International Nuclear Information System (INIS)

    Objective: To study the difference of gene expression profile between the radioresistant human nasopharyngeal carcinoma cell line CNE-2R and CNE-2, and to screen the signaling pathway associated with radioresistance of nasopharyngeal carcinoma. Methods: The radioresistant nasopharyngeal carcinoma cell line CNE-2R was constructed from the original cell line CNE-2. CNE-2R and CNE-2 cells were cultured and administered with 60Co γ-ray irradiation at the dose of 400 cGy for 15 times. Human-6v 3.0 whole genome expression profile was used to screen the differentially expressed genes. Bioinformatic analysis was used to identify the pathways related to radioresistance. Results: The number of the differentially expressed genes that were found in these 2 experiments was 374. The Kegg pathway and Biocarta pathway analysis of the differentially expressed genes showed the biological importance of Toll-like receptor signaling pathway and IL-1 R-mediated signal transduction pathway to the radioresistance of the CNE-2R cells and the significant differences of 13 genes in these 2 pathways,including JUN, MYD88, CCL5, CXCL10, STAT1, LY96, FOS, CCL3, IL-6, IL-8, IL-1α, IL-1β, and IRAK2 (t=13.47-66.57, P<0.05). Conclusions: Toll-like receptor signaling pathway and IL-1R-mediated signal transduction pathway might be related to the occurrence of radioresistance. (authors)

  14. Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Ya-Hsin, E-mail: yhcheng@mail.cmu.edu.tw [Department of Physiology, School of Medicine, China Medical University, Taichung 40402, Taiwan, ROC (China); Li, Lih-Ann; Lin, Pinpin; Cheng, Li-Chuan [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan, ROC (China); Hung, Chein-Hui [Graduate Institute of Clinical Medicine Sciences, Chang Gung University, Puizi City, Chiayi 613, Taiwan, ROC (China); Chang, Nai Wen [Department of Biochemistry, School of Medicine, China Medical University, Taichung, Taiwan, ROC (China); Lin, Chingju [Department of Physiology, School of Medicine, China Medical University, Taichung 40402, Taiwan, ROC (China)

    2012-09-15

    Baicalein is a flavonoid, known to have anti-inflammatory and anti-cancer effects. As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell cycle, we suspected that the anti-cancer effect of baicalein is associated with AhR. This study investigated the molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3, including whether such effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose-dependent manner. Cell cycle was arrested at the G1 phase and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased. When the AhR was suppressed by siRNA, the reduction of pRb was partially reversed, accompanied by a decrease of cell population at G1 phase and an increase at S phase, while the reduction of cyclin D1 and CDK4 did not change. This finding suggests that the baicalein activation of AhR is indeed associated with the reduction of pRb, but is independent of the reduction of cyclin D1 and CDK4. When cells were pre-treated with LiCl, the inhibitor of GSK-3β, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is both mediated by baicalein through activation of AhR and facilitation of cyclin D1 degradation, which causes cell cycle arrest at the G1 phase, and results in the inhibition of cell proliferation. -- Highlights: ► Baicalein causes the G1 phase arrest by decreasing Rb phosphorylation. ► Baicalein modulates AhR-mediated cell proliferation. ► Both AhR activation and cyclin D1 degradation results in hypophosphorylation of Rb. ► Baicalein facilitates cyclin D1 degradation by signalling the GSK-3β pathway.

  15. Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation

    International Nuclear Information System (INIS)

    Baicalein is a flavonoid, known to have anti-inflammatory and anti-cancer effects. As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell cycle, we suspected that the anti-cancer effect of baicalein is associated with AhR. This study investigated the molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3, including whether such effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose-dependent manner. Cell cycle was arrested at the G1 phase and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased. When the AhR was suppressed by siRNA, the reduction of pRb was partially reversed, accompanied by a decrease of cell population at G1 phase and an increase at S phase, while the reduction of cyclin D1 and CDK4 did not change. This finding suggests that the baicalein activation of AhR is indeed associated with the reduction of pRb, but is independent of the reduction of cyclin D1 and CDK4. When cells were pre-treated with LiCl, the inhibitor of GSK-3β, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is both mediated by baicalein through activation of AhR and facilitation of cyclin D1 degradation, which causes cell cycle arrest at the G1 phase, and results in the inhibition of cell proliferation. -- Highlights: ► Baicalein causes the G1 phase arrest by decreasing Rb phosphorylation. ► Baicalein modulates AhR-mediated cell proliferation. ► Both AhR activation and cyclin D1 degradation results in hypophosphorylation of Rb. ► Baicalein facilitates cyclin D1 degradation by signalling the GSK-3β pathway.

  16. The Fibroblast Growth Factor signaling pathway

    OpenAIRE

    Ornitz, David M.; Itoh, Nobuyuki

    2015-01-01

    The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins. Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STA...

  17. Intricacies of hedgehog signaling pathways: A perspective in tumorigenesis

    International Nuclear Information System (INIS)

    The hedgehog (HH) signaling pathway is a crucial negotiator of developmental proceedings in the embryo governing a diverse array of processes including cell proliferation, differentiation, and tissue patterning. The overall activity of the pathway is significantly curtailed after embryogenesis as well as in adults, yet it retains many of its functional capacities. However, aberration in HH signaling mediates the initiation, proliferation and continued sustenance of malignancy in different tissues to varying degrees through different mechanisms. In this review, we provide an overview of the role of constitutively active aberrant HH signaling pathway in different types of human cancer and the underlying molecular and genetic mechanisms that drive tumorigenesis in that particular tissue. An insight into the various modes of anomalous HH signaling in different organs will provide a comprehensive knowledge of the pathway in these tissues and open a window for individually tailored, tissue-specific therapeutic interventions. The synergistic cross talking of HH pathway with many other regulatory molecules and developmentally inclined signaling pathways may offer many avenues for pharmacological advances. Understanding the molecular basis of abnormal HH signaling in cancer will provide an opportunity to inhibit the deregulated pathway in many aggressive and therapeutically challenging cancers where promising options are not available.

  18. Intricacies of hedgehog signaling pathways: A perspective in tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kar, Swayamsiddha; Deb, Moonmoon; Sengupta, Dipta; Shilpi, Arunima; Bhutia, Sujit Kumar [Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008 (India); Patra, Samir Kumar, E-mail: samirp@nitrkl.ac.in [Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008 (India)

    2012-10-01

    The hedgehog (HH) signaling pathway is a crucial negotiator of developmental proceedings in the embryo governing a diverse array of processes including cell proliferation, differentiation, and tissue patterning. The overall activity of the pathway is significantly curtailed after embryogenesis as well as in adults, yet it retains many of its functional capacities. However, aberration in HH signaling mediates the initiation, proliferation and continued sustenance of malignancy in different tissues to varying degrees through different mechanisms. In this review, we provide an overview of the role of constitutively active aberrant HH signaling pathway in different types of human cancer and the underlying molecular and genetic mechanisms that drive tumorigenesis in that particular tissue. An insight into the various modes of anomalous HH signaling in different organs will provide a comprehensive knowledge of the pathway in these tissues and open a window for individually tailored, tissue-specific therapeutic interventions. The synergistic cross talking of HH pathway with many other regulatory molecules and developmentally inclined signaling pathways may offer many avenues for pharmacological advances. Understanding the molecular basis of abnormal HH signaling in cancer will provide an opportunity to inhibit the deregulated pathway in many aggressive and therapeutically challenging cancers where promising options are not available.

  19. Understanding disease mechanisms with models of signaling pathway activities

    OpenAIRE

    Sebastian-Leon, Patricia; Vidal, Enrique; Minguez, Pablo; Conesa, Ana; Tarazona, Sonia; Amadoz, Alicia; Armero, Carmen; Salavert, Francisco; VIDAL-PUIG, Antonio; Montaner, David; Dopazo, Joaquín

    2014-01-01

    Background Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine. Results Here we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements in...

  20. Modelling and Analysis of Biochemical Signalling Pathway Cross-talk

    Directory of Open Access Journals (Sweden)

    Robin Donaldson

    2010-02-01

    Full Text Available Signalling pathways are abstractions that help life scientists structure the coordination of cellular activity. Cross-talk between pathways accounts for many of the complex behaviours exhibited by signalling pathways and is often critical in producing the correct signal-response relationship. Formal models of signalling pathways and cross-talk in particular can aid understanding and drive experimentation. We define an approach to modelling based on the concept that a pathway is the (synchronising parallel composition of instances of generic modules (with internal and external labels. Pathways are then composed by (synchronising parallel composition and renaming; different types of cross-talk result from different combinations of synchronisation and renaming. We define a number of generic modules in PRISM and five types of cross-talk: signal flow, substrate availability, receptor function, gene expression and intracellular communication. We show that Continuous Stochastic Logic properties can both detect and distinguish the types of cross-talk. The approach is illustrated with small examples and an analysis of the cross-talk between the TGF-b/BMP, WNT and MAPK pathways.

  1. Temporal and evolutionary dynamics of two-component signaling pathways.

    Science.gov (United States)

    Salazar, Michael E; Laub, Michael T

    2015-04-01

    Bacteria sense and respond to numerous environmental signals through two-component signaling pathways. Typically, a given stimulus will activate a sensor histidine kinase to autophosphorylate and then phosphotransfer to a cognate response regulator, which can mount an appropriate response. Although these signaling pathways often appear to be simple switches, they can also orchestrate surprisingly sophisticated and complex responses. These temporal dynamics arise from several key regulatory features, including the bifunctionality of histidine kinases as well as positive and negative feedback loops. Two-component signaling pathways are also dynamic on evolutionary time-scales, expanding dramatically in many species through gene duplication and divergence. Here, we review recent work probing the temporal and evolutionary dynamics of two-component signaling systems. PMID:25589045

  2. Role of Hedgehog Signaling Pathway in NASH

    Directory of Open Access Journals (Sweden)

    Mariana Verdelho Machado

    2016-06-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual’s response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease.

  3. Role of Hedgehog Signaling Pathway in NASH.

    Science.gov (United States)

    Verdelho Machado, Mariana; Diehl, Anna Mae

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual's response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease. PMID:27258259

  4. Disruption of developmental signaling pathways by toxic organic pollutants affecting liver cells

    Czech Academy of Sciences Publication Activity Database

    Vondráček, Jan; Procházková, Jiřina; Bryja, Vítězslav; Richterová, Markéta; Kozubík, Alois; Krčmář, P.; Machala, M.

    Brno, 2009. s. 158. ISSN 1337-6853. [TOXCON 2009, 14th Interdisciplinary Toxicology Conference. 01.06.2009-03.06.2009, Brno] R&D Projects: GA ČR(CZ) GA524/09/1337 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : AhR * Wnt signaling * liver progenitor cells Subject RIV: BO - Biophysics

  5. Signaling pathway networks mined from human pituitary adenoma proteomics data

    Directory of Open Access Journals (Sweden)

    Zhan Xianquan

    2010-04-01

    Full Text Available Abstract Background We obtained a series of pituitary adenoma proteomic expression data, including protein-mapping data (111 proteins, comparative proteomic data (56 differentially expressed proteins, and nitroproteomic data (17 nitroproteins. There is a pressing need to clarify the significant signaling pathway networks that derive from those proteins in order to clarify and to better understand the molecular basis of pituitary adenoma pathogenesis and to discover biomarkers. Here, we describe the significant signaling pathway networks that were mined from human pituitary adenoma proteomic data with the Ingenuity pathway analysis system. Methods The Ingenuity pathway analysis system was used to analyze signal pathway networks and canonical pathways from protein-mapping data, comparative proteomic data, adenoma nitroproteomic data, and control nitroproteomic data. A Fisher's exact test was used to test the statistical significance with a significance level of 0.05. Statistical significant results were rationalized within the pituitary adenoma biological system with literature-based bioinformatics analyses. Results For the protein-mapping data, the top pathway networks were related to cancer, cell death, and lipid metabolism; the top canonical toxicity pathways included acute-phase response, oxidative-stress response, oxidative stress, and cell-cycle G2/M transition regulation. For the comparative proteomic data, top pathway networks were related to cancer, endocrine system development and function, and lipid metabolism; the top canonical toxicity pathways included mitochondrial dysfunction, oxidative phosphorylation, oxidative-stress response, and ERK/MAPK signaling. The nitroproteomic data from a pituitary adenoma were related to cancer, cell death, lipid metabolism, and reproductive system disease, and the top canonical toxicity pathways mainly related to p38 MAPK signaling and cell-cycle G2/M transition regulation. Nitroproteins from a

  6. AlzPathway: a comprehensive map of signaling pathways of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Mizuno Satoshi

    2012-05-01

    Full Text Available Abstract Background Alzheimer’s disease (AD is the most common cause of dementia among the elderly. To clarify pathogenesis of AD, thousands of reports have been accumulating. However, knowledge of signaling pathways in the field of AD has not been compiled as a database before. Description Here, we have constructed a publicly available pathway map called “AlzPathway” that comprehensively catalogs signaling pathways in the field of AD. We have collected and manually curated over 100 review articles related to AD, and have built an AD pathway map using CellDesigner. AlzPathway is currently composed of 1347 molecules and 1070 reactions in neuron, brain blood barrier, presynaptic, postsynaptic, astrocyte, and microglial cells and their cellular localizations. AlzPathway is available as both the SBML (Systems Biology Markup Language map for CellDesigner and the high resolution image map. AlzPathway is also available as a web service (online map based on Payao system, a community-based, collaborative web service platform for pathway model curation, enabling continuous updates by AD researchers. Conclusions AlzPathway is the first comprehensive map of intra, inter and extra cellular AD signaling pathways which can enable mechanistic deciphering of AD pathogenesis. The AlzPathway map is accessible at http://alzpathway.org/.

  7. Signal Transduction Pathways that Regulate CAB Gene Expression

    Energy Technology Data Exchange (ETDEWEB)

    Chory, Joanne

    2006-01-16

    The process of chloroplast differentiation, involves the coordinate regulation of many nuclear and chloroplast genes. The cues for the initiation of this developmental program are both extrinsic (e.g., light) and intrinsic (cell-type and plastid signals). During this project period, we utilized a molecular genetic approach to select for Arabidopsis mutants that did not respond properly to environmental light conditions, as well as mutants that were unable to perceive plastid damage. These latter mutants, called gun mutants, define two retrograde signaling pathways that regulate nuclear gene expression in response to chloroplasts. A major finding was to identify a signal from chloroplasts that regulates nuclear gene transcription. This signal is the build-up of Mg-Protoporphyrin IX, a key intermediate of the chlorophyll biosynthetic pathway. The signaling pathways downstream of this signal are currently being studied. Completion of this project has provided an increased understanding of the input signals and retrograde signaling pathways that control nuclear gene expression in response to the functional state of chloroplasts. These studies should ultimately influence our abilities to manipulate plant growth and development, and will aid in the understanding of the developmental control of photosynthesis.

  8. Signal Transduction Pathways that Regulate CAB Gene Expression

    Energy Technology Data Exchange (ETDEWEB)

    Chory, Joanne

    2004-12-31

    The process of chloroplast differentiation, involves the coordinate regulation of many nuclear and chloroplast genes. The cues for the initiation of this developmental program are both extrinsic (e.g., light) and intrinsic (cell-type and plastid signals). During this project period, we utilized a molecular genetic approach to select for Arabidopsis mutants that did not respond properly to environmental light conditions, as well as mutants that were unable to perceive plastid damage. These latter mutants, called gun mutants, define two retrograde signaling pathways that regulate nuclear gene expression in response to chloroplasts. A major finding was to identify a signal from chloroplasts that regulates nuclear gene transcription. This signal is the build-up of Mg-Protoporphyrin IX, a key intermediate of the chlorophyll biosynthetic pathway. The signaling pathways downstream of this signal are currently being studied. Completion of this project has provided an increased understanding of the input signals and retrograde signaling pathways that control nuclear gene expression in response to the functional state of chloroplasts. These studies should ultimately influence our abilities to manipulate plant growth and development, and will aid in the understanding of the developmental control of photosynthesis.

  9. Targeting Signaling Pathways in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Johannes Haybaeck

    2013-05-01

    Full Text Available Ovarian carcinoma (OC is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. Purpose: We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data: In 2012, the vascular endothelial growth factor (VEGF inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR inhibitors, poly-ADP-ribose polymerase (PARP inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy. Conclusion: Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity.

  10. TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling.

    Science.gov (United States)

    Zhong, Jun; Sharma, Jyoti; Raju, Rajesh; Palapetta, Shyam Mohan; Prasad, T S Keshava; Huang, Tai-Chung; Yoda, Akinori; Tyner, Jeffrey W; van Bodegom, Diederik; Weinstock, David M; Ziegler, Steven F; Pandey, Akhilesh

    2014-01-01

    Thymic stromal lymphopoietin (TSLP) is a four-helix bundle cytokine that plays a critical role in the regulation of immune responses and in the differentiation of hematopoietic cells. TSLP signals through a heterodimeric receptor complex consisting of an interleukin-7 receptor α chain and a unique TSLP receptor (TSLPR) [also known as cytokine receptor-like factor 2 (CRLF2)]. Cellular targets of TSLP include dendritic cells, B cells, mast cells, regulatory T (Treg) cells and CD4+ and CD8+ T cells. The TSLP/TSLPR axis can activate multiple signaling transduction pathways including the JAK/STAT pathway and the PI-3 kinase pathway. Aberrant TSLP/TSLPR signaling has been associated with a variety of human diseases including asthma, atopic dermatitis, nasal polyposis, inflammatory bowel disease, eosinophilic eosophagitis and, most recently, acute lymphoblastic leukemia. A centralized resource of the TSLP signaling pathway cataloging signaling events is not yet available. In this study, we present a literature-annotated resource of reactions in the TSLP signaling pathway. This pathway map is publicly available through NetPath (http://www.netpath.org/), an open access signal transduction pathway resource developed previously by our group. This map includes 236 molecules and 252 reactions that are involved in TSLP/TSLPR signaling pathway. We expect that the TSLP signaling pathway map will provide a rich resource to study the biology of this important cytokine as well as to identify novel therapeutic targets for diseases associated with dysregulated TSLP/TSLPR signaling. Database URL: http://www.netpath.org/pathways?path_id=NetPath_24. PMID:24573880

  11. A Bioinformatics Resource for TWEAK-Fn14 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Mitali Bhattacharjee

    2012-01-01

    Full Text Available TNF-related weak inducer of apoptosis (TWEAK is a new member of the TNF superfamily. It signals through TNFRSF12A, commonly known as Fn14. The TWEAK-Fn14 interaction regulates cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis, tissue remodeling and inflammation. Although TWEAK has been reported to be associated with autoimmune diseases, cancers, stroke, and kidney-related disorders, the downstream molecular events of TWEAK-Fn14 signaling are yet not available in any signaling pathway repository. In this paper, we manually compiled from the literature, in particular those reported in human systems, the downstream reactions stimulated by TWEAK-Fn14 interactions. Our manual amassment of the TWEAK-Fn14 pathway has resulted in cataloging of 46 proteins involved in various biochemical reactions and TWEAK-Fn14 induced expression of 28 genes. We have enabled the availability of data in various standard exchange formats from NetPath, a repository for signaling pathways. We believe that this composite molecular interaction pathway will enable identification of new signaling components in TWEAK signaling pathway. This in turn may lead to the identification of potential therapeutic targets in TWEAK-associated disorders.

  12. Signal transduction pathway profiling of individual tumor samples

    Directory of Open Access Journals (Sweden)

    Peterson Carsten

    2005-06-01

    Full Text Available Abstract Background Signal transduction pathways convey information from the outside of the cell to transcription factors, which in turn regulate gene expression. Our objective is to analyze tumor gene expression data from microarrays in the context of such pathways. Results We use pathways compiled from the TRANSPATH/TRANSFAC databases and the literature, and three publicly available cancer microarray data sets. Variation in pathway activity, across the samples, is gauged by the degree of correlation between downstream targets of a pathway. Two correlation scores are applied; one considers all pairs of downstream targets, and the other considers only pairs without common transcription factors. Several pathways are found to be differentially active in the data sets using these scores. Moreover, we devise a score for pathway activity in individual samples, based on the average expression value of the downstream targets. Statistical significance is assigned to the scores using permutation of genes as null model. Hence, for individual samples, the status of a pathway is given as a sign, + or -, and a p-value. This approach defines a projection of high-dimensional gene expression data onto low-dimensional pathway activity scores. For each dataset and many pathways we find a much larger number of significant samples than expected by chance. Finally, we find that several sample-wise pathway activities are significantly associated with clinical classifications of the samples. Conclusion This study shows that it is feasible to infer signal transduction pathway activity, in individual samples, from gene expression data. Furthermore, these pathway activities are biologically relevant in the three cancer data sets.

  13. ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Yin, Xinhua [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China); Wang, Xiaoyuan [Department of Nephrology, Xi An Honghui Hospital, Xi an (China); Hu, Xiongke; Chen, Yong; Zeng, Kefeng [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China); Zhang, Hongqi, E-mail: zhq9699@126.com [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China)

    2015-07-01

    Although 17β-estradial (E2) is known to stimulate bone formation, the underlying mechanisms are not fully understood. Recent studies have implicated the Wnt/β-catenin pathway as a major signaling cascade in bone biology. The interactions between Wnt/β-catenin signaling pathway and estrogen signaling pathways have been reported in many tissues. In this study, E2 significantly increased the expression of β-catenin by inducing phosphorylations of GSK3β at serine 9. ERβ siRNAs were transfected into MC3T3-E1 cells and revealed that ERβ involved E2-induced osteoblasts proliferation and differentiation via Wnt/β-catenin signaling. The osteoblast differentiation genes (BGP, ALP and OPN) and proliferation related gene (cyclin D1) expression were significantly induced by E2-mediated ERβ. Furthermore immunofluorescence and immunoprecipitation analysis demonstrated that E2 induced the accumulation of β-catenin protein in the nucleus which leads to interaction with T-cell-specific transcription factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors. Taken together, these findings suggest that E2 promotes osteoblastic proliferation and differentiation by inducing proliferation-related and differentiation-related gene expression via ERβ/GSK-3β-dependent Wnt/β-catenin signaling pathway. Our findings provide novel insights into the mechanisms of action of E2 in osteoblastogenesis. - Highlights: • 17β-estradial (E2) promotes GSK3-β phosphorylation. • E2 activates the Wnt/β-catenin signaling pathway. • The Wnt/β-catenin signaling pathway interacts with estrogen signaling pathways. • E2-mediated ER induced osteoblast differentiation and proliferation related genes expression.

  14. ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways

    International Nuclear Information System (INIS)

    Although 17β-estradial (E2) is known to stimulate bone formation, the underlying mechanisms are not fully understood. Recent studies have implicated the Wnt/β-catenin pathway as a major signaling cascade in bone biology. The interactions between Wnt/β-catenin signaling pathway and estrogen signaling pathways have been reported in many tissues. In this study, E2 significantly increased the expression of β-catenin by inducing phosphorylations of GSK3β at serine 9. ERβ siRNAs were transfected into MC3T3-E1 cells and revealed that ERβ involved E2-induced osteoblasts proliferation and differentiation via Wnt/β-catenin signaling. The osteoblast differentiation genes (BGP, ALP and OPN) and proliferation related gene (cyclin D1) expression were significantly induced by E2-mediated ERβ. Furthermore immunofluorescence and immunoprecipitation analysis demonstrated that E2 induced the accumulation of β-catenin protein in the nucleus which leads to interaction with T-cell-specific transcription factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors. Taken together, these findings suggest that E2 promotes osteoblastic proliferation and differentiation by inducing proliferation-related and differentiation-related gene expression via ERβ/GSK-3β-dependent Wnt/β-catenin signaling pathway. Our findings provide novel insights into the mechanisms of action of E2 in osteoblastogenesis. - Highlights: • 17β-estradial (E2) promotes GSK3-β phosphorylation. • E2 activates the Wnt/β-catenin signaling pathway. • The Wnt/β-catenin signaling pathway interacts with estrogen signaling pathways. • E2-mediated ER induced osteoblast differentiation and proliferation related genes expression

  15. Using Proteomics To Elucidate Critical Signaling Pathways

    KAUST Repository

    Ahmed, Heba

    2012-11-01

    Despite important advances in the therapy of acute myeloid leukemia (AML) the majority of patients will die from their disease (Appelbaum, Rowe, Radich, & Dick, 2001). Characterization of the aberrant molecular pathways responsible for this malignancy provides a platform to discover alternative treatments to help alter the fate of patients. AML is characterized by a blockage in the differentiation of myeloid cells resulting in the accumulation of highly proliferating immature hematopoietic cells. Since treatments such as chemotherapy rarely destroy the leukemic cells entirely, differentiation induction therapy has become a very attractive treatment option. Interestingly, previous experiments have shown that ligation of CD44, a cell surface glycoprotein strongly expressed on all AML cells, with anti-CD44 monoclonal antibodies (mAbs) could reverse this block in differentiation of leukemic blasts regardless of the AML subtype. To expand the understanding of the cellular regulation and circuitry involved, we aim to apply quantitative phosphoproteomics to monitor dynamic changes in phosphorylation state in response to anti-CD44 treatment. Protein phosphorylation and dephosphorylation is a highly controlled biochemical process that responds to various intracellular and extracellular stimuli. As phosphorylation is a dynamic process, quantification of these phosphorylation events would be vastly insightful. The main objective of this project is to determine the differentiation-dependent phosphoproteome of AML cells upon treatment of cells with the anti-CD44 mAb.In these experiments, optimization of protein extraction, phosphopeptide enrichment and data processing and analysis has been achieved. The primary results show successful phosphoproteome extraction complemented with efficient phosphopeptide enrichment and informative data processing. Further quantification with stable isotope labeling techniques is anticipated to provide candidates for targeted therapy.

  16. Notch-regulated miR-223 targets the aryl hydrocarbon receptor pathway and increases cytokine production in macrophages from rheumatoid arthritis patients

    Science.gov (United States)

    Ogando, Jesús; Tardáguila, Manuel; Díaz-Alderete, Andrea; Usategui, Alicia; Miranda-Ramos, Vanessa; Martínez-Herrera, Dannys Jorge; de la Fuente, Lorena; García-León, María J.; Moreno, María C.; Escudero, Sara; Cañete, Juan D.; Toribio, María L.; Cases, Ildefonso; Pascual-Montano, Alberto; Pablos, José Luis; Mañes, Santos

    2016-01-01

    Evidence links aryl hydrocarbon receptor (AHR) activation to rheumatoid arthritis (RA) pathogenesis, although results are inconsistent. AHR agonists inhibit pro-inflammatory cytokine expression in macrophages, pivotal cells in RA aetiopathogenesis, which hints at specific circuits that regulate the AHR pathway in RA macrophages. We compared microRNA (miR) expression in CD14+ cells from patients with active RA or with osteoarthritis (OA). Seven miR were downregulated and one (miR-223) upregulated in RA compared to OA cells. miR-223 upregulation correlated with reduced Notch3 and Notch effector expression in RA patients. Overexpression of the Notch-induced repressor HEY-1 and co-culture of healthy donor monocytes with Notch ligand-expressing cells showed direct Notch-mediated downregulation of miR-223. Bioinformatics predicted the AHR regulator ARNT (AHR nuclear translocator) as a miR-223 target. Pre-miR-223 overexpression silenced ARNT 3’UTR-driven reporter expression, reduced ARNT (but not AHR) protein levels and prevented AHR/ARNT-mediated inhibition of pro-inflammatory cytokine expression. miR-223 counteracted AHR/ARNT-induced Notch3 upregulation in monocytes. Levels of ARNT and of CYP1B1, an AHR/ARNT signalling effector, were reduced in RA compared to OA synovial tissue, which correlated with miR-223 levels. Our results associate Notch signalling to miR-223 downregulation in RA macrophages, and identify miR-223 as a negative regulator of the AHR/ARNT pathway through ARNT targeting. PMID:26838552

  17. New microRNAS regulating the P53 signaling pathway

    OpenAIRE

    Bisso, Andrea

    2010-01-01

    A vast body of evidence from clinical and basic research studies has demonstrated that the p53 pathway acts as an essential barrier in preventing cancer onset and development. ------------------------ A vast body of evidence from clinical and basic research studies has demonstrated that the p53 pathway acts as an essential barrier in preventing cancer onset and development. p53 receives and integrates a wide variety of cytotoxic and genotoxic stress signals from upstream sensors transla...

  18. Bone biology, signaling pathways, and therapeutic targets for osteoporosis.

    Science.gov (United States)

    Iñiguez-Ariza, Nicole M; Clarke, Bart L

    2015-10-01

    Major advances have occurred recently in the treatment of osteoporosis in recent years. Most patients are currently treated with bisphosphonates, denosumab, raloxifene, or teriparatide, and in some countries, strontium ranelate. Strontium ranelate and calcitonin have recently had their use restricted due to cardiovascular concerns and malignancy, respectively. The available agents have generally provided excellent options that effectively reduce fracture risk. New targets are being sought based on appreciation of the bone biology and signaling pathways involved in bone formation and resorption. These agents will directly target these signaling pathways, and further expand the options available for treatment of osteoporosis. PMID:26255682

  19. POSTRANSLATIONAL MODIFICATIONS OF P53: UPSTREAM SIGNALING PATHWAYS.

    Energy Technology Data Exchange (ETDEWEB)

    ANDERSON,C.W.APPELLA,E.

    2003-10-23

    The p53 tumor suppressor is a tetrameric transcription factor that is posttranslational modified at >20 different sites by phosphorylation, acetylation, or sumoylation in response to various cellular stress conditions. Specific posttranslational modifications, or groups of modifications, that result from the activation of different stress-induced signaling pathways are thought to modulate p53 activity to regulate cell fate by inducing cell cycle arrest, apoptosis, or cellular senescence. Here we review recent progress in characterizing the upstream signaling pathways whose activation in response to various genotoxic and non-genotoxic stresses result in p53 posttranslational modifications.

  20. A network map of Interleukin-10 signaling pathway.

    Science.gov (United States)

    Verma, Renu; Balakrishnan, Lavanya; Sharma, Kusum; Khan, Aafaque Ahmad; Advani, Jayshree; Gowda, Harsha; Tripathy, Srikanth Prasad; Suar, Mrutyunjay; Pandey, Akhilesh; Gandotra, Sheetal; Prasad, T S Keshava; Shankar, Subramanian

    2016-03-01

    Interleukin-10 (IL-10) is an anti-inflammatory cytokine with important immunoregulatory functions. It is primarily secreted by antigen-presenting cells such as activated T-cells, monocytes, B-cells and macrophages. In biologically functional form, it exists as a homodimer that binds to tetrameric heterodimer IL-10 receptor and induces downstream signaling. IL-10 is associated with survival, proliferation and anti-apoptotic activities of various cancers such as Burkitt lymphoma, non-Hodgkins lymphoma and non-small scell lung cancer. In addition, it plays a central role in survival and persistence of intracellular pathogens such as Leishmania donovani, Mycobacterium tuberculosis and Trypanosoma cruzi inside the host. The signaling mechanisms of IL-10 cytokine are not well explored and a well annotated pathway map has been lacking. To this end, we developed a pathway resource by manually annotating the IL-10 induced signaling molecules derived from literature. The reactions were categorized under molecular associations, activation/inhibition, catalysis, transport and gene regulation. In all, 37 molecules and 76 reactions were annotated. The IL-10 signaling pathway can be freely accessed through NetPath, a resource of signal transduction pathways previously developed by our group. PMID:26253919

  1. Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Daniel L. Suzman

    2015-09-01

    Full Text Available Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer.

  2. Phylogenetic diversity of stress signalling pathways in fungi

    Directory of Open Access Journals (Sweden)

    Stansfield Ian

    2009-02-01

    Full Text Available Abstract Background Microbes must sense environmental stresses, transduce these signals and mount protective responses to survive in hostile environments. In this study we have tested the hypothesis that fungal stress signalling pathways have evolved rapidly in a niche-specific fashion that is independent of phylogeny. To test this hypothesis we have compared the conservation of stress signalling molecules in diverse fungal species with their stress resistance. These fungi, which include ascomycetes, basidiomycetes and microsporidia, occupy highly divergent niches from saline environments to plant or mammalian hosts. Results The fungi displayed significant variation in their resistance to osmotic (NaCl and sorbitol, oxidative (H2O2 and menadione and cell wall stresses (Calcofluor White and Congo Red. There was no strict correlation between fungal phylogeny and stress resistance. Rather, the human pathogens tended to be more resistant to all three types of stress, an exception being the sensitivity of Candida albicans to the cell wall stress, Calcofluor White. In contrast, the plant pathogens were relatively sensitive to oxidative stress. The degree of conservation of osmotic, oxidative and cell wall stress signalling pathways amongst the eighteen fungal species was examined. Putative orthologues of functionally defined signalling components in Saccharomyces cerevisiae were identified by performing reciprocal BLASTP searches, and the percent amino acid identities of these orthologues recorded. This revealed that in general, central components of the osmotic, oxidative and cell wall stress signalling pathways are relatively well conserved, whereas the sensors lying upstream and transcriptional regulators lying downstream of these modules have diverged significantly. There was no obvious correlation between the degree of conservation of stress signalling pathways and the resistance of a particular fungus to the corresponding stress. Conclusion Our

  3. Metabolic pathway engineering using the central signal processor PII

    OpenAIRE

    Watzer, Björn; Engelbrecht, Alicia; Hauf, Waldemar; Stahl, Mark; Maldener, Iris; Forchhammer, Karl

    2015-01-01

    Background PII signal processor proteins are wide spread in prokaryotes and plants where they control a multitude of anabolic reactions. Efficient overproduction of metabolites requires relaxing the tight cellular control circuits. Here we demonstrate that a single point mutation in the PII signaling protein from the cyanobacterium Synechocystis sp. PCC 6803 is sufficient to unlock the arginine pathway causing over accumulation of the biopolymer cyanophycin (multi-l-arginyl-poly-l-aspartate)....

  4. Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Vorrink, Sabine U. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Severson, Paul L. [Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ (United States); Kulak, Mikhail V. [Department of Surgery, The University of Iowa, Iowa City, IA (United States); Futscher, Bernard W. [Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ (United States); Domann, Frederick E., E-mail: frederick-domann@uiowa.edu [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Department of Surgery, The University of Iowa, Iowa City, IA (United States)

    2014-02-01

    The aryl hydrocarbon receptor (AhR) is an important mediator of toxic responses after exposure to xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like polychlorinated biphenyls (PCBs). Activation of AhR responsive genes requires AhR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner also shared by the hypoxia-inducible factor-1α (HIF-1α) protein. TCDD-stimulated AhR transcriptional activity can be influenced by hypoxia; however, it less well known whether hypoxia interferes with AhR transcriptional transactivation in the context of PCB-mediated AhR activation in human cells. Elucidation of this interaction is important in liver hepatocytes which extensively metabolize ingested PCBs and experience varying degrees of oxygen tension during normal physiologic function. This study was designed to assess the effect of hypoxia on AhR transcriptional responses after exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Exposure to 1% O{sub 2} prior to PCB 126 treatment significantly inhibited CYP1A1 mRNA and protein expression in human HepG2 and HaCaT cells. CYP1A1 transcriptional activation was significantly decreased upon PCB 126 stimulation under conditions of hypoxia. Additionally, hypoxia pre-treatment reduced PCB 126 induced AhR binding to CYP1 target gene promoters. Importantly, ARNT overexpression rescued cells from the inhibitory effect of hypoxia on XRE-luciferase reporter activity. Therefore, the mechanism of interference of the signaling crosstalk between the AhR and hypoxia pathways appears to be at least in part dependent on ARNT availability. Our results show that AhR activation and CYP1A1 expression induced by PCB 126 were significantly inhibited by hypoxia and hypoxia might therefore play an important role in PCB metabolism and toxicity. - Highlights: • Significant crosstalk exists between AhR and HIF-1α signaling. • Hypoxia perturbs PCB 126 induced AhR function and

  5. Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines

    International Nuclear Information System (INIS)

    The aryl hydrocarbon receptor (AhR) is an important mediator of toxic responses after exposure to xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like polychlorinated biphenyls (PCBs). Activation of AhR responsive genes requires AhR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner also shared by the hypoxia-inducible factor-1α (HIF-1α) protein. TCDD-stimulated AhR transcriptional activity can be influenced by hypoxia; however, it less well known whether hypoxia interferes with AhR transcriptional transactivation in the context of PCB-mediated AhR activation in human cells. Elucidation of this interaction is important in liver hepatocytes which extensively metabolize ingested PCBs and experience varying degrees of oxygen tension during normal physiologic function. This study was designed to assess the effect of hypoxia on AhR transcriptional responses after exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Exposure to 1% O2 prior to PCB 126 treatment significantly inhibited CYP1A1 mRNA and protein expression in human HepG2 and HaCaT cells. CYP1A1 transcriptional activation was significantly decreased upon PCB 126 stimulation under conditions of hypoxia. Additionally, hypoxia pre-treatment reduced PCB 126 induced AhR binding to CYP1 target gene promoters. Importantly, ARNT overexpression rescued cells from the inhibitory effect of hypoxia on XRE-luciferase reporter activity. Therefore, the mechanism of interference of the signaling crosstalk between the AhR and hypoxia pathways appears to be at least in part dependent on ARNT availability. Our results show that AhR activation and CYP1A1 expression induced by PCB 126 were significantly inhibited by hypoxia and hypoxia might therefore play an important role in PCB metabolism and toxicity. - Highlights: • Significant crosstalk exists between AhR and HIF-1α signaling. • Hypoxia perturbs PCB 126 induced AhR function and target

  6. YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Yi-Ting; Ding, Jing-Ya [Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Li, Ming-Yang [Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan (China); Yeh, Tien-Shun [Department of Anatomy and Cell Biology, National Yang-Ming University, Taipei 112, Taiwan (China); Wang, Tsu-Wei, E-mail: twwang@ntnu.edu.tw [Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan (China); Yu, Jenn-Yah, E-mail: jyyu@ym.edu.tw [Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan (China)

    2012-09-10

    Tight regulation of cell numbers by controlling cell proliferation and apoptosis is important during development. Recently, the Hippo pathway has been shown to regulate tissue growth and organ size in Drosophila. In mammalian cells, it also affects cell proliferation and differentiation in various tissues, including the nervous system. Interplay of several signaling cascades, such as Notch, Wnt, and Sonic Hedgehog (Shh) pathways, control cell proliferation during neuronal differentiation. However, it remains unclear whether the Hippo pathway coordinates with other signaling cascades in regulating neuronal differentiation. Here, we used P19 cells, a mouse embryonic carcinoma cell line, as a model to study roles of YAP, a core component of the Hippo pathway, in neuronal differentiation. P19 cells can be induced to differentiate into neurons by expressing a neural bHLH transcription factor gene Ascl1. Our results showed that YAP promoted cell proliferation and inhibited neuronal differentiation. Expression of Yap activated Shh but not Wnt or Notch signaling activity during neuronal differentiation. Furthermore, expression of Yap increased the expression of Patched homolog 1 (Ptch1), a downstream target of the Shh signaling. Knockdown of Gli2, a transcription factor of the Shh pathway, promoted neuronal differentiation even when Yap was over-expressed. We further demonstrated that over-expression of Yap inhibited neuronal differentiation in primary mouse cortical progenitors and Gli2 knockdown rescued the differentiation defect in Yap over-expressing cells. In conclusion, our study reveals that Shh signaling acts downstream of YAP in regulating neuronal differentiation. -- Highlights: Black-Right-Pointing-Pointer YAP promotes cell proliferation and inhibits neuronal differentiation in P19 cells. Black-Right-Pointing-Pointer YAP promotes Sonic hedgehog signaling activity during neuronal differentiation. Black-Right-Pointing-Pointer Knockdown of Gli2 rescues the Yap

  7. DMPD: Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 12213596 Multiple signaling pathways leading to the activation of interferon regulatoryfactor...(.html) (.csml) Show Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3.... PubmedID 12213596 Title Multiple signaling pathways leading to the activation of... interferon regulatoryfactor 3. Authors Servant MJ, Grandvaux N, Hiscott J. Publication Biochem Pharmacol. 2

  8. Ah Receptor Signaling Controls the Expression of Cardiac Development and Homeostasis Genes.

    Science.gov (United States)

    Carreira, Vinicius S; Fan, Yunxia; Wang, Qing; Zhang, Xiang; Kurita, Hisaka; Ko, Chia-I; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

    2015-10-01

    Congenital heart disease (CHD) is the most common congenital abnormality and one of the leading causes of newborn death throughout the world. Despite much emerging scientific information, the precise etiology of this disease remains elusive. Here, we show that the aryl hydrocarbon receptor (AHR) regulates the expression of crucial cardiogenesis genes and that interference with endogenous AHR functions, either by gene ablation or by agonist exposure during early development, causes overlapping structural and functional cardiac abnormalities that lead to altered fetal heart physiology, including higher heart rates, right and left ventricle dilation, higher stroke volume, and reduced ejection fraction. With striking similarity between AHR knockout (Ahr(-/-)) and agonist-exposed wild type (Ahr(+/+)) embryos, in utero disruption of endogenous AHR functions converge into dysregulation of molecular mechanisms needed for attainment and maintenance of cardiac differentiation, including the pivotal signals regulated by the cardiogenic transcription factor NKH2.5, energy balance via oxidative phosphorylation and TCA cycle and global mitochondrial function and homeostasis. Our findings suggest that AHR signaling in the developing mammalian heart is central to the regulation of pathways crucial for cellular metabolism, cardiogenesis, and cardiac function, which are potential targets of environmental factors associated with CHD. PMID:26139165

  9. Signaling transduction pathways involved in basophil adhesion and histamine release

    DEFF Research Database (Denmark)

    Sha, Quan; Poulsen, Lars K.; Gerwien, Jens; Ødum, Niels; Skov, Per Stahl

    2006-01-01

    Little is known about basophil with respect to the different signaling transduction pathways involved in spontaneous, cytokine or anti-IgE induced adhesion and how this compares to IgE-dependent and IgE-independent mediator secretion. The purpose of the present study was to investigate the roles ...

  10. Hedgehog signaling pathway in small bovine ovarian follicles

    Science.gov (United States)

    The hedgehog signaling pathway is involved in the regulation of cell proliferation, differentiation, and turnover in a variety of mammalian embryonic and adult tissues including bovine ovarian granulosa and theca cells. Binding of hedgehog to the patch receptor derepresses smoothened resulting in t...

  11. Beyond microarrays: Finding key transcription factors controlling signal transduction pathways

    Science.gov (United States)

    Kel, Alexdander; Voss, Nico; Jauregui, Ruy; Kel-Margoulis, Olga; Wingender, Edgar

    2006-01-01

    Background Massive gene expression changes in different cellular states measured by microarrays, in fact, reflect just an "echo" of real molecular processes in the cells. Transcription factors constitute a class of the regulatory molecules that typically require posttranscriptional modifications or ligand binding in order to exert their function. Therefore, such important functional changes of transcription factors are not directly visible in the microarray experiments. Results We developed a novel approach to find key transcription factors that may explain concerted expression changes of specific components of the signal transduction network. The approach aims at revealing evidence of positive feedback loops in the signal transduction circuits through activation of pathway-specific transcription factors. We demonstrate that promoters of genes encoding components of many known signal transduction pathways are enriched by binding sites of those transcription factors that are endpoints of the considered pathways. Application of the approach to the microarray gene expression data on TNF-alpha stimulated primary human endothelial cells helped to reveal novel key transcription factors potentially involved in the regulation of the signal transduction pathways of the cells. Conclusion We developed a novel computational approach for revealing key transcription factors by knowledge-based analysis of gene expression data with the help of databases on gene regulatory networks (TRANSFAC® and TRANSPATH®). The corresponding software and databases are available at . PMID:17118134

  12. Quantitative phosphoproteomics applied to the yeast pheromone signaling pathway

    DEFF Research Database (Denmark)

    Gruhler, Albrecht; Olsen, Jesper Velgaard; Mohammed, Shabaz;

    2005-01-01

    /MS/MS) for identification. This integrated phosphoproteomic technology identified and quantified phosphorylation in key regulator and effector proteins of a prototypical G-protein-coupled receptor signaling pathway, the yeast pheromone response. SILAC encoding of yeast proteomes was achieved by incorporation...

  13. Targeting glioma stem cells via the Hedgehog signaling pathway

    Directory of Open Access Journals (Sweden)

    Yang Liu

    2014-09-01

    Full Text Available Cancer is one of the leading causes of death worldwide. Gliomas are among the most devastating tumor types, and current clinical therapies are unsatisfactory. Recent reports revealed the importance of glioma-propagating cells in the malignancy of gliomas. These cells, also referred to as glioma stem cells (GSCs, share similarities with neural stem cells (NSCs. The Hedgehog (Hh signaling pathway controls tissue polarity, patterning maintenance, and maintenance of NSCs during embryonic development. Aberrant activation of the Hh pathway resulting from mutation and deregulation has recently been recognized to cause tumorigenesis in a wide variety of tissues, including gliomas and GSCs. In this review, we explore the role of the Hh signaling pathway in GSCs and its potential as a therapeutic strategy.

  14. Integration of Shh and Wnt Signaling Pathways Regulating Hematopoiesis.

    Science.gov (United States)

    Zhou, Zhigang; Wan, Liping; Wang, Chun; Zhou, Kun

    2015-12-01

    To investigate the spatial and temporal programmed expression of Shh and Wnt members during key stages of definitive hematopoiesis and the possible mechanism of Shh and Wnt signaling pathways regulating the proliferation of hematopoietic progenitor cells (HPCs). Spatial and temporal programmed gene expression of Shh and Wnt signaling during hematopoiesis corresponded with c-kit(+)lin(-) HPCs proliferation. C-kit(+)Lin(-) populations derived from aorta-gonad-mesonephros (AGM) of Balb/c mice at E10.5 with increased expression of Shh and Wnt3a demonstrated a greater potential for proliferation. Additionally, supplementation with soluble Shh N-terminal peptide promoted the proliferation of c-kit(+)Lin(-) populations by activating the Wnt signaling pathway, an effect which was inhibited by blocking Shh signaling. A specific inhibitor of wnt signaling was capable of inhibiting Shh-induced proliferation in a similar manner to shh inhibitor. Our results provide valuable information on Shh and Wnt signaling involved in hematopoiesis and highlight the importance of interaction of Shh and Wnt signaling in regulating HPCs proliferation. PMID:26378473

  15. Current perspectives of the signaling pathways directing neural crest induction.

    Science.gov (United States)

    Stuhlmiller, Timothy J; García-Castro, Martín I

    2012-11-01

    The neural crest is a migratory population of embryonic cells with a tremendous potential to differentiate and contribute to nearly every organ system in the adult body. Over the past two decades, an incredible amount of research has given us a reasonable understanding of how these cells are generated. Neural crest induction involves the combinatorial input of multiple signaling pathways and transcription factors, and is thought to occur in two phases from gastrulation to neurulation. In the first phase, FGF and Wnt signaling induce NC progenitors at the border of the neural plate, activating the expression of members of the Msx, Pax, and Zic families, among others. In the second phase, BMP, Wnt, and Notch signaling maintain these progenitors and bring about the expression of definitive NC markers including Snail2, FoxD3, and Sox9/10. In recent years, additional signaling molecules and modulators of these pathways have been uncovered, creating an increasingly complex regulatory network. In this work, we provide a comprehensive review of the major signaling pathways that participate in neural crest induction, with a focus on recent developments and current perspectives. We provide a simplified model of early neural crest development and stress similarities and differences between four major model organisms: Xenopus, chick, zebrafish, and mouse. PMID:22547091

  16. Asymptotic Analysis of the Wnt/β Signaling Pathway

    International Nuclear Information System (INIS)

    The Wnt/β-catenin pathway is a signal transduction pathway made of proteins, which plays an important role in oncogenesis. Ethan Lee and and co-workers introduced in 2003 a detailed mathematical model of this pathway, incorporating the kinetics of protein-protein interactions, protein synthesis/degradation and phosphorylation/dephosphorylation. The fast/slow dynamics of Lee's system are examined here, by employing the Computational Singular Perturbation (CSP) algorithm. CSP reproduces the results of the classical singular perturbation analysis in an algorithmic fashion, producing an approximation of (i) the low dimensional Slow Invariant Manifold (SIM), where the solution evolves and (ii) the reduced model that governs the flow there. The temporal variation of the dimensions of the SIM will be presented and the components of the pathway that are responsible (i) for the generation of the SIM and (ii) for driving the system on it will be identified

  17. A novel role of the aryl hydrocarbon receptor (AhR in centrosome amplification - implications for chemoprevention

    Directory of Open Access Journals (Sweden)

    Chatterjee Payel

    2010-06-01

    Full Text Available Abstract Background Centrosome aberrations can cause genomic instability and correlate with malignant progression in common human malignancies such as breast and prostate cancer. Deregulation of cyclin/cyclin-dependent kinase 2 (CDK2 activity has previously been shown to be critically involved in centrosome overduplication. We therefore test here whether small molecule CDK inhibitors derived from the bis-indole indirubin can be used to suppress centrosome aberrations as a novel approach to chemoprevention of malignant progression. Results As expected, we found that the CDK inhibitor indirubin-3'-oxime (IO suppresses centrosome amplification in breast cancer cells. However, we made the unexpected discovery that indirubin-derived compounds that have been chemically modified to be inactive as kinase inhibitors such as 1-methyl-indirubin-3'-oxime (MeIO still significantly reduced centrosome amplification. All indirubins used in the present study are potent agonists of the aryl hydrocarbon receptor (AhR, which is known for its important role in the cellular metabolism of xenobiotics. To corroborate our results, we first show that the coincidence of nuclear AhR overexpression, reflecting a constitutive activation, and numerical centrosome aberrations correlates significantly with malignancy in mammary tissue specimens. Remarkably, a considerable proportion (72.7% of benign mammary tissue samples scored also positive for nuclear AhR overexpression. We furthermore provide evidence that continued expression of endogenous AhR is critical to promote centriole overduplication induced by cyclin E and that AhR and cyclin E may function in the same pathway. Overexpression of the AhR in the absence of exogenous ligands was found to rapidly disrupt centriole duplication control. Nonetheless, the AhR agonists IO and MeIO were still found to significantly reduce centriole overduplication stimulated by ectopic AhR expression. Conclusions Our results indicate that

  18. Cellular-signaling pathways unveil the carcinogenic potential of chemicals.

    Science.gov (United States)

    Hendriks, Giel; van de Water, Bob; Schoonen, Willem; Vrieling, Harry

    2013-06-01

    Most of the current in vitro carcinogenicity assays assess the potential carcinogenic properties of chemicals through the detection of inflicted DNA damage or subsequent chromosome damage and gene mutations. Unfortunately, these assays generally do not provide mechanistic insight into the reactive properties of a chemical. Upon chemical-induced damage of biomolecules, molecular sensors will activate general and damage-specific cellular response pathways that provide protection against the (geno)toxic and potential carcinogenic properties of chemicals. These cellular defense mechanisms include activation of cell-cycle checkpoints, DNA repair systems and induction of apoptosis or necrosis. Visualization of activated cellular-signaling pathways forms a powerful means to readily detect the genotoxic potential of chemical compounds and simultaneously gain insight into their reactive properties. Over the past years, various in vitro reporter assays have been developed that monitor activation of general and more specific cellular-signaling pathways, including the GreenScreen HC and ToxTracker assays. In this review we provide a perspective on how we can exploit activation of cellular signaling pathways to shed light on the mode of action of the chemical exposure and to develop sophisticated mechanism-based in vitro assays for cancer risk assessment. PMID:23339022

  19. Inflammation-and stress-related signaling pathways in hepatocarcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Hayato Nakagawa; Shin Maeda

    2012-01-01

    It has been established that cancer can be promoted and exacerbated by inflammation.Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide,and its long-term prognosis remains poor.Although HCC is a complex and heterogeneous tumor with several genomic mutations,it usually develops in the context of chronic liver damage and inflammation,suggesting that understanding the mechanism(s) of inflammation-mediated hepatocarcinogenesis is essential for the treatment and prevention of HCC.Chronic liver damage induces a persistent cycle of necroinflammation and hepatocyte regeneration,resulting in genetic mutations in hepatocytes and expansion of initiated cells,eventually leading to HCC development.Recently,several inflammation-and stress-related signaling pathways have been identified as key players in these processes,which include the nuclear factorκB,signal transducer and activator of transcription,and stress-activated mitogen-activated protein kinase pathways.Although these pathways may suggest potential therapeutic targets,they have a wide range of functions and complex crosstalk occurs among them.This review focuses on recent advances in our understanding of the roles of these signaling pathways in hepatocarcinogenesis.

  20. Activation of the Canonical Wnt Signaling Pathway Induces Cementum Regeneration.

    Science.gov (United States)

    Han, Pingping; Ivanovski, Saso; Crawford, Ross; Xiao, Yin

    2015-07-01

    Canonical Wnt signaling is important in tooth development but it is unclear whether it can induce cementogenesis and promote the regeneration of periodontal tissues lost because of disease. Therefore, the aim of this study is to investigate the influence of canonical Wnt signaling enhancers on human periodontal ligament cell (hPDLCs) cementogenic differentiation in vitro and cementum repair in a rat periodontal defect model. Canonical Wnt signaling was induced by (1) local injection of lithium chloride; (2) local injection of sclerostin antibody; and (3) local injection of a lentiviral construct overexpressing β-catenin. The results showed that the local activation of canonical Wnt signaling resulted in significant new cellular cementum deposition and the formation of well-organized periodontal ligament fibers, which was absent in the control group. In vitro experiments using hPDLCs showed that the Wnt signaling pathway activators significantly increased mineralization, alkaline phosphatase (ALP) activity, and gene and protein expression of the bone and cementum markers osteocalcin (OCN), osteopontin (OPN), cementum protein 1 (CEMP1), and cementum attachment protein (CAP). Our results show that the activation of the canonical Wnt signaling pathway can induce in vivo cementum regeneration and in vitro cementogenic differentiation of hPDLCs. PMID:25556853

  1. The mTOR Signalling Pathway in Human Cancer

    Directory of Open Access Journals (Sweden)

    Paula Soares

    2012-02-01

    Full Text Available The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin, a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.

  2. Targeting of proangiogenic signalling pathways in chronic inflammation.

    Science.gov (United States)

    Tas, Sander W; Maracle, Chrissta X; Balogh, Emese; Szekanecz, Zoltán

    2016-02-01

    Angiogenesis is de novo capillary outgrowth from pre-existing blood vessels. This process not only is crucial for normal development, but also has an important role in supplying oxygen and nutrients to inflamed tissues, as well as in facilitating the migration of inflammatory cells to the synovium in rheumatoid arthritis, spondyloarthritis and other systemic autoimmune diseases. Neovascularization is dependent on the balance of proangiogenic and antiangiogenic mediators, including growth factors, cytokines, chemokines, cell adhesion molecules and matrix metalloproteinases. This Review describes the various intracellular signalling pathways that govern these angiogenic processes and discusses potential approaches to interfere with pathological angiogenesis, and thereby ameliorate inflammatory disease, by targeting these pathways. PMID:26633288

  3. Amnesic shellfish poisoning toxin stimulates the transcription of CYP1A possibly through AHR and ARNT in the liver of red sea bream Pagrus major

    International Nuclear Information System (INIS)

    To investigate the role of detoxification-related liver genes in amnesic shellfish poisoning toxin metabolism, red sea bream Pagrus major were exposed to domoic acid (DA, 2 μg g-1 wet weight) for 24 h. Hepatic mRNA expression levels of AHR, ARNT, CYP1 and GSTs were determined by semi-quantitative RT-PCR. The cytosolic factors aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) mRNA levels of DA exposure group were substantially enhanced by 113.3% and 90.9%, respectively. Consistent with this result, the phase I xenobiotic metabolizing enzyme (XME) cytochrome P-450 1A (CYP1A) was significantly induced. In contrast, the transcriptions of three major phase II XME glutathione S-transferases as well as heat shock protein 70 were not significantly affected by DA exposure. These results suggest a possible role of CYP1A after DA exposure in the toxin metabolism of marine fish, possibly through the AHR/ARNT signaling pathway.

  4. Expression pattern of the Hedgehog signaling pathway in pituitary adenomas.

    Science.gov (United States)

    Yavropoulou, Maria P; Maladaki, Anna; Topouridou, Konstantina; Kotoula, Vasiliki; Poulios, Chris; Daskalaki, Emily; Foroglou, Nikolaos; Karkavelas, George; Yovos, John G

    2016-01-12

    Several studies have demonstrated the role of Wnt and Notch signaling in the pathogenesis of pituitary adenomas, but data are scarce regarding the role of Hedgehog signaling. In this study we investigated the differential expression of gene targets of the Hedgehog signaling pathway. Formalin-fixed, paraffin-embedded specimens from adult patients who underwent transphenoidal resection and normal human pituitary tissues that were obtained from autopsies were used. Clinical information and data from pre-operative MRI scan (extracellular tumor extension, tumor size, displacement of the optic chiasm) were retrieved from the Hospital's database. We used a customized RT(2) Profiler PCR Array, to investigate the expression of genes related to Notch and Hedgehog signaling pathways (PTCH1, PTCH2, GLI1, GLI3, NOTCH3, JAG1, HES1, and HIP). A total of 52 pituitary adenomas (32 non-functioning adenomas, 15 somatotropinomas and 5 prolactinomas) were used in the final analysis. In non-functioning pituitary adenomas there was a significant decrease (approximately 75%) in expression of all Hedgehog related genes that were tested, while Notch3 and Jagged-1 expression was found significantly increased, compared with normal pituitary tissue controls. In contrast, somatotropinomas demonstrated a significant increase in expression of all Hedgehog related genes and a decrease in the expression of Notch3 and Jagged-1. There was no significant difference in the expression of Hedgehog and Notch related genes between prolactinomas and healthy pituitary tissues. Hedgehog signalling appears to be activated in somatotropinomas but not in non-functioning pituitary adenomas in contrast to the expression pattern of Notch signalling pathway. PMID:26620835

  5. Parameter sensitivity analysis of IL-6 signalling pathways.

    Science.gov (United States)

    Chu, Y; Jayaraman, A; Hahn, J

    2007-11-01

    Signal transduction pathways generally consist of a large number of individual components and have an even greater number of parameters describing their reaction kinetics. Although the structure of some signalling pathways can be found in the literature, many of the parameters are not well known and they would need to be re-estimated from experimental data for each specific case. However it is not feasible to estimate hundreds of parameters because of the cost of the experiments associated with generating data. Parameter sensitivity analysis can address this situation as it investigates how the system behaviour is changed by variations of parameters and the analysis identifies which parameters play a key role in signal transduction. Only these important parameters need then be re-estimated using data from further experiments. This article presents a detailed parameter sensitivity analysis of the JAK/STAT and MAPK signal transduction pathway that is used for signalling by the cytokine IL-6. As no parameter sensitivity analysis technique is known to work best for all situations, a comparison of the results returned by four techniques is presented: differential analysis, the Morris method, a sampling-based approach and the Fourier amplitude sensitivity test. The recruitment of the transcription factor STAT3 to the dimer of the phosphorylated receptor complex is determined as the most important step by the sensitivity analysis. Additionally, the desphosphorylation of the nuclear STAT3 dimer by PP2 as well as feedback inhibition by SOCS3 are found to play an important role for signal transduction. PMID:18203580

  6. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

    International Nuclear Information System (INIS)

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (− 105/+ 1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. - Highlights: • TCDD induced Fgf21 expression at both mRNA and protein levels. • Fgf21 induction by TCDD is AhR-dependent. • DEHP attenuated TCDD-induced Fgf21 expression

  7. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Xingguo, E-mail: chengx@stjohns.edu [Department of Pharmaceutical Sciences, St. John' s University, 8000 Utopia Parkway, Queens, NY 11439 (United States); Vispute, Saurabh G. [Department of Pharmaceutical Sciences, St. John' s University, 8000 Utopia Parkway, Queens, NY 11439 (United States); Liu, Jie [Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States); Cheng, Christine; Kharitonenkov, Alexei [Lilly Research Laboratories, Division of Eli Lilly and Co., Indianapolis, IN 46285 (United States); Klaassen, Curtis D., E-mail: curtisklaassenphd@gmail.com [Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States)

    2014-07-01

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (− 105/+ 1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. - Highlights: • TCDD induced Fgf21 expression at both mRNA and protein levels. • Fgf21 induction by TCDD is AhR-dependent. • DEHP attenuated TCDD-induced Fgf21 expression.

  8. Shared signaling pathways in normal and breast cancer stem cells

    Directory of Open Access Journals (Sweden)

    Gautam K Malhotra

    2011-01-01

    Full Text Available Recent advances in our understanding of breast cancer biology have led to the identification of a subpopulation of cells within tumors that appear to be responsible for initiating and propagating the cancer. These tumor initiating cells are not only unique in their ability to generate tumors, but also share many similarities with elements of normal adult tissue stem cells, and have therefore been termed cancer stem cells (CSCs. These CSCs often inappropriately use many of the same signaling pathways utilized by their normal stem cell counterparts which may present a challenge to the development of CSC specific therapies. Here, we discuss three major stem cell signaling pathways (Notch, Wnt, and Hedgehog; with a focus on their function in normal mammary gland development and their misuse in breast cancer stem cell fate determination.

  9. Leptin signaling: A key pathway in immune responses

    OpenAIRE

    Procaccini, Claudio; Lourenco, Elaine V.; Matarese, Giuseppe; La Cava, Antonio

    2009-01-01

    Leptin is a hormone whose central role is to regulate endocrine functions and to control energy expenditure. After the discovery that leptin can also have pro-inflammatory effects, several studies have tried to address - at the molecular level - the pathways involved in leptin-induced modulation of the immune functions in normal and pathologic conditions. The signaling events influenced by leptin after its binding to the leptin receptor have been under scrutiny in the past few years, and cons...

  10. Therapeutic Targeting of Signaling Pathways in Muscular Dystrophy

    OpenAIRE

    Bhatnagar, Shephali; Kumar, Ashok

    2009-01-01

    Muscular dystrophy refers to a group of genetic diseases that cause severe muscle weakness and loss of skeletal muscle mass. Although research has helped understanding the molecular basis of muscular dystrophy, there is still no cure for this devastating disorder. Numerous lines of investigation suggest that the primary deficiency of specific proteins causes aberrant activation of several cell signaling pathways in skeletal and cardiac muscle leading to the pathogenesis of muscular dystrophy....

  11. Current perspectives of the signaling pathways directing neural crest induction

    OpenAIRE

    Stuhlmiller, Timothy J.; García-Castro, Martín I.

    2012-01-01

    The neural crest is a migratory population of embryonic cells with a tremendous potential to differentiate and contribute to nearly every organ system in the adult body. Over the past two decades, an incredible amount of research has given us a reasonable understanding of how these cells are generated. Neural crest induction involves the combinatorial input of multiple signaling pathways and transcription factors, and is thought to occur in two phases from gastrulation to neurulation. In the ...

  12. Parameter inference and model selection in signaling pathway models

    OpenAIRE

    Toni, Tina; Stumpf, Michael P. H.

    2009-01-01

    To support and guide an extensive experimental research into systems biology of signaling pathways, increasingly more mechanistic models are being developed with hopes of gaining further insight into biological processes. In order to analyse these models, computational and statistical techniques are needed to estimate the unknown kinetic parameters. This chapter reviews methods from frequentist and Bayesian statistics for estimation of parameters and for choosing which model is best for model...

  13. Intrinsic and extrinsic pathway signaling during neuronal apoptosis

    OpenAIRE

    Putcha, Girish V.; Harris, Charles A; Moulder, Krista L.; Easton, Rachael M.; Thompson, Craig B.; Johnson, Eugene M.

    2002-01-01

    Trophic factor deprivation (TFD)-induced apoptosis in sympathetic neurons requires macromolecular synthesis–dependent BAX translocation, cytochrome c (cyt c) release, and caspase activation. Here, we report the contributions of other intrinsic and extrinsic pathway signals to these processes. Sympathetic neurons expressed all antiapoptotic BCL-2 proteins examined, yet expressed only certain BH3-only and multidomain proapoptotic BCL-2 family members. All coexpressed proapoptotic proteins did n...

  14. Mapping Complex Networks: Exploring Boolean Modeling of Signal Transduction Pathways

    OpenAIRE

    Bhardwaj, Gaurav; Wells, Christine P.; Albert, Reka; van Rossum, Damian B.; Patterson, Randen L

    2009-01-01

    In this study, we explored the utility of a descriptive and predictive bionetwork model for phospholipase C-coupled calcium signaling pathways, built with non-kinetic experimental information. Boolean models generated from these data yield oscillatory activity patterns for both the endoplasmic reticulum resident inositol-1,4,5-trisphosphate receptor (IP3R) and the plasma-membrane resident canonical transient receptor potential channel 3 (TRPC3). These results are specific as randomization of ...

  15. Regulation of mRNA Translation by Signaling Pathways

    OpenAIRE

    Roux, Philippe P.; Topisirovic, Ivan

    2012-01-01

    mRNA translation is the most energy consuming process in the cell. In addition, it plays a pivotal role in the control of gene expression and is therefore tightly regulated. In response to various extracellular stimuli and intracellular cues, signaling pathways induce quantitative and qualitative changes in mRNA translation by modulating the phosphorylation status and thus the activity of components of the translational machinery. In this work we focus on the phosphoinositide 3-kinase (PI3K)/...

  16. [Sonic Hedgehog signaling pathway and regulation of inner ear development].

    Science.gov (United States)

    Chen, Zhi-Qiang; Han, Xin-Huan; Cao, Xin

    2013-09-01

    During inner ear development, Sonic Hedgehog (Shh) signaling pathway is involved in the ventral otic identity, cell fate determination of statoacoustic ganglion neurons and hair cell development. Shh protein, secreted from floor plate, antagonizes Wnt protein from roof plate, which refines and maintains dorsoventral axial patterning in the ear. Shh, served as a mitogen during neurogenesis, directly promotes the development of spiral ganglion neuron. After Shh signaling pathway is activated, Ngn1 is freed from Tbx1 repression. As a result, Shh indirectly upregulates the expression of Ngn1, thus regulating neurogenic patterning of inner ear. In addition, Shh regulates the differentiation of hair cells by influencing cell cycle of the progenitor cells located in the cochlea. The basal-to-apical wave of Shh decline ensures the normal devel- opment pattern of hair cells. It is confirmed by a quantity of researches conducted in both animals and patients with hereditary hearing impairment that abnormal Shh signaling results in aberrant transcription of target genes, disturbance of the proper development of inner ear, and human hearing impairment. In humans, diseases accompanied by hearing disorders caused by abnormal Shh signaling include Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS), Waardenburg syndrome (WS) and medulloblastoma, etc. This review would provide a theoretical basis for further study of molecular mechanisms and clinical use of inner ear development. PMID:24400478

  17. Muscle redox signalling pathways in exercise. Role of antioxidants.

    Science.gov (United States)

    Mason, Shaun A; Morrison, Dale; McConell, Glenn K; Wadley, Glenn D

    2016-09-01

    Recent research highlights the importance of redox signalling pathway activation by contraction-induced reactive oxygen species (ROS) and nitric oxide (NO) in normal exercise-related cellular and molecular adaptations in skeletal muscle. In this review, we discuss some potentially important redox signalling pathways in skeletal muscle that are involved in acute and chronic responses to contraction and exercise. Specifically, we discuss redox signalling implicated in skeletal muscle contraction force, mitochondrial biogenesis and antioxidant enzyme induction, glucose uptake and muscle hypertrophy. Furthermore, we review evidence investigating the impact of major exogenous antioxidants on these acute and chronic responses to exercise. Redox signalling pathways involved in adaptive responses in skeletal muscle to exercise are not clearly elucidated at present, and further research is required to better define important signalling pathways involved. Evidence of beneficial or detrimental effects of specific antioxidant compounds on exercise adaptations in muscle is similarly limited, particularly in human subjects. Future research is required to not only investigate effects of specific antioxidant compounds on skeletal muscle exercise adaptations, but also to better establish mechanisms of action of specific antioxidants in vivo. Although we feel it remains somewhat premature to make clear recommendations in relation to application of specific antioxidant compounds in different exercise settings, a bulk of evidence suggests that N-acetylcysteine (NAC) is ergogenic through its effects on maintenance of muscle force production during sustained fatiguing events. Nevertheless, a current lack of evidence from studies using performance tests representative of athletic competition and a potential for adverse effects with high doses (>70mg/kg body mass) warrants caution in its use for performance enhancement. In addition, evidence implicates high dose vitamin C (1g/day) and E

  18. Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.

    Science.gov (United States)

    Piccolo, Stephen R; Hoffman, Laura M; Conner, Thomas; Shrestha, Gajendra; Cohen, Adam L; Marks, Jeffrey R; Neumayer, Leigh A; Agarwal, Cori A; Beckerle, Mary C; Andrulis, Irene L; Spira, Avrum E; Moos, Philip J; Buys, Saundra S; Johnson, William Evan; Bild, Andrea H

    2016-03-01

    The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway-based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC. In this study, we performed integrated analyses of gene expression and exome-sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC. The dysregulation of cell adhesion pathways in high-risk women was also identified by pathway-based profiling applied to normal breast tissue data from two independent cohorts. The results of our genomic analyses were validated in normal primary mammary epithelial cells from high-risk and control women, using cell-based functional assays, drug-response assays, fluorescence microscopy, and Western blotting assays. Both genomic and cell-based experiments indicate that cell-cell and cell-extracellular matrix adhesion processes seem to be disrupted in non-malignant cells of women at high risk for FBC and suggest a potential role for these processes in FBC development. PMID:26969729

  19. Wnt signaling pathway in non-small cell lung cancer.

    Science.gov (United States)

    Stewart, David J

    2014-01-01

    Wnt/β-catenin alterations are prominent in human malignancies. In non-small cell lung cancer (NSCLC), β-catenin and APC mutations are uncommon, but Wnt signaling is important in NSCLC cell lines, and Wnt inhibition reduces proliferation. Overexpression of Wnt-1, -2, -3, and -5a and of Wnt-pathway components Frizzled-8, Dishevelled, Porcupine, and TCF-4 is common in resected NSCLC and is associated with poor prognosis. Conversely, noncanonical Wnt-7a suppresses NSCLC development and is often downregulated. Although β-catenin is often expressed in NSCLCs, it was paradoxically associated with improved prognosis in some series, possibly because of E-cadherin interactions. Downregulation of Wnt inhibitors (eg, by hypermethylation) is common in NSCLC tumor cell lines and resected samples; may be associated with high stage, dedifferentiation, and poor prognosis; and has been reported for AXIN, sFRPs 1-5, WIF-1, Dkk-1, Dkk-3, HDPR1, RUNX3, APC, CDX2, DACT2, TMEM88, Chibby, NKD1, EMX2, ING4, and miR-487b. AXIN is also destabilized by tankyrases, and GSK3β may be inactivated through phosphorylation by EGFR. Preclinically, restoration of Wnt inhibitor function is associated with reduced Wnt signaling, decreased cell proliferation, and increased apoptosis. Wnt signaling may also augment resistance to cisplatin, docetaxel, and radiotherapy, and Wnt inhibitors may restore sensitivity. Overall, available data indicate that Wnt signaling substantially impacts NSCLC tumorigenesis, prognosis, and resistance to therapy, with loss of Wnt signaling inhibitors by promoter hypermethylation or other mechanisms appearing to be particularly important. Wnt pathway antagonists warrant exploration clinically in NSCLC. Agents blocking selected specific β-catenin interactions and approaches to increase expression of downregulated Wnt inhibitors may be of particular interest. PMID:24309006

  20. Oxidative stress and signal transduction pathways in alcoholic liver disease.

    Science.gov (United States)

    Zima, Tomás; Kalousová, Marta

    2005-11-01

    Ethanol is linked to several pathologies like alcohol liver injury, neurotoxicity, cardiomyopathy, fetal alcoholic syndrome or cancer. It is generally accepted that oxidative stress plays a central role in their pathogenesis. After chronic and excessive consumption, alcohol may accelerate oxidative mechanisms both directly via increased production of reactive oxygen species and indirectly by impairing protective mechanisms against them. Ethanol, its metabolites arising during its metabolic degradation as well as novel compounds formed via ethanol induced oxidative stress, especially during the action of the ethanol inducible microsomal cytochrome CYP2E1, may apart from direct damage to biological structures affect signal transduction pathways thus modulating and potentiating damage. Alteration of the redox status of cells following chronic ethanol misuse may have profound effects on cellular function and viability and lead to cell death and tissue damage. These changes linked to pathologic processes in the organism, are related to alteration of intracellular signaling pathways associated with protein kinases and transcription factor activation. Mainly mitogen activated protein kinase (MAPK) family, transcription factors-nuclear factor kappaB (NF-kappaB) and activating protein 1 (AP-1) are involved in the deterioration of cells and organs. The response is cell-type specific and depends on the dose of ethanol. Oxido-reduction balance, regulatory disturbances and signal transduction cascades responsible for alcoholic damage have been partially described, nevertheless, further studies are required to allow future novel diagnostic and therapeutical strategies. We are only at the beginning ... PMID:16344594

  1. Parallel quorum sensing signaling pathways in Vibrio cholerae.

    Science.gov (United States)

    Jung, Sarah A; Hawver, Lisa A; Ng, Wai-Leung

    2016-05-01

    Quorum sensing (QS) is a microbial signaling process for monitoring population density and complexity. Communication among bacterial cells via QS relies on the production, secretion, and detection of small molecules called autoinducers. Many bacteria have evolved their QS systems with different network architectures to incorporate information from multiple signals. In the human pathogen Vibrio cholerae, at least four parallel signaling pathways converge to control the activity of a single regulator to modulate its QS response. By integrating multiple signal inputs, it is believed that Vibrio species can survey intra-species, intra-genus, and inter-species populations and program their gene expression accordingly. Our recent studies suggest that this "many-to-one" circuitry is also important for maintaining the integrity of the input-output relationship of the system and minimizes premature commitment to QS due to signal perturbation. Here we discuss the implications of this specific parallel network setup for V. cholerae intercellular communication and how this system arrangement affects our approach to manipulate the QS response of this clinically important pathogen. PMID:26545759

  2. The Lophotrochozoan TGF-β signalling cassette - diversification and conservation in a key signalling pathway.

    Science.gov (United States)

    Kenny, Nathan J; Namigai, Erica K O; Dearden, Peter K; Hui, Jerome H L; Grande, Cristina; Shimeld, Sebastian M

    2014-01-01

    TGF-β signalling plays a key role in the patterning of metazoan body plans and growth. It is widely regarded as a 'module' capable of co-option into novel functions. The TGF-β pathway arose in the Metazoan lineage, and while it is generally regarded as well conserved across evolutionary time, its components have been largely studied in the Ecdysozoa and Deuterostomia. The recent discovery of the Nodal molecule in molluscs has underlined the necessity of untangling this signalling network in lophotrochozoans in order to truly comprehend the evolution, conservation and diversification of this key pathway. Three novel genome resources, the mollusc Patella vulgata, annelid Pomatoceros lamarcki and rotifer Brachionus plicatilis, along with other publicly available data, were searched for the presence of TGF-β pathway genes. Bayesian and Maximum Likelihood analyses, along with some consideration of conserved domain structure, was used to confirm gene identity. Analysis revealed conservation of key components within the canonical pathway, allied with extensive diversification of TGF-β ligands and partial loss of genes encoding pathway inhibitors in some lophotrochozoan lineages. We fully describe the TGF-β signalling cassette of a range of lophotrochozoans, allowing firm inference to be drawn as to the ancestral state of this pathway in this Superphylum. The TGF-β signalling cascade's reputation as being highly conserved across the Metazoa is reinforced. Diversification within the activin-like complement, as well as potential wide loss of regulatory steps in some Phyla, hint at specific evolutionary implications for aspects of this cascade's functionality in this Superphylum. PMID:25690968

  3. Cell volume homeostatic mechanisms: effectors and signalling pathways

    DEFF Research Database (Denmark)

    Hoffmann, E K; Pedersen, Stine Helene Falsig

    2011-01-01

    the historical context of studies of cell volume regulation, focusing on the lineage started by Krogh, Bodil Schmidt-Nielsen, Hans-Henrik Ussing, and their students. The early work was focused on understanding the functional behaviour, kinetics and thermodynamics of the volume-regulatory ion transport......Cell volume homeostasis and its fine-tuning to the specific physiological context at any given moment are processes fundamental to normal cell function. The understanding of cell volume regulation owes much to August Krogh, yet has advanced greatly over the last decades. In this review, we outline...... mechanisms. Later work addressed the mechanisms through which cellular signalling pathways regulate the volume regulatory effectors or flux pathways. These studies were facilitated by the molecular identification of most of the relevant channels and transporters, and more recently also by the increased...

  4. Crosstalk between pathways enhances the controllability of signalling networks.

    Science.gov (United States)

    Wang, Dingjie; Jin, Suoqin; Zou, Xiufen

    2016-02-01

    The control of complex networks is one of the most challenging problems in the fields of biology and engineering. In this study, the authors explored the controllability and control energy of several signalling networks, which consisted of many interconnected pathways, including networks with a bow-tie architecture. On the basis of the theory of structure controllability, they revealed that biological mechanisms, such as cross-pathway interactions, compartmentalisation and so on make the networks easier to fully control. Furthermore, using numerical simulations for two realistic examples, they demonstrated that the control energy of normal networks with crosstalk is lower than in networks without crosstalk. These results indicate that the biological networks are optimally designed to achieve their normal functions from the viewpoint of the control theory. The authors' work provides a comprehensive understanding of the impact of network structures and properties on controllability. PMID:26816393

  5. Transcriptomic assessment of resistance to effects of an aryl hydrocarbon receptor (AHR agonist in embryos of Atlantic killifish (Fundulus heteroclitus from a marine Superfund site

    Directory of Open Access Journals (Sweden)

    Franks Diana G

    2011-05-01

    Full Text Available Abstract Background Populations of Atlantic killifish (Fundulus heteroclitus have evolved resistance to the embryotoxic effects of polychlorinated biphenyls (PCBs and other halogenated and nonhalogenated aromatic hydrocarbons that act through an aryl hydrocarbon receptor (AHR-dependent signaling pathway. The resistance is accompanied by reduced sensitivity to induction of cytochrome P450 1A (CYP1A, a widely used biomarker of aromatic hydrocarbon exposure and effect, but whether the reduced sensitivity is specific to CYP1A or reflects a genome-wide reduction in responsiveness to all AHR-mediated changes in gene expression is unknown. We compared gene expression profiles and the response to 3,3',4,4',5-pentachlorobiphenyl (PCB-126 exposure in embryos (5 and 10 dpf and larvae (15 dpf from F. heteroclitus populations inhabiting the New Bedford Harbor, Massachusetts (NBH Superfund site (PCB-resistant and a reference site, Scorton Creek, Massachusetts (SC; PCB-sensitive. Results Analysis using a 7,000-gene cDNA array revealed striking differences in responsiveness to PCB-126 between the populations; the differences occur at all three stages examined. There was a sizeable set of PCB-responsive genes in the sensitive SC population, a much smaller set of PCB-responsive genes in NBH fish, and few similarities in PCB-responsive genes between the two populations. Most of the array results were confirmed, and additional PCB-regulated genes identified, by RNA-Seq (deep pyrosequencing. Conclusions The results suggest that NBH fish possess a gene regulatory defect that is not specific to one target gene such as CYP1A but rather lies in a regulatory pathway that controls the transcriptional response of multiple genes to PCB exposure. The results are consistent with genome-wide disruption of AHR-dependent signaling in NBH fish.

  6. Understanding Resolvin Signaling Pathways to Improve Oral Health

    Directory of Open Access Journals (Sweden)

    Laura De Oleo

    2013-03-01

    Full Text Available The discovery of resolvins has been a major breakthrough for understanding the processes involved in resolution of inflammation. Resolvins belong to a family of novel lipid mediators that possess dual anti-inflammatory and pro-resolution actions. Specifically, they protect healthy tissue during immune-inflammatory responses to infection or injury, thereby aiding inflammation resolution and promoting tissue healing. One of the major concerns in modern medicine is the management and treatment of oral diseases, as they are related to systemic outcomes impacting the quality of life of many patients. This review summarizes known signaling pathways utilized by resolvins to regulate inflammatory responses associated with the oral cavity.

  7. The new sideway of CNTF signal transduction pathway

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The action of ciliary neurotrophic factor (CNTF) on intercellular free Ca2+ concentrations [Ca2+]I induced by glutamate (Glu) in primary cultured hippocampal neurons were detected with Fura2/AM,a Ca2+-sensitive fluorophore,and the morphological influence of G-protein on it was ob- jected. Glu could induce rapid increase of [Ca2+]I in hippo- campal neurons. CNTF had no significant action on [Ca2+]I in resting hippocampal neurons. However,after incubation of CNTF for 5 min,the increase of [Ca2+]I in hippocampal neurons rapidly induced by Glu was inhibited. Pretussis toxin (PTX)-sensitive G protein could block the action. These results indicate that a new non-genomic rapid sideway might exist in the upper stream of CNTF signal transduction pathway,which was related to Ca2+ signal transduction.

  8. Roles of MAP kinase signaling pathway in oocyte meiosis

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Mitogen-activated protein kinase (MAPK) is a family of Ser/Thr protein kinases expressed widely in eukaryotic cells. MAPK is activated by a cascade of protein kinase phosphorylation and plays pivotal roles in regulating meiosis process in oocytes. As an important physical substrate of MAPK, p90rsk mediates numerous MAPK functions. MAPK was activated at G2/M transition during meiosis. Its activity reached the peak at MⅠ stage and maintained at this level until the time before the pronuclear formation after fertilization. There is complex interplay between MAPK and MPF in the meiosis regulation. Furthermore, other intracellular signal transducers, such as cAMP, protein kinase C and protein phosphotase, ect., also regulated the activity of MAPK at different stages during meiosis in oocytes. In the present article, the roles of MAPK signaling pathway in oocyte meiosis are reviewed and discussed.

  9. Activation and signaling of the p38 MAP kinase pathway

    Institute of Scientific and Technical Information of China (English)

    Tyler ZARUBIN; Jiahuai HAN

    2005-01-01

    The family members of the mitogen-activated protein (MAP) kinases mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes. In this review, we highlight the known characteristics and components of the p38 pathway along with the mechanism and consequences of p38 activation. We focus on the role of p38 as a signal transduction mediator and examine the evidence linking p38 to inflammation, cell cycle, cell death, development, cell differentiation, senescence and tumorigenesis in specific cell types. Upstream and downstream components of p38 are described and questions remaining to be answered are posed. Finally, we propose several directions for future research on p38.

  10. Angiotensin II activates different calcium signaling pathways in adipocytes.

    Science.gov (United States)

    Dolgacheva, Lyudmila P; Turovskaya, Maria V; Dynnik, Vladimir V; Zinchenko, Valery P; Goncharov, Nikolay V; Davletov, Bazbek; Turovsky, Egor A

    2016-03-01

    Angiotensin II (Ang II) is an important mammalian neurohormone involved in reninangiotensin system. Ang II is produced both constitutively and locally by RAS systems, including white fat adipocytes. The influence of Ang II on adipocytes is complex, affecting different systems of signal transduction from early Са(2+) responses to cell proliferation and differentiation, triglyceride accumulation, expression of adipokine-encoding genes and adipokine secretion. It is known that white fat adipocytes express all RAS components and Ang II receptors (АТ1 and АТ2). The current work was carried out with the primary white adipocytes culture, and Са(2+) signaling pathways activated by Ang II were investigated using fluorescent microscopy. Са(2+)-oscillations and transient responses of differentiated adipocytes to Ang II were registered in cells with both small and multiple lipid inclusions. Using inhibitory analysis and selective antagonists, we now show that Ang II initiates periodic Са(2+)-oscillations and transient responses by activating АТ1 and АТ2 receptors and involving branched signaling cascades:In these cascades, AT1 receptors play the leading role. The results of the present work open a perspective of using Ang II for correction of signal resistance of adipocytes often observed during obesity and type 2diabetes. PMID:26850364

  11. From uncertainty to reward: BOLD characteristics differentiate signaling pathways

    Directory of Open Access Journals (Sweden)

    Grön Georg

    2009-12-01

    Full Text Available Abstract Background Reward value and uncertainty are represented by dopamine neurons in monkeys by distinct phasic and tonic firing rates. Knowledge about the underlying differential dopaminergic pathways is crucial for a better understanding of dopamine-related processes. Using functional magnetic resonance blood-oxygen level dependent (BOLD imaging we analyzed brain activation in 15 healthy, male subjects performing a gambling task, upon expectation of potential monetary rewards at different reward values and levels of uncertainty. Results Consistent with previous studies, ventral striatal activation was related to both reward magnitudes and values. Activation in medial and lateral orbitofrontal brain areas was best predicted by reward uncertainty. Moreover, late BOLD responses relative to trial onset were due to expectation of different reward values and likely to represent phasic dopaminergic signaling. Early BOLD responses were due to different levels of reward uncertainty and likely to represent tonic dopaminergic signals. Conclusions We conclude that differential dopaminergic signaling as revealed in animal studies is not only represented locally by involvement of distinct brain regions but also by distinct BOLD signal characteristics.

  12. Aspirin Promotes Oligodendroglial Differentiation Through Inhibition of Wnt Signaling Pathway.

    Science.gov (United States)

    Huang, Nanxin; Chen, Dong; Wu, Xiyan; Chen, Xianjun; Zhang, Xuesi; Niu, Jianqin; Shen, Hai-Ying; Xiao, Lan

    2016-07-01

    Aspirin, one of the most commonly used anti-inflammatory drugs, has been recently reported to display multiple effects in the central nervous system (CNS), including neuroprotection and upregulation of ciliary neurotrophic factor (CNTF) expression in astrocytes. Although it was most recently reported that aspirin could promote the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) after white matter lesion, the underlying mechanisms remain unclear. To dissect the effects of aspirin on oligodendroglial development and explore possible mechanisms, we here demonstrated the following: (i) in vitro treatment of aspirin on OPC cultures significantly increased the number of differentiated oligodendrocytes (OLs) but had no effect on the number of proliferative OPCs, indicating that aspirin can promote OPC differentiation but not proliferation; (ii) in vivo treatment of aspirin on neonatal (P3) rats for 4 days led to a nearly twofold increase in the expression of myelin basic protein (MBP), devoid of change in OPC proliferaion, in the corpus callosum (CC); (iii) finally, aspirin treatment increased the phosphorylation level of β-catenin and counteracted Wnt signaling pathway synergist QS11-induced suppression on OPC differentiation. Together, our data show that aspirin can directly target oligodendroglial lineage cells and promote their differentiation through inhibition of Wnt/β-catenin signaling pathway. These findings suggest that aspirin may be a novel candidate for the treatment of demyelinating diseases. PMID:26059811

  13. Puerarin Suppress Apoptosis of Human Osteoblasts via ERK Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Ling-juan Liu

    2013-01-01

    Full Text Available Puerarin, the main isoflavone glycoside extracted from Radix Puerariae, is an isoflavone traditional Chinese herb. Previous studies have demonstrated that puerarin could regulate osteoblast proliferation and differentiation to promote bone formation. However, the effect of puerarin on the process of human osteoblasts (hOBs apoptosis is still unclear. In this study, we detected the function of puerarin on serum-free-induced cell apoptosis using ELISA and TUNEL arrays and then found that the mortality of hOBs was significantly decreased after exposure to 10−10–10−6 M puerarin and reached the maximal antiapoptotic effect at the concentration of 10−8 M. In addition, compared with the control group, puerarin notably increased the Bcl-2 protein levels while it decreased the Bax protein levels in the hOBs in a dose-dependent way. 10−7 M puerarin decreased the Bax/Bcl-2 ratio with a maximal decrease to 0.08. Moreover, puerarin activated ERK signaling pathways in hOBs, and the antiapoptotic effect induced by puerarin was abolished by incubation of ERK inhibitor PD98059. Similarly, the estrogen receptor antagonist ICI182780 also suppressed the inhibitory effect of puerarin on hOBs apoptosis. In conclusion, puerarin could prevent hOBs apoptosis via ERK signaling pathway, which might be effective in providing protection against bone loss and bone remolding associated with osteoporosis.

  14. The chromatin remodeler SPLAYED regulates specific stress signaling pathways.

    Directory of Open Access Journals (Sweden)

    Justin W Walley

    2008-12-01

    Full Text Available Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structure are brought about by a number of different mechanisms, including chromatin modifications, which covalently modify histone proteins; incorporation of histone variants; and chromatin remodeling, which utilizes ATP hydrolysis to alter histone-DNA contacts. While considerable insight into the mechanisms of chromatin remodeling has been gained, the biological role of chromatin remodeling complexes beyond their function as regulators of cellular differentiation and development has remained poorly understood. Here, we provide genetic, biochemical, and biological evidence for the critical role of chromatin remodeling in mediating plant defense against specific biotic stresses. We found that the Arabidopsis SWI/SNF class chromatin remodeling ATPase SPLAYED (SYD is required for the expression of selected genes downstream of the jasmonate (JA and ethylene (ET signaling pathways. SYD is also directly recruited to the promoters of several of these genes. Furthermore, we show that SYD is required for resistance against the necrotrophic pathogen Botrytis cinerea but not the biotrophic pathogen Pseudomonas syringae. These findings demonstrate not only that chromatin remodeling is required for selective pathogen resistance, but also that chromatin remodelers such as SYD can regulate specific pathways within biotic stress signaling networks.

  15. Aberrant signaling pathways in medulloblastomas: a stem cell connection

    Directory of Open Access Journals (Sweden)

    Carolina Oliveira Rodini

    2010-12-01

    Full Text Available Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio- and chemo-resistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible involvement of developmental signaling pathways as critical biochemical switches determining normal neurogenesis or tumorigenesis. From the clinical viewpoint, modulation of signaling pathways such as TGFβ, regulating neural stem cell proliferation and tumor development, might be attempted as an alternative strategy for future drug development aiming at more efficient therapies and improved clinical outcome of patients with pediatric brain cancers.

  16. MicroRNA-gene signaling pathways in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Alexandra Drakaki

    2013-10-01

    Full Text Available Pancreatic cancer is the fourth most frequent cause of cancer-related deaths and is characterized by early metastasis and pronounced resistance to chemotherapy and radiation therapy. Despite extensive esearch efforts, there is not any substantial progress regarding the identification of novel drugs against pancreatic cancer. Although the introduction of the chemotherapeutic agent gemcitabine improved clinical response, the prognosis of these patients remained extremely poor with a 5-year survival rate of 3-5%. Thus, the identification of the novel molecular pathways involved in pancreatic oncogenesis and the development of new and potent therapeutic options are highly desirable. Here, we describe how microRNAs control signaling pathways that are frequently deregulated during pancreatic oncogenesis. In addition, we provide evidence that microRNAs could be potentially used as novel pancreatic cancer therapeutics through reversal of chemotherapy and radiotherapy resistance or regulation of essential molecular pathways. Further studies should integrate the deregulated genes and microRNAs into molecular networks in order to identify the central regulators of pancreatic oncogenesis. Targeting these central regulators could lead to the development of novel targeted therapeutic approaches for pancreatic cancer patients.

  17. Signaling Pathways and Molecular Mechanisms of Oxidative Stress in Skeletal Muscle

    Institute of Scientific and Technical Information of China (English)

    Haibing HU; Wenjing LI; Zhi FANG; Bo XUE; Longzhou LIU; Ye YANG

    2015-01-01

    Oxidative stress is a major factor affecting animal health and production performance. This paper briefly introduced the signaling pathways(i.e. NF-κB signal-ing pathway, MAPK, AP-1 and PGC-1α) of oxidative stress and the main genes regulating the signals of oxidative stress in skeletal muscle, providing a theoretical basis for reducing oxidative stress damage.

  18. Peroxiredoxins in Regulation of MAPK Signalling Pathways; Sensors and Barriers to Signal Transduction.

    Science.gov (United States)

    Latimer, Heather R; Veal, Elizabeth A

    2016-01-01

    Peroxiredoxins are highly conserved and abundant peroxidases. Although the thioredoxin peroxidase activity of peroxiredoxin (Prx) is important to maintain low levels of endogenous hydrogen peroxide, Prx have also been shown to promote hydrogen peroxide-mediated signalling. Mitogen activated protein kinase (MAPK) signalling pathways mediate cellular responses to a variety of stimuli, including reactive oxygen species (ROS). Here we review the evidence that Prx can act as both sensors and barriers to the activation of MAPK and discuss the underlying mechanisms involved, focusing in particular on the relationship with thioredoxin. PMID:26813660

  19. Mitochondrial function in ageing: coordination with signalling and transcriptional pathways.

    Science.gov (United States)

    Yin, Fei; Sancheti, Harsh; Liu, Zhigang; Cadenas, Enrique

    2016-04-15

    Mitochondrial dysfunction entailing decreased energy-transducing capacity and perturbed redox homeostasis is an early and sometimes initiating event in ageing and age-related disorders involving tissues with high metabolic rate such as brain, liver and heart. In the central nervous system (CNS), recent findings from our and other groups suggest that the mitochondrion-centred hypometabolism is a key feature of ageing brains and Alzheimer's disease. This hypometabolic state is manifested by lowered neuronal glucose uptake, metabolic shift in the astrocytes, and alternations in mitochondrial tricarboxylic acid cycle function. Similarly, in liver and adipose tissue, mitochondrial capacity around glucose and fatty acid metabolism and thermogenesis is found to decline with age and is implicated in age-related metabolic disorders such as obesity and type 2 diabetes mellitus. These mitochondrion-related disorders in peripheral tissues can impact on brain functions through metabolic, hormonal and inflammatory signals. At the cellular level, studies in CNS and non-CNS tissues support the notion that instead of being viewed as autonomous organelles, mitochondria are part of a dynamic network with close interactions with other cellular components through energy- or redox-sensitive cytosolic kinase signalling and transcriptional pathways. Hence, it would be critical to further understand the molecular mechanisms involved in the communication between mitochondria and the rest of the cell. Therapeutic strategies that effectively preserves or improve mitochondrial function by targeting key component of these signalling cascades could represent a novel direction for numerous mitochondrion-implicated, age-related disorders. PMID:26293414

  20. Hormone Signaling Pathways in Plants: The Role of Jasmonic Acid in Plant Cell Signaling

    OpenAIRE

    TİRYAKİ, İskender

    2004-01-01

    Plant growth and metabolism are affected by various biotic and abiotic stimuli including microorganisms and insects attack as well as light and environmental stresses. Such a diverse plant response requires a communication system that uses a group of chemical messengers called hormones. Hormones promote, inhibit, or qualitatively modify plant growth and development. This complex process requires a signal transduction that defines a specific information pathway within a cell that translat...

  1. G protein-coupled receptor 30 ligand G-1 increases aryl hydrocarbon receptor signalling by inhibition of tubulin assembly and cell cycle arrest in human MCF-7 cells.

    Science.gov (United States)

    Tarnow, Patrick; Tralau, Tewes; Luch, Andreas

    2016-08-01

    Regulatory crosstalk between the aryl hydrocarbon receptor (AHR) and oestrogen receptor α (ERα) is well established. Apart from the nuclear receptors ERα and ERβ, oestrogen signalling further involves an unrelated G protein-coupled receptor termed GPR30. In order to investigate potential regulatory crosstalk, this study investigated the influence of G-1 as one of the few GPR30-specific ligands on the AHR regulon in MCF-7 cells. As a well-characterised model system, these human mammary carcinoma cells co-express all three receptors (AHR, ERα and GPR30) and are thus ideally suited to study corresponding regulatory pathway interactions on transcript level. Indeed, treatment with micromolar concentrations of the GPR30-specific agonist G-1 resulted in up-regulation of AHR as well as the transcripts for cytochromes P450 1A1 and 1B1, two well-known targets of the AHR regulon. While this was partly attributable to G-1-mediated inhibition of tubulin assembly and subsequent cell cycle arrest in the G2/M phase, the effects nevertheless required functional AHR. However, G-1-induced up-regulation of CYP 1A1 was not mediated by GPR30, as G15 antagonist treatment as well as a knockdown of GPR30 and AHR failed to inhibit this effect. PMID:26475489

  2. In vitro reconstitution of an abscisic acid signalling pathway

    KAUST Repository

    Fujii, Hiroaki

    2009-11-18

    The phytohormone abscisic acid (ABA) regulates the expression of many genes in plants; it has critical functions in stress resistance and in growth and development. Several proteins have been reported to function as ABA receptors, and many more are known to be involved in ABA signalling. However, the identities of ABA receptors remain controversial and the mechanism of signalling from perception to downstream gene expression is unclear. Here we show that by combining the recently identified ABA receptor PYR1 with the type 2C protein phosphatase (PP2C) ABI1, the serine/threonine protein kinase SnRK2.6/OST1 and the transcription factor ABF2/AREB1, we can reconstitute ABA-triggered phosphorylation of the transcription factor in vitro. Introduction of these four components into plant protoplasts results in ABA-responsive gene expression. Protoplast and test-tube reconstitution assays were used to test the function of various members of the receptor, protein phosphatase and kinase families. Our results suggest that the default state of the SnRK2 kinases is an autophosphorylated, active state and that the SnRK2 kinases are kept inactive by the PP2Cs through physical interaction and dephosphorylation. We found that in the presence of ABA, the PYR/PYL (pyrabactin resistance 1/PYR1-like) receptor proteins can disrupt the interaction between the SnRK2s and PP2Cs, thus preventing the PP2C-mediated dephosphorylation of the SnRK2s and resulting in the activation of the SnRK2 kinases. Our results reveal new insights into ABA signalling mechanisms and define a minimal set of core components of a complete major ABA signalling pathway. © 2009 Macmillan Publishers Limited. All rights reserved.

  3. Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

    Institute of Scientific and Technical Information of China (English)

    Jing-tao LU; Wen-di ZHAO; Wei HE; Wei WEI

    2012-01-01

    To investigate the role of Hedgehog (Hh) signaling pathway in the invasion and metastasis of human hepatocellular carcinoma (HCC).Methods:Eighty six HCC tissues samples and HCC cell line Bel-7402 were examined.The protein expression of sonic hedgehog (Shh),nuclear glioma-associated oncogene-1 (Gli1),MMP-9 and p-ERK1/2 in HCC was analyzed using immunohistochemistry and Western blot analysis.Boyden chamber assay and wound-healing assay were used to quantify the invasion and metastasis of Bel-7402 cells.Results:In 86 HCC tissue samples,the positive ratio of Shh and nucleus Gli1 was 67.44% (58/86) and 60.47% (52/86),respectively;the expression of nucleus Gli1 was correlated with the tumor pathological grade (P=0.034),and with the ability of the tumor to invade and metastasize (P=0.001); the expression of nucleus Gli1 was also correlated with p-ERK1/2 (P=0.031) and with MMP-9 (P=0.034).Neither Shh,nor nucleus Gli1 was observed in normal liver tissue.KAAD-cyclopamine (KAAD-cyc),a specific inhibitor of the Hh pathway,at the concentrations of 1 and 4 μmol/L inhibited the invasion and migration of Bel-7402 cells and decreased the expression of Gli1 in nucleus and MMP-9,p-ERK1/2 proteins in Bel-7402 cells,On the other hand,Shh,a ligand of the Hh pathway,at the concentration of 0.5 μg/mL produced opposite effects.The MAPK pathway inhibitors U0126 and PD98059 at the concentrations of 5 and 10μmol/L inhibited invasion and metastasis of Bel-7402 cells induced by Shh,and decreased the expression of p-ERK1/2 and MMP-9.However,U0126 and PD98059 had no effect on the expression of Gii1.Conclusion:Hh signaling pathway mediates invasion and metastasis of human HCC by up-regulating the protein expression of MMP-9via ERK pathway.

  4. From Phosphoproteome to Modeling of Plant Signaling Pathways.

    Science.gov (United States)

    Zakhartsev, Maksim; Pertl-Obermeyer, Heidi; Schulze, Waltraud X

    2016-01-01

    Quantitative proteomic experiments in recent years became almost routine in many aspects of biology. Particularly the quantification of peptides and corresponding phosphorylated counterparts from a single experiment is highly important for understanding of dynamics of signaling pathways. We developed an analytical method to quantify phosphopeptides (pP) in relation to the quantity of the corresponding non-phosphorylated parent peptides (P). We used mixed-mode solid-phase extraction to purify total peptides from tryptic digest and separated them from most of the phosphorous-containing compounds (e.g., phospholipids, nucleotides) which enhances pP enrichment on TiO2 beads. Phosphoproteomic data derived with this designed method allows quantifying pP/P stoichiometry, and qualifying experimental data for mathematical modeling. PMID:26700054

  5. Signaling pathways in the epithelial origins of pulmonary fibrosis.

    Science.gov (United States)

    Hardie, William D; Hagood, James S; Dave, Vrushank; Perl, Anne-Karina T; Whitsett, Jeffrey A; Korfhagen, Thomas R; Glasser, Stephan

    2010-07-15

    Pulmonary fibrosis complicates a number of disease processes and leads to substantial morbidity and mortality. Idiopathic pulmonary fibrosis (IPF) is perhaps the most pernicious and enigmatic form of the greater problem of lung fibrogenesis with a median survival of three years from diagnosis in affected patients. In this review, we will focus on the pathology of IPF as a model of pulmonary fibrotic processes, review possible cellular mechanisms, review current treatment approaches and review two transgenic mouse models of lung fibrosis to provide insight into processes that cause lung fibrosis. We will also summarize the potential utility of signaling pathway inhibitors as a future treatment in pulmonary fibrosis. Finally, we will present data demonstrating a minimal contribution of epithelial-mesenchymal transition in the development of fibrotic lesions in the transforming growth factor-alpha transgenic model of lung fibrosis. PMID:20676040

  6. Pathogenesis of cholangiocarcinoma: From genetics to signalling pathways.

    Science.gov (United States)

    Kongpetch, Sarinya; Jusakul, Apinya; Ong, Choon Kiat; Lim, Weng Khong; Rozen, Steven G; Tan, Patrick; Teh, Bin Tean

    2015-04-01

    Cholangiocarcinoma (CCA) is a malignant tumour of bile duct epithelial cells with dismal prognosis and rising incidence. Chronic inflammation resulting from liver fluke infection, hepatitis and other inflammatory bowel diseases is a major contributing factor to cholangiocarcinogenesis, likely through accumulation of serial genetic and epigenetic alterations resulting in aberration of oncogenes and tumour suppressors. Recent studies making use of advances in high-throughput genomics have revealed the genetic landscape of CCA, greatly increasing our understanding of its underlying biology. A series of highly recurrent mutations in genes such as TP53, KRAS, SMAD4, BRAF, MLL3, ARID1A, PBRM1 and BAP1, which are known to be involved in cell cycle control, cell signalling pathways and chromatin dynamics, have led to investigations of their roles, through molecular to mouse modelling studies, in cholangiocarcinogenesis. This review focuses on the landscape genetic alterations in CCA and its functional relevance to the formation and progression of CCA. PMID:25966424

  7. Current Views of Toll-Like Receptor Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Masahiro Yamamoto

    2010-01-01

    Full Text Available On microbial invasion, the host immediately evokes innate immune responses. Recent studies have demonstrated that Toll-like receptors (TLRs play crucial roles in innate responses that lead not only to the clearance of pathogens but also to the efficient establishment of acquired immunity by directly detecting molecules from microbes. In terms of intracellular TLR-mediated signaling pathways, cytoplasmic adaptor molecules containing Toll/IL-1R (TIR domains play important roles in inflammatory immune responses through the production of proinflammatory cytokines, nitric oxide, and type I interferon, and upregulation of costimulatory molecules. In this paper, we will describe our current understanding of the relationship between TLRs and their ligands derived from pathogens such as viruses, bacteria, fungi, and parasites. Moreover, we will review the historical and current literature to describe the mechanisms behind TLR-mediated activation of innate immune responses.

  8. Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway.

    Science.gov (United States)

    Bautista-Pérez, Rocio; del Valle-Mondragón, Leonardo; Cano-Martínez, Agustina; Pérez-Méndez, Oscar; Escalante, Bruno; Franco, Martha

    2015-05-15

    The possibility that angiotensin II (ANG II) exerts its effects through the activation of neutral sphingomyelinase (nSMase) has not been tested in kidneys. The results of the present study provide evidence for the activity and expression of nSMase in rat kidneys. In isolated perfused rat kidney, ANG II-induced renal vasoconstriction was inhibited by GW4869, an inhibitor of nSMase. We used nSMase for investigating the signal transduction downstream of ceramide. nSMase constricted the renal vasculature. An inhibitor of ceramidase (CDase), N-oleoylethanolamine (OEA), enhanced either ANG II- or nSMase-induced renal vasoconstriction. To demonstrate the interaction between the nSMase and cytosolic phospholipase A2 (cPLA2) signal transduction pathways, we evaluated the response to nSMase in the presence and absence of inhibitors of arachidonic acid (AA) metabolism: arachidonyl trifluoromethyl ketone (AACOCF3), an inhibitor of cPLA2; 5,8,11,14-eicosatetraynoic acid (ETYA), an inhibitor of all AA pathways; indomethacin, an inhibitor of cyclooxygenase (COX); furegrelate, a thromboxane A2 (TxA2)-synthase inhibitor; and SQ29548, a TxA2-receptor antagonist. In these experiments, the nSMase-induced renal vasoconstriction decreased. ANG II or nSMase was associated with an increase in the release of thromboxane B2 (TxB2) in the renal perfusate of isolated perfused rat kidney. In addition, the coexpression of the ceramide with cPLA2, was found in the smooth muscle layer of intrarenal vessels. Our results suggest that ANG II stimulates ceramide formation via the activation of nSMase; thus ceramide may indirectly regulate vasoactive processes that modulate the activity of cPLA2 and the release of TxA2. PMID:25354938

  9. Kavain Involvement in LPS-Induced Signaling Pathways.

    Science.gov (United States)

    Tang, Xiaoren; Amar, Salomon

    2016-10-01

    Kavain, a compound extracted from the Kava plant, Piper methysticum, is found to be involved in TNF-α expression in human and mouse cells via regulation of transcriptional factors such as NF-kB and LITAF. LITAF is known to activate the transcription of more than 20 cytokines that are involved in a variety of cellular processes and is associated with many inflammatory diseases, including angiogenesis, cancer, arthritis, and more. The modulation of LITAF is expected to positively affect cytokine-mediated diseases. Thus, intensive efforts have been deployed in search of LITAF inhibitors. In this work, we found that, in vitro, Kavain reduced LPS- induced TNF-α secretion in mouse macrophages, mouse bone marrow macrophages (BMM), and human peripheral blood mononuclear cells (HPBMC). We also found that Kavain treatment in RAW264.7 cells deactivated MyD88 and Akt, inhibited LITAF, and reduced the production of TNF-α, IL-27, and MIG in response to LPS. Similarly, it had a significant in vivo anti-inflammatory effect on wild-type (WT) mice that developed Collagen Antibody Induced Arthritis (CAIA). Overall, MyD88 was found to be an important mediator of the LPS-induced inflammatory response that can be distinguished from the NF-κB pathway. We also found that MyD88 is involved in the pathway linking LPS/LITAF to TNF-α. Therefore, given that Kavain modulates LPS-induced signaling pathways leading to cytokine expression, therapeutic interventions involving Kavain in inflammatory diseases are warranted. J. Cell. Biochem. 117: 2272-2280, 2016. © 2016 Wiley Periodicals, Inc. PMID:26917453

  10. mTOR signaling pathway genes in focal epilepsies.

    Science.gov (United States)

    Baulac, S

    2016-01-01

    Focal epilepsies, where seizures initiate in spatially limited networks, are the most frequent epilepsy type, accounting for two-thirds of patients. Focal epilepsies have long been thought to be acquired disorders; several focal epilepsy syndromes are now proven to be (genetically heterogeneous) monogenic disorders. While earlier genetic studies have demonstrated a strong contribution of ion channel and neurotransmitter receptor genes, or synaptic secreted protein genes, later work has revealed a new class of genes encoding components of the mechanistic target of rapamycin (mTOR) signal transduction pathway. The mTOR pathway controls a myriad of biological processes among which cell growth and protein synthesis in response to several extracellular and intracellular. Recently, germline mutations have been found in genes encoding the components of the GATOR1 complex (DEPDC5, NPRL2, NPRL3), a repressor of mTORC1. These mutations are increasingly recognized as causing a wide and yet evolving spectrum of focal epilepsy syndromes, with and without cortical structural abnormalities (usually focal cortical dysplasia). Brain somatic mutations in the gene encoding mTOR (MTOR) have recently been linked to focal cortical dysplasia and other associated brain pathologies including hemimegalencephaly. This chapter reviews the genetics and neurobiology of DEPDC5, NPRL2, and NPRL3, and summarizes the clinical and molecular spectrum of GATOR1-related epilepsies. PMID:27323939

  11. Gene Expression Profiling Identifies Cell Proliferation and Inflammation as the Predominant Pathways Regulated by Aryl Hydrocarbon Receptor in Primary Human Fetal Lung Cells Exposed to Hyperoxia.

    Science.gov (United States)

    Shivanna, Binoy; Maity, Suman; Zhang, Shaojie; Patel, Ananddeep; Jiang, Weiwu; Wang, Lihua; Welty, Stephen E; Belmont, John; Coarfa, Cristian; Moorthy, Bhagavatula

    2016-07-01

    Exposure to hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. We observed that aryl hydrocarbon receptor (AhR) signaling protects newborn mice and primary fetal human pulmonary microvascular endothelial cells (HPMECs) against hyperoxic injury. Additionally, a recent genome-wide transcriptome study in a newborn mouse model of BPD identified AhR as a key regulator of hyperoxia-induced gene dysregulation. Whether the AhR similarly deregulates genes in HPMEC is unknown. Therefore, the objective of this study was to characterize transcriptome level gene expression profile in AhR-sufficient and -deficient HPMEC exposed to normoxic and hyperoxic conditions. Global gene expression profiling was performed using Illumina microarray platform and selected genes were validated by real-time RT-PCR. AhR gene expression and hyperoxia independently affected the expression of 540 and 593 genes, respectively. Two-way ANOVA further identified 85 genes that were affected by an interaction between AhR expression and exposure to hyperoxia. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology, and Reactome pathway analysis identified cell proliferation, immune function, cytokine signaling, and organ development as the major pathways affected in AhR-deficient cells. The biological processes that were significantly enriched by hyperoxia included metabolic process, stress response, signal transduction, cell cycle, and immune regulation. Cell cycle was the predominant pathway affected by the combined effect of AhR knockdown and hyperoxia. Functional analysis of cell cycle showed that AhR-deficient cells had decreased proliferation compared with AhR-sufficient cells. These findings suggest that AhR modulates hyperoxic lung injury by regulating the genes that are necessary for cell proliferation and inflammation. PMID:27103661

  12. Signaling pathways regulating production of hyaluronic acid in pig oocyte-cumulus cell-complexes

    Czech Academy of Sciences Publication Activity Database

    Procházka, Radek; Nagyová, Eva

    Luxembourg: Recherches Scientifiques Luxembourg, 2006. s. 647. [Cell Signaling World 2006, Signal Transduction Pathways therapeutic targets. 25.01.2006-28.01.2006, Luxembourg] R&D Projects: GA ČR GA523/04/0574 Institutional research plan: CEZ:AV0Z50450515 Keywords : signaling pathways Subject RIV: EB - Genetics ; Molecular Biology

  13. Signalling pathway impact analysis based on the strength of interaction between genes.

    Science.gov (United States)

    Bao, Zhenshen; Li, Xianbin; Zan, Xiangzhen; Shen, Liangzhong; Ma, Runnian; Liu, Wenbin

    2016-08-01

    Signalling pathway analysis is a popular approach that is used to identify significant cancer-related pathways based on differentially expressed genes (DEGs) from biological experiments. The main advantage of signalling pathway analysis lies in the fact that it assesses both the number of DEGs and the propagation of signal perturbation in signalling pathways. However, this method simplifies the interactions between genes by categorising them only as activation (+1) and suppression (-1), which does not encompass the range of interactions in real pathways, where interaction strength between genes may vary. In this study, the authors used newly developed signalling pathway impact analysis (SPIA) methods, SPIA based on Pearson correlation coefficient (PSPIA), and mutual information (MSPIA), to measure the interaction strength between pairs of genes. In analyses of a colorectal cancer dataset, a lung cancer dataset, and a pancreatic cancer dataset, PSPIA and MSPIA identified more candidate cancer-related pathways than were identified by SPIA. Generally, MSPIA performed better than PSPIA. PMID:27444024

  14. FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells.

    Science.gov (United States)

    Katoh, Yuriko; Katoh, Masaru

    2006-03-01

    WNT, FGF and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. FGF16, FGF18, and FGF20 genes are targets of WNT-mediated TCF/LEF-beta-catenin-BCL9/BCL9L-PYGO transcriptional complex. SPROUTY (SPRY) and SPRED family genes encode inhibitors for receptor tyrosine kinase signaling cascades, such as those of FGF receptor family members and EGF receptor family members. Here, transcriptional regulation of SPRY1, SPRY2, SPRY3, SPRY4, SPRED1, SPRED2, and SPRED3 genes by WNT/beta-catenin signaling cascade was investigated by using bioinformatics and human intelligence (humint). Because double TCF/LEF-binding sites were identified within the 5'-promoter region of human SPRY4 gene, comparative genomics analyses on SPRY4 orthologs were further performed. SPRY4-FGF1 locus at human chromosome 5q31.3 and FGF2-NUDT6-SPATA5-SPRY1 locus at human chromosome 4q27-q28.1 were paralogous regions within the human genome. Chimpanzee SPRY4 gene was identified within NW_107083.1 genome sequence. Human, chimpanzee, rat and mouse SPRY4 orthologs, consisting of three exons, were well conserved. SPRY4 gene was identified as the evolutionarily conserved target of WNT/beta-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian SPRY4 orthologs. Human SPRY4 mRNA was expressed in embryonic stem (ES) cells, brain, pancreatic islet, colon cancer, head and neck tumor, melanoma, and pancreatic cancer. WNT signaling activation in progenitor cells leads to the growth regulation of progenitor cells themselves through SPRY4 induction, and also to the growth stimulation of proliferating cells through FGF secretion. Epigenetic silencing and loss-of-function mutations of SPRY4 gene in progenitor cells could lead to carcinogenesis. SPRY4 is the pharmacogenomics target in the fields of oncology and regenerative medicine. PMID:16465403

  15. Sunlight UV-induced skin cancer relies upon activation of the p38α signaling pathway

    OpenAIRE

    LIU, KANGDONG; Yu, Donghoon; Cho, Yong-Yeon; Ann M Bode; Ma, Weiya; Yao, Ke; Li, Shengqing; Li, Jixia; Bowden, G. Tim; Dong, Ziming; Dong, Zigang

    2013-01-01

    The activation of cellular signal transduction pathways by solar ultraviolet (SUV) irradiation plays a vital role in skin tumorigenesis. Although many pathways have been studied using pure ultraviolet A (UVA) or ultraviolet B (UVB) irradiation, the signaling pathways induced by SUV (i.e., sunlight) are not understood well enough to permit improvements for prevention, prognosis and treatment. Here we report parallel protein kinase array studies aimed at determining the dominant signaling pathw...

  16. Micro-RNA Feedback Loops Modulating the Calcineurin/NFAT Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Shichina Kannambath

    2016-05-01

    Full Text Available Nuclear factor of activated T cells (NFAT is a family of transcription factors important for innate and adaptive immune responses. NFAT activation is tightly regulated through the calcineurin/NFAT signaling pathway. There is increasing evidence on non-coding RNAs such as miRNAs playing a crucial role in regulating transcription factors and signaling pathways. However, not much is known about microRNAs (miRNAs targeting the calcineurin/NFAT signaling pathway involved in immune response in human. In this study, a comprehensive pathway level analysis has been carried out to identify miRNAs regulating the calcineurin/NFAT signaling pathway. Firstly, by incorporating experimental data and computational predictions, 191 unique miRNAs were identified to be targeting the calcineurin/NFAT signaling pathway in humans. Secondly, combining miRNA expression data from activated T cells and computational predictions, 32 miRNAs were observed to be induced by NFAT transcription factors. Finally, 11 miRNAs were identified to be involved in a feedback loop to modulate the calcineurin/NFAT signaling pathway activity. This data demonstrate the potential role of miRNAs as regulators of the calcineurin/NFAT signaling pathway. The present study thus emphasizes the importance of pathway level analysis to identify miRNAs and understands their role in modulating signaling pathways and transcription factor activity.

  17. Modelling and simulation of signal transductions in an apoptosis pathway by using timed Petri nets

    Indian Academy of Sciences (India)

    Chen Li; Qi-Wei Ge; Mitsuru Nakata; Hiroshi Matsuno; Satoru Miyano

    2007-01-01

    This paper first presents basic Petri net components representing molecular interactions and mechanisms of signalling pathways, and introduces a method to construct a Petri net model of a signalling pathway with these components. Then a simulation method of determining the delay time of transitions, by using timed Petri nets – i.e. the time taken in firing of each transition – is proposed based on some simple principles that the number of tokens flowed into a place is equivalent to the number of tokens flowed out. Finally, the availability of proposed method is confirmed by observing signalling transductions in biological pathways through simulation experiments of the apoptosis signalling pathways as an example.

  18. Molecular Signaling Pathways Mediating Osteoclastogenesis Induced by Prostate Cancer Cells

    International Nuclear Information System (INIS)

    Advanced prostate cancer commonly metastasizes to bone leading to osteoblastic and osteolytic lesions. Although an osteolytic component governed by activation of bone resorbing osteoclasts is prominent in prostate cancer metastasis, the molecular mechanisms of prostate cancer-induced osteoclastogenesis are not well-understood. We studied the effect of soluble mediators released from human prostate carcinoma cells on osteoclast formation from mouse bone marrow and RAW 264.7 monocytes. Soluble factors released from human prostate carcinoma cells significantly increased viability of naïve bone marrow monocytes, as well as osteoclastogenesis from precursors primed with receptor activator of nuclear factor κ-B ligand (RANKL). The prostate cancer-induced osteoclastogenesis was not mediated by RANKL as it was not inhibited by osteoprotegerin (OPG). However inhibition of TGFβ receptor I (TβRI), or macrophage-colony stimulating factor (MCSF) resulted in attenuation of prostate cancer-induced osteoclastogenesis. We characterized the signaling pathways induced in osteoclast precursors by soluble mediators released from human prostate carcinoma cells. Prostate cancer factors increased basal calcium levels and calcium fluctuations, induced nuclear localization of nuclear factor of activated t-cells (NFAT)c1, and activated prolonged phosphorylation of ERK1/2 in RANKL-primed osteoclast precursors. Inhibition of calcium signaling, NFATc1 activation, and ERK1/2 phosphorylation significantly reduced the ability of prostate cancer mediators to stimulate osteoclastogenesis. This study reveals the molecular mechanisms underlying the direct osteoclastogenic effect of prostate cancer derived factors, which may be beneficial in developing novel osteoclast-targeting therapeutic approaches

  19. Nuclear Receptor Signaling Atlas: Opening Access to the Biology of Nuclear Receptor Signaling Pathways.

    Directory of Open Access Journals (Sweden)

    Lauren B Becnel

    Full Text Available Signaling pathways involving nuclear receptors (NRs, their ligands and coregulators, regulate tissue-specific transcriptomes in diverse processes, including development, metabolism, reproduction, the immune response and neuronal function, as well as in their associated pathologies. The Nuclear Receptor Signaling Atlas (NURSA is a Consortium focused around a Hub website (www.nursa.org that annotates and integrates diverse 'omics datasets originating from the published literature and NURSA-funded Data Source Projects (NDSPs. These datasets are then exposed to the scientific community on an Open Access basis through user-friendly data browsing and search interfaces. Here, we describe the redesign of the Hub, version 3.0, to deploy "Web 2.0" technologies and add richer, more diverse content. The Molecule Pages, which aggregate information relevant to NR signaling pathways from myriad external databases, have been enhanced to include resources for basic scientists, such as post-translational modification sites and targeting miRNAs, and for clinicians, such as clinical trials. A portal to NURSA's Open Access, PubMed-indexed journal Nuclear Receptor Signaling has been added to facilitate manuscript submissions. Datasets and information on reagents generated by NDSPs are available, as is information concerning periodic new NDSP funding solicitations. Finally, the new website integrates the Transcriptomine analysis tool, which allows for mining of millions of richly annotated public transcriptomic data points in the field, providing an environment for dataset re-use and citation, bench data validation and hypothesis generation. We anticipate that this new release of the NURSA database will have tangible, long term benefits for both basic and clinical research in this field.

  20. Nuclear Receptor Signaling Atlas: Opening Access to the Biology of Nuclear Receptor Signaling Pathways

    Science.gov (United States)

    Becnel, Lauren B.; Darlington, Yolanda F.; Ochsner, Scott A.; Easton-Marks, Jeremy R.; Watkins, Christopher M.; McOwiti, Apollo; Kankanamge, Wasula H.; Wise, Michael W.; DeHart, Michael; Margolis, Ronald N.; McKenna, Neil J.

    2015-01-01

    Signaling pathways involving nuclear receptors (NRs), their ligands and coregulators, regulate tissue-specific transcriptomes in diverse processes, including development, metabolism, reproduction, the immune response and neuronal function, as well as in their associated pathologies. The Nuclear Receptor Signaling Atlas (NURSA) is a Consortium focused around a Hub website (www.nursa.org) that annotates and integrates diverse ‘omics datasets originating from the published literature and NURSA-funded Data Source Projects (NDSPs). These datasets are then exposed to the scientific community on an Open Access basis through user-friendly data browsing and search interfaces. Here, we describe the redesign of the Hub, version 3.0, to deploy “Web 2.0” technologies and add richer, more diverse content. The Molecule Pages, which aggregate information relevant to NR signaling pathways from myriad external databases, have been enhanced to include resources for basic scientists, such as post-translational modification sites and targeting miRNAs, and for clinicians, such as clinical trials. A portal to NURSA’s Open Access, PubMed-indexed journal Nuclear Receptor Signaling has been added to facilitate manuscript submissions. Datasets and information on reagents generated by NDSPs are available, as is information concerning periodic new NDSP funding solicitations. Finally, the new website integrates the Transcriptomine analysis tool, which allows for mining of millions of richly annotated public transcriptomic data points in the field, providing an environment for dataset re-use and citation, bench data validation and hypothesis generation. We anticipate that this new release of the NURSA database will have tangible, long term benefits for both basic and clinical research in this field. PMID:26325041

  1. Progesterone in pregnancy; receptor-ligand interaction and signaling pathways.

    Science.gov (United States)

    Szekeres-Bartho, Julia; Halasz, Melinda; Palkovics, Tamas

    2009-12-01

    Progesterone is indispensable in creating a suitable endometrial environment for implantation, and also for the maintenance of pregnancy. Successful pregnancy depends on an appropriate maternal immune response to the fetus. Along with its endocrine effects, progesterone also acts as an "immunosteroid", by contributing to the establishment of a pregnancy protective immune milieu. Progesterone plays a role in uterine homing of NK cells and upregulates HLA-G gene expression, the ligand for NK inhibitory and activating receptors. At high concentrations, progesterone is a potent inducer of Th2-type cytokines as well as of LIF and M-CSF production by T cells. A protein called progesterone-induced blocking factor (PIBF), by inducing a Th2-dominant cytokine production mediates the immunological effects of progesterone. PIBF binds to a novel type of the IL-4 receptor and signals via the Jak/STAT pathway, to induce a number of genes, that not only affect the immune response, but might also play a role in trophoblast invasiveness. PMID:19880194

  2. The VEGF signaling pathway in cancer: the road ahead

    Directory of Open Access Journals (Sweden)

    Steven A. Stacker

    2013-06-01

    Full Text Available The vascular endothelial growth factor (VEGF family of soluble protein growth factors consists of key mediators of angiogenesis and lymphangiogenesis in the context of tumor biology. The members of the family, VEGF-A (also known as VEGF, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF, play important roles in vascular biology in both normal physiology and pathology. The generation of a humanized neutralizing antibody to VEGF-A (bevacizumab, also known as Avastin and the demonstration of its benefit in numerous human cancers have confirmed the merit of an anti-angiogenesis approach to cancer treatment and have validated the VEGF-A signaling pathway as a therapeutic target. Other members of the VEGF family are now being targeted, and their relevance to human cancer and the development of resistance to anti-VEGF-A treatment are being evaluated in the clinic. Here, we discuss the potential of targeting VEGF family members in the diagnosis and treatment of cancer.

  3. Functional comparison of innate immune signaling pathways in primates.

    Directory of Open Access Journals (Sweden)

    Luis B Barreiro

    2010-12-01

    Full Text Available Humans respond differently than other primates to a large number of infections. Differences in susceptibility to infectious agents between humans and other primates are probably due to inter-species differences in immune response to infection. Consistent with that notion, genes involved in immunity-related processes are strongly enriched among recent targets of positive selection in primates, suggesting that immune responses evolve rapidly, yet providing only indirect evidence for possible inter-species functional differences. To directly compare immune responses among primates, we stimulated primary monocytes from humans, chimpanzees, and rhesus macaques with lipopolysaccharide (LPS and studied the ensuing time-course regulatory responses. We find that, while the universal Toll-like receptor response is mostly conserved across primates, the regulatory response associated with viral infections is often lineage-specific, probably reflecting rapid host-virus mutual adaptation cycles. Additionally, human-specific immune responses are enriched for genes involved in apoptosis, as well as for genes associated with cancer and with susceptibility to infectious diseases or immune-related disorders. Finally, we find that chimpanzee-specific immune signaling pathways are enriched for HIV-interacting genes. Put together, our observations lend strong support to the notion that lineage-specific immune responses may help explain known inter-species differences in susceptibility to infectious diseases.

  4. Urotensin II inhibits skeletal muscle glucose transport signaling pathways via the NADPH oxidase pathway.

    Directory of Open Access Journals (Sweden)

    Hong-Xia Wang

    Full Text Available Our previous studies have demonstrated that the urotensin (UII and its receptor are up-regulated in the skeletal muscle of mice with type II diabetes mellitus (T2DM, but the significance of UII in skeletal muscle insulin resistance remains unknown. The purpose of this study was to investigate the effect of UII on NADPH oxidase and glucose transport signaling pathways in the skeletal muscle of mice with T2DM and in C2C12 mouse myotube cells. KK/upj-AY/J mice (KK mice were divided into the following groups: KK group, with saline treatment for 2 weeks; KK+ urantide group, with daily 30 µg/kg body weight injections over the same time period of urantide, a potent urotensin II antagonist peptide; Non-diabetic C57BL/6J mice were used as normal controls. After urantide treatment, mice were subjected to an intraperitoneal glucose tolerance test, in addition to measurements of the levels of ROS, NADPH oxidase and the phosphorylated AKT, PKC and ERK. C2C12 cells were incubated with serum-free DMEM for 24 hours before conducting the experiments, and then administrated with 100 nM UII for 2 hours or 24 hours. Urantide treatment improved glucose tolerance, decreased the translocation of the NADPH subunits p40-phox and p47-phox, and increased levels of the phosphorylated PKC, AKT and ERK. In contrast, UII treatment increased ROS production and p47-phox and p67-phox translocation, and decreased the phosphorylated AKT, ERK1/2 and p38MAPK; Apocynin abrogated this effect. In conclusion, UII increased ROS production by NADPH oxidase, leading to the inhibition of signaling pathways involving glucose transport, such as AKT/PKC/ERK. Our data imply a role for UII at the molecular level in glucose homeostasis, and possibly in skeletal muscle insulin resistance in T2DM.

  5. Signaling transduction pathways involved in basophil adhesion and histamine release

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Background Little is known about basophil with respect to the different signaling transduction pathways involved in spontaneous, cytokine or anti-IgE induced adhesion and how this compares to IgE-dependent and IgE-independent mediator secretion. The purpose of the present study was to investigate the roles of β1 andβ2 integrins in basophil adhesion as well as hosphatidylinositol 3-kinase (PI3K), src-kinases and extracellular signal regulated kinase (ERK)1/2 in basophil adhesion and histamine release (HR). Methods Basophils (purity of 10%-50%) were preincubated with anti-CD29 or anti-CD18 blocking antibodies before used for adhesion study. Basophils were preincubated with the pharmacological inhibitors wortmannin, PP1, PD98059 before used for adhesion and HR study. Cell adherence to bovine serum albumin (BSA) or fibronectin (Fn) was monitored using cell associated histamine as a basophil marker and the histamine was measured by the glass fiber assay.Results Basophil spontaneous adhesion to Fn was inhibited by anti-CD29. Interleukin (IL)-3, granulocyte/macrophage colony stimulating factor (GM-CSF) induced adhesion to BSA was inhibited by anti-CD18. Wortmannin at 1 μmol/L and PP1 at 20 μmol/L strongly interfered with, whereas PD98059 at 50 μmol/L weakly inhibited basophil spontaneous adhesion to Fn. One μmol/L wortmannin strongly inhibited IL-3, IL-5, GM-CSF and anti-IgE induced adhesion to BSA. PP1 at 20 μmol/L partly inhibited anti-IgE induced adhesion. Fifty μmol/L PD98059 marginally inhibited IL-5, weakly inhibited anti-IgE, partly inhibited GM-CSF induced adhesion. Wortmannin, PP1 and PD98059 inhibited anti-IgE (1:100 or 1:1000) induced basophil HR in a dose dependent manner. They inhibited calcium ionophore A23187 (10 μmol/L, 5 μmol/L) induced basophil HR in a dose dependent manner, but to different extend with PP1 being the most efficient.Conclusions Basophil spontaneous adhesion to Fn is mediated by β1-integrins whereas cytokine induced adhesion

  6. Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.

    Directory of Open Access Journals (Sweden)

    Tertia D Purves-Tyson

    Full Text Available Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase, breakdown (catechol-O-methyl transferase; monoamine oxygenase, transport [vesicular monoamine transporter (VMAT, dopamine transporter (DAT] and receptors (DRD1-D5] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen

  7. Possible Molecular Targets of Cinnamon in the Insulin Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Sana Eijaz

    2014-01-01

    Full Text Available Cinnamon (CN is known for its anti-diabetic activities in traditional medicine. CN extracts are reported to have beneficial effects on normal and impaired glucose tolerance, insulin resistance and type-2 diabetes. However, molecular characterization of cinnamon effects is limited. The aim of this study is to observe the effect of CN extract on certain diabetogenes involved in insulin signaling. Streptozotocin (STZ induced type-2 diabetic rats were given CN extract for one month and its effect was observed on blood glucose levels, body weights and gene expression levels of protein tyrosine phosphatase-1B (PTP-1B, insulin receptor (INSR, insulin receptor substrate-1 (IRS-1, phosphoinositide 3-kinase (PI3K, protein kinase B (PKB, protein kinase C-theta (PKCθ and phosphoinositide-dependent protein kinase-1 (PDK1 in skeletal muscle and adipose tissue. Statistically significant difference was found in the glucose levels and body weights (p = <0.001; 0.002 respectively of test and diabetic control groups. In muscle, statistically significant difference was observed in gene expression levels of PTP-1B, IRS-1, PKB, PDK1, PI3K and PKCθ (p = 0.03; <0.001; 0.02; 0.001; 0.01; <0.001 respectively between test and diabetic control groups and PTP-1B, IRS-1, PKB, PDK1 and PKCθ (p = 0.01; 0.01; 0.03; 0.01; <0.001 respectively between normal and diabetic control groups. In adipose tissue, statistically significant difference was found in gene expression levels of PTP-1B, PKCθ, IRS-1 (p = <0.001; 0.04; 0.01 respectively between test and diabetic control groups and PTP-1B, PDK1, PI3K, PKCθ and IRS-1 (p = 0.002; 0.02; 0.02; 0.002; <0.001 respectively between normal and diabetic control groups. These results suggest that cinnamon normalizes blood glucose level and body weight and affect certain molecular targets in the insulin signaling pathway and therefore, possess strong anti-diabetogenic and hypoglycemic action in HFD and STZ-induced type-2 diabetic rat model

  8. Genome-wide association study knowledge-driven pathway analysis of alcohol dependence implicates the calcium signaling pathway

    Institute of Scientific and Technical Information of China (English)

    Li Danni; Li Jinming; Guo Yanfang

    2014-01-01

    Background Alcohol dependence (AD) is a serious and common public health problem.The identification of genes that contribute to the AD variation will improve our understanding of the genetic mechanism underlying this complex disease.Previous genome-wide association studies (GWAS) and candidate gene genetic association studies identified individual genes as candidates for alcohol phenotypes,but efforts to generate an integrated view of accumulative genetic variants and pathways under alcohol drinking are lacking.Methods We applied enrichment gene set analysis to existing genetic association results to identify pertinent pathways to AD in this study.A total of 1 438 SNPs (P <1.0×10-3) associated to alcohol drinking related traits have been collected from 31 studies (10 candidate gene association studies,19 GWAS of SNPs,and 2 GWAS of copy number variants).Results Among all of the KEGG pathways,the calcium signaling pathway (hsa04020) showed the most significant enrichment of associations (21 genes) to alcohol consumption phenotypes (P=5.4×10-5).Furthermore,the calcium signaling pathway is the only pathway that turned out to be significant after multiple test adjustments,achieving Bonferroni P value of 0.8×10-3 and FDR value of 0.6×10-2,respectively.Interestingly,the calcium signaling pathway was previously found to be essential to regulate brain function,and genes in this pathway link to a depressive effect of alcohol consumption on the body.Conclusions Our findings,together with previous biological evidence,suggest the importance of gene polymorphisms of calcium signaling pathway to AD susceptibility.Still,further investigations are warranted to uncover the role of this pathway in AD and related traits.

  9. From tyrosine to melanin: Signaling pathways and factors regulating melanogenesis.

    Science.gov (United States)

    Rzepka, Zuzanna; Buszman, Ewa; Beberok, Artur; Wrześniok, Dorota

    2016-01-01

    Melanins are natural pigments of skin, hair and eyes and can be classified into two main types: brown to black eumelanin and yellow to reddish-brown pheomelanin. Biosynthesis of melanins takes place in melanosomes, which are specialized cytoplasmic organelles of melanocytes - dendritic cells located in the basal layer of the epidermis, uveal tract of the eye, hair follicles, as well as in the inner ear, central nervous system and heart. Melanogenesis is a multistep process and begins with the conversion of amino acid L-tyrosine to DOPAquinone. The addition of cysteine or glutathione to DOPAquinone leads to the intermediates formation, followed by subsequent transformations and polymerization to the final product, pheomelanin. In the absence of thiol compounds DOPAquinone undergoes an intramolecular cyclization and oxidation to form DOPAchrome, which is then converted to 5,6-dihydroksyindole (DHI) or 5,6-dihydroxyindole-2-carboxylic acid (DHICA). Eumelanin is formed by polymerization of DHI and DHICA and their quinones. Regulation of melanogenesis is achieved by physical and biochemical factors. The article presents the intracellular signaling pathways: cAMP/PKA/CREB/MITF cascade, MAP kinases cascade, PLC/DAG/PKCβ cascade and NO/cGMP/PKG cascade, which are involved in the regulation of expression and activity of the melanogenesis-related proteins by ultraviolet radiation and endogenous agents (cytokines, hormones). Activity of the key melanogenic enzyme, tyrosinase, is also affected by pH and temperature. Many pharmacologically active substances are able to inhibit or stimulate melanin biosynthesis, as evidenced by in vitro studies on cultured pigment cells. PMID:27356601

  10. Genome Editing of the CYP1A1 Locus in iPSCs as a Platform to Map AHR Expression throughout Human Development

    Directory of Open Access Journals (Sweden)

    Brenden W. Smith

    2016-01-01

    Full Text Available The aryl hydrocarbon receptor (AHR is a ligand activated transcription factor that increases the expression of detoxifying enzymes upon ligand stimulation. Recent studies now suggest that novel endogenous roles of the AHR exist throughout development. In an effort to create an optimized model system for the study of AHR signaling in several cellular lineages, we have employed a CRISPR/CAS9 genome editing strategy in induced pluripotent stem cells (iPSCs to incorporate a reporter cassette at the transcription start site of one of its canonical targets, cytochrome P450 1A1 (CYP1A1. This cell line faithfully reports on CYP1A1 expression, with luciferase levels as its functional readout, when treated with an endogenous AHR ligand (FICZ at escalating doses. iPSC-derived fibroblast-like cells respond to acute exposure to environmental and endogenous AHR ligands, and iPSC-derived hepatocytes increase CYP1A1 in a similar manner to primary hepatocytes. This cell line is an important innovation that can be used to map AHR activity in discrete cellular subsets throughout developmental ontogeny. As further endogenous ligands are proposed, this line can be used to screen for safety and efficacy and can report on the ability of small molecules to regulate critical cellular processes by modulating the activity of the AHR.

  11. Segregation of Axial Motor and Sensory Pathways via Heterotypic Trans-Axonal Signaling

    OpenAIRE

    Gallarda, Benjamin W.; Bonanomi, Dario; Müller, Daniel; Brown, Arthur; Alaynick, William A; Andrews, Shane E.; Lemke, Greg; Pfaff, Samuel L.; Marquardt, Till

    2008-01-01

    Execution of motor behaviors relies on circuitries effectively integrating immediate sensory feedback to efferent pathways controlling muscle activity. It remains unclear how, during neuromuscular circuit assembly, sensory and motor projections become incorporated into tightly coordinated, yet functionally separate pathways. We report that, within axial nerves, establishment of discrete afferent and efferent pathways depends on coordinate signaling between coextending sensory and motor projec...

  12. Conserved features and evolutionary shifts of the EDA signaling pathway involved in vertebrate skin appendage development.

    OpenAIRE

    2008-01-01

    It is widely accepted that evolutionary changes in conserved developmental signaling pathways play an important role in morphological evolution. However, few in silico studies were interested in tracking such changes in a signaling pathway. The Ectodysplasin (EDA) pathway provides an opportunity to fill this gap because it is involved in vertebrate skin appendage development such as scales, teeth, hair, and feathers that take an obvious part in the adaptation of species to their environment. ...

  13. Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

    Energy Technology Data Exchange (ETDEWEB)

    Beildeck, Marcy E. [Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057 (United States); Gelmann, Edward P. [Columbia University, Department of Medicine, New York, NY (United States); Byers, Stephen W., E-mail: byerss@georgetown.edu [Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057 (United States)

    2010-07-01

    Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

  14. The Q-rich/PST domain of the AHR regulates both ligand-induced nuclear transport and nucleocytoplasmic shuttling.

    Science.gov (United States)

    Tkachenko, Anna; Henkler, Frank; Brinkmann, Joep; Sowada, Juliane; Genkinger, Doris; Kern, Christian; Tralau, Tewes; Luch, Andreas

    2016-01-01

    The aryl hydrocarbon receptor (AHR) shuttles continuously between cytoplasm and nucleus, unless ligand-binding triggers association with the AHR nuclear translocator (ARNT) and subsequent binding to cognate DNA motifs. We have now identified Val 647 as mandatory residue for export from the nucleus and AHR-function. This residue prevents inactivation of the receptor as a consequence of nuclear sequestration via constitutive import. Concomitantly mutants lacking this residue are exclusively localised in the nucleus. Although ligands accelerate nuclear import transiently, stable nuclear transition depends on a motif adjacent to Val 647 that comprises residues 650-661. Together, this defined region within the Q-rich domain regulates intracellular trafficking of the AHR in context of both nucleocytoplasmic shuttling and receptor activation. Nuclear export therefore depends on the previously characterised N-terminal NES and the newly identified motif that includes V647. Nucleocytoplasmic distribution of full-length human AHR is further affected by a section of the PST domain that shows sequence similarities with nuclear export signals. In concert, these motifs maintain a predominant cytoplasmic compartmentalisation, receptive for ligand binding. PMID:27535013

  15. INOH: ontology-based highly structured database of signal transduction pathways

    OpenAIRE

    Yamamoto, Satoko; Sakai, Noriko; Nakamura, Hiromi; Fukagawa, Hiroshi; Fukuda, Ken; Takagi, Toshihisa

    2011-01-01

    The Integrating Network Objects with Hierarchies (INOH) database is a highly structured, manually curated database of signal transduction pathways including Mammalia, Xenopus laevis, Drosophila melanogaster, Caenorhabditis elegans and canonical. Since most pathway knowledge resides in scientific articles, the database focuses on curating and encoding textual knowledge into a machine-processable form. We use a hierarchical pathway representation model with a compound graph, and every pathway c...

  16. An alternative pathway for signal flow from rod photoreceptors to ganglion cells in mammalian retina.

    OpenAIRE

    DeVries, S H; Baylor, D A

    1995-01-01

    Rod signals in the mammalian retina are thought to reach ganglion cells over the circuit rod-->rod depolarizing bipolar cell-->AII amacrine cell-->cone bipolar cells-->ganglion cells. A possible alternative pathway involves gap junctions linking the rods and cones, the circuit being rod-->cone-->cone bipolar cells-->ganglion cells. It is not clear whether this second pathway indeed relays rod signals to ganglion cells. We studied signal flow in the isolated rabbit retina with a multielectrode...

  17. Interactions among oscillatory pathways in NF-kappa B signaling

    Directory of Open Access Journals (Sweden)

    White Michael RH

    2011-02-01

    Full Text Available Abstract Background Sustained stimulation with tumour necrosis factor alpha (TNF-alpha induces substantial oscillations—observed at both the single cell and population levels—in the nuclear factor kappa B (NF-kappa B system. Although the mechanism has not yet been elucidated fully, a core system has been identified consisting of a negative feedback loop involving NF-kappa B (RelA:p50 hetero-dimer and its inhibitor I-kappa B-alpha. Many authors have suggested that this core oscillator should couple to other oscillatory pathways. Results First we analyse single-cell data from experiments in which the NF-kappa B system is forced by short trains of strong pulses of TNF-alpha. Power spectra of the ratio of nuclear-to-cytoplasmic concentration of NF-kappa B suggest that the cells' responses are entrained by the pulsing frequency. Using a recent model of the NF-kappa B system due to Caroline Horton, we carried out extensive numerical simulations to analyze the response frequencies induced by trains of pulses of TNF-alpha stimulation having a wide range of frequencies and amplitudes. These studies suggest that for sufficiently weak stimulation, various nonlinear resonances should be observable. To explore further the possibility of probing alternative feedback mechanisms, we also coupled the model to sinusoidal signals with a wide range of strengths and frequencies. Our results show that, at least in simulation, frequencies other than those of the forcing and the main NF-kappa B oscillator can be excited via sub- and superharmonic resonance, producing quasiperiodic and even chaotic dynamics. Conclusions Our numerical results suggest that the entrainment phenomena observed in pulse-stimulated experiments is a consequence of the high intensity of the stimulation. Computational studies based on current models suggest that resonant interactions between periodic pulsatile forcing and the system's natural frequencies may become evident for sufficiently

  18. Lung cancer, intracellular signaling pathways, and preclinical models

    International Nuclear Information System (INIS)

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced anti-tumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the anti-tumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing anti-tumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. We then focus on animal models. Preclinical models of NSCLC require better clinical relevance to study disease mechanisms and innovative

  19. Simulator for SUPO, a Benchmark Aqueous Homogeneous Reactor (AHR)

    Energy Technology Data Exchange (ETDEWEB)

    Klein, Steven Karl [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Determan, John C. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-10-14

    A simulator has been developed for SUPO (Super Power) an aqueous homogeneous reactor (AHR) that operated at Los Alamos National Laboratory (LANL) from 1951 to 1974. During that period SUPO accumulated approximately 600,000 kWh of operation. It is considered the benchmark for steady-state operation of an AHR. The SUPO simulator was developed using the process that resulted in a simulator for an accelerator-driven subcritical system, which has been previously reported.

  20. Simulator for SUPO, a Benchmark Aqueous Homogeneous Reactor (AHR)

    International Nuclear Information System (INIS)

    A simulator has been developed for SUPO (Super Power) an aqueous homogeneous reactor (AHR) that operated at Los Alamos National Laboratory (LANL) from 1951 to 1974. During that period SUPO accumulated approximately 600,000 kWh of operation. It is considered the benchmark for steady-state operation of an AHR. The SUPO simulator was developed using the process that resulted in a simulator for an accelerator-driven subcritical system, which has been previously reported.

  1. Comparison of growth factor signalling pathway utilisation in cultured normal melanocytes and melanoma cell lines

    International Nuclear Information System (INIS)

    The phosphatidylinositol-3-kinase (PI3K-PKB), mitogen activated protein kinase (MEK-ERK) and the mammalian target of rapamycin (mTOR- p70S6K), are thought to regulate many aspects of tumour cell proliferation and survival. We have examined the utilisation of these three signalling pathways in a number of cell lines derived from patients with metastatic malignant melanoma of known PIK3CA, PTEN, NRAS and BRAF mutational status. Western blotting was used to compare the phosphorylation status of components of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways, as indices of pathway utilisation. Normal melanocytes could not be distinguished from melanoma cells on the basis of pathway utilisation when grown in the presence of serum, but could be distinguished upon serum starvation, where signalling protein phosphorylation was generally abrogated. Surprisingly, the differential utilisation of individual pathways was not consistently associated with the presence of an oncogenic or tumour suppressor mutation of genes in these pathways. Utilisation of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways in melanoma, as determined by phosphorylation of signalling components, varies widely across a series of cell lines, and does not directly reflect mutation of genes coding these components. The main difference between cultured normal melanocytes and melanoma cells is not the pathway utilisation itself, but rather in the serum dependence of pathway utilisation

  2. Hypertrophy signaling pathways in experimental chronic aortic regurgitation

    DEFF Research Database (Denmark)

    Olsen, Niels Thue; Dimaano, Veronica L; Fritz-Hansen, Thomas;

    2013-01-01

    The development of left ventricular hypertrophy and dysfunction in aortic regurgitation (AR) has only been sparsely studied experimentally. In a new model of chronic AR in rats, we examined activation of molecular pathways involved in myocardial hypertrophy. Chronic AR was produced by damaging on...... of activation of intracellular pathways different from that seen with pathological hypertrophy in pressure overload, and more similar to that associated with benign physiological hypertrophy....

  3. Signaling pathways and stem cells in uterus and fallopian tubes

    OpenAIRE

    Wang, Yongqian

    2012-01-01

    textabstractDuring her fertile years, the endometrium of fertile women undergoes regular cycles of regeneration, differentiation and shedding, driven by changing concentrations of the steroid hormones estradiol and progesterone. In the present study, the role of Wnt/β-catenin signaling in relation to steroid hormone signaling and the balance between proliferation and differentiation was investigated. Furthermore, since the consequence of hormone signaling in the endometrium is tissue degradat...

  4. Noise in cellular signaling pathways: causes and effects

    OpenAIRE

    Ladbury, John E.; Arold, Stefan T.

    2012-01-01

    Noise caused by stochastic fluctuations in genetic circuits (transcription and translation) is now appreciated as a central aspect of cell function and phenotypic behavior. Noise has also been detected in signaling networks, but the origin of this noise and how it shapes cellular outcomes remain poorly understood. Here, we argue that noise in signaling networks results from the intrinsic promiscuity of protein-protein interactions, and that this noise has shaped cellular signal transduction. ...

  5. Down regulation of hepatic PPARalpha function by AhR ligand.

    Science.gov (United States)

    Shaban, Zein; El-Shazly, Samir; Abdelhady, Shawky; Fattouh, Ibrahim; Muzandu, Kaampwe; Ishizuka, Mayumi; Kimura, Kazuhiro; Kazusaka, Akio; Fujita, Shoichi

    2004-11-01

    Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a spectrum of toxic and biological effects of 2,3,7,8-tetrachloro dibenzo-p-dioxin (TCDD) and related compounds. Peroxisome proliferator activated receptor alpha (PPARalpha) is a nuclear receptor involved in the maintenance of lipid and glucose homeostasis. In this study we hypothesized that one of the possible mechanisms for the effect of TCDD and its related chemicals on fat metabolism could be through down regulation of PPARalpha functions. We treated Wistar rats with an AhR ligand, Sudan III (S.III), and/or PPARalpha ligand, Clofibric Acid (CA), for 3 days. We analysed the expression of one of the PPARalpha-target gene products, CYP4A protein and its mRNA. We also tested HepG2 cells with the afore-mentioned treatments and evaluated their effects on PPARalpha and RXRalpha protein. Treatment of Wistar rats with S.III was found to down regulates CYP4A protein expression and reduced its induction with CA. It also decreased mRNA expressions of CYP4A1, CYP4A2, CYP4A3 and PPARalpha. In HepG2 cells, PPARalpha and RXRalpha protein expression was decreased by S.III treatment in a dose dependent manner. Our results suggest that AhR has an inhibitory effect on PPARalpha function and a new pathway by which AhR ligands could disturb lipid metabolism. PMID:15585952

  6. Liposomal Lipopolysaccharide Initiates TRIF-Dependent Signaling Pathway Independent of CD14

    OpenAIRE

    Sachiko Watanabe; Yoshio Kumazawa; Joe Inoue

    2013-01-01

    Lipopolysaccharide (LPS) is recognized by CD14 with Toll-like receptor 4 (TLR4), and initiates 2 major pathways of TLR4 signaling, the MyD88-dependent and TRIF-dependent signaling pathways. The MyD88-dependent pathway induces inflammatory responses such as the production of TNF-α, IL-6, and IL-12 via the activation of NFκB and MAPK. The TRIF-dependent pathway induces the production of type-I IFN, and RANTES via the activation of IRF-3 and NFκB, and is also important for the induction of adapt...

  7. Aryl hydrocarbon receptor (AHR-regulated transcriptomic changes in rats sensitive or resistant to major dioxin toxicities

    Directory of Open Access Journals (Sweden)

    Okey Allan B

    2010-04-01

    Full Text Available Abstract Background The major toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD appear to result from dysregulation of mRNA levels mediated by the aryl hydrocarbon receptor (AHR. Dioxin-like chemicals alter expression of numerous genes in liver, but it remains unknown which lie in pathways leading to major toxicities such as hepatotoxicity, wasting and lethality. To identify genes involved in these responses we exploited a rat genetic model. Rats expressing an AHR splice-variant lacking a portion of the transactivation domain are highly resistant to dioxin-induced toxicities. We examined changes in hepatic mRNA abundances 19 hours after TCDD treatment in two dioxin-resistant rat strains/lines and two dioxin-sensitive rat strains/lines. Results Resistant rat strains/lines exhibited fewer transcriptional changes in response to TCDD than did rats with wildtype AHR. However, well-known AHR-regulated and dioxin-inducible genes such as CYP1A1, CYP1A2, and CYP1B1 remained fully responsive to TCDD in all strains/lines. Pathway analysis indicated that the genes which respond differently to TCDD between sensitive and resistant rats are mainly involved in lipid metabolism, cellular membrane function and energy metabolism. These pathways previously have been shown to respond differently to dioxin treatment in dioxin-sensitive versus dioxin-resistant rats at a biochemical level and in the differential phenotype of toxicologic responses. Conclusion The transactivation-domain deletion in dioxin-resistant rats does not abolish global AHR transactivational activity but selectively interferes with expression of subsets of genes that are candidates to mediate or protect from major dioxin toxicities such as hepatotoxicity, wasting and death.

  8. Neuro-protective effects of CNTF on hippocampal neurons via an unknown signal transduction pathway

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In our previous study, we proposed that there may be an unknown pathway in the upper stream of the known signal transduction pathway of Ciliary neurotrophic factor (CNTF) that mediates the neuro-protective function of CNTF. In the present experiment, we observed that the neuro-protective function of the non-classic signal transduction pathway in a L-NMDA (a glutamic acid ion type receptor atagonist) induced hippocampal neuron injury model, using primary culture rat hippocampal neurons, continuous photography and gp130 immunohistochemical assay. The results showed that L-NMDA induced injurious reaction of hippocampal neurons, and CNTF was able to inhibit the toxic action of L-NMDA on hippocampal neurons. Additionally, when JAK/STATs in the known classic signal transduction pathway of CNTF were blocked by PTPi-2, the protective effect of CNTF against L-NMDA injury still existed. L-NMDA caused a rapid increase in the concentration of hippocampal intracellular free [Ca2+]i. CNTF was able to attenuate L-NMDA-induced elevation of [Ca2+]i, and blocking JAK/STATs in the known classic signal trans- duction pathway of CNTF did not affect L-NMDA- induced elevation of [Ca2+]i, indicating that, apart from the known classic signal transduction pathway, there may be some other transduction pathways for CNTF to exert the protective effect on hippocampal neurons, and this pathway is related to [Ca2+].

  9. CLE peptides and their signaling pathways in plant development.

    Science.gov (United States)

    Yamaguchi, Yasuka L; Ishida, Takashi; Sawa, Shinichiro

    2016-08-01

    Cell-to-cell communication is crucial for the coherent functioning of multicellular organisms, and they have evolved intricate molecular mechanisms to achieve such communication. Small, secreted peptide hormones participate in cell-to-cell communication to regulate various physiological processes. One such family of plant peptide hormones is the CLAVATA3 (CLV3)/EMBRYO SURROUNDING REGION-related (CLE) family, whose members play crucial roles in the differentiation of shoot and root meristems. Recent biochemical and genetic studies have characterized various CLE signaling modules, which include CLE peptides, transmembrane receptors, and downstream intracellular signaling components. CLE signaling systems are conserved across the plant kingdom but have divergent modes of action in various developmental processes in different species. Moreover, several CLE peptides play roles in symbiosis, parasitism, and responses to abiotic cues. Here we review recent studies that have provided new insights into the mechanisms of CLE signaling. PMID:27229733

  10. No-dependent signaling pathways in unloaded skeletal muscle

    OpenAIRE

    Shenkman, Boris S.; Nemirovskaya, Tatiana L.; Lomonosova, Yulia N.

    2015-01-01

    The main focus of the current review is the nitric oxide (NO)-mediated signaling mechanism in unloaded skeletal. Review of the published data describing muscles during physical activity and inactivity demonstrates that NO is an essential trigger of signaling processes, which leads to structural and metabolic changes of the muscle fibers. The experiments with modulation of NO-synthase (NOS) activity during muscle unloading demonstrate the ability of an activated enzyme to stabilize degradation...

  11. BowTieBuilder: modeling signal transduction pathways

    OpenAIRE

    Schröder Adrian; Dräger Andreas; Planatscher Hannes; Spangenberg Lucía; Supper Jochen; Zell Andreas

    2009-01-01

    Abstract Background Sensory proteins react to changing environmental conditions by transducing signals into the cell. These signals are integrated into core proteins that activate downstream target proteins such as transcription factors (TFs). This structure is referred to as a bow tie, and allows cells to respond appropriately to complex environmental conditions. Understanding this cellular processing of information, from sensory proteins (e.g., cell-surface proteins) to target proteins (e.g...

  12. MicroRNAs Regulating Signaling Pathways: Potential Biomarkers in Systemic Sclerosis

    Directory of Open Access Journals (Sweden)

    Yisha Li

    2015-08-01

    Full Text Available Systemic sclerosis (SSc is a multisystem fibrotic and autoimmune disease. Both genetic and epigenetic elements mediate SSc pathophysiology. This review summarizes the role of one epigenetic element, known as microRNAs (miRNAs, involved in different signaling pathways of SSc pathogenesis. The expression of key components in transforming growth factor-β (TGF-β signaling pathway has been found to be regulated by miRNAs both upstream and downstream of TGF-β. We are specifically interested in the pathway components upstream of TGF-β, while miRNAs in other signaling pathways have not been extensively studied. The emerging role of miRNAs in vasculopathy of SSc suggests a promising new direction for future investigation. Elucidation of the regulatory role of miRNAs in the expression of signaling factors may facilitate the discovery of novel biomarkers in SSc and improve the understanding and treatment of this disease.

  13. MicroRNAs Regulating Signaling Pathways:Potential Biomarkers in Systemic Sclerosis

    Institute of Scientific and Technical Information of China (English)

    Yisha Li; Jing Huang; Muyao Guo; Xiaoxia Zuo

    2015-01-01

    Systemic sclerosis (SSc) is a multisystem fibrotic and autoimmune disease. Both genetic and epigenetic elements mediate SSc pathophysiology. This review summarizes the role of one epigenetic element, known as microRNAs (miRNAs), involved in different signaling pathways of SSc pathogenesis. The expression of key components in transforming growth factor-b (TGF-b) signaling pathway has been found to be regulated by miRNAs both upstream and downstream of TGF-b. We are specifically interested in the pathway components upstream of TGF-b, while miRNAs in other signaling pathways have not been extensively studied. The emerging role of miRNAs in vasculopathy of SSc suggests a promising new direction for future investigation. Elu-cidation of the regulatory role of miRNAs in the expression of signaling factors may facilitate the discovery of novel biomarkers in SSc and improve the understanding and treatment of this disease.

  14. Differential Modulation of Nods Signaling Pathways by Fatty Acids in Human Colonic Epithelial HCT116 cells

    Science.gov (United States)

    Nucleotide-binding oligomerization domain containing proteins (Nods) are intracellular pattern recognition receptors (PRRs) recognizing conserved moieties of bacterial peptidoglycan through their leucine-rich repeats (LRR) domain. The agonists for Nods activate proinflammtory signaling pathways incl...

  15. Redox and zinc signalling pathways converging on protein tyrosine phosphatases.

    Science.gov (United States)

    Bellomo, Elisa; Hogstrand, Christer; Maret, Wolfgang

    2014-10-01

    Zinc ions, though redox-inert, have either pro-antioxidant or pro-oxidant functions at critical junctures in redox metabolism and redox signalling. They are released from cells and in cells, e.g. from metallothionein, a protein that transduces redox signals into zinc signals (1). The released zinc ions inhibit enzymes such as protein tyrosine phosphatases (PTPs), key regulatory enzymes of cellular phosphorylation signalling. The Ki(Zn) value for inhibition of receptor PTPB is 21pM (2). The binding is about as tight as the binding of zinc to zinc metalloenzymes and suggests tonic zinc inhibition. PTP1-B (PTPN1), an enzyme regulating the insulin and leptin receptors and involved in cancer and diabetes pathobiochemistry, has a Ki(Zn) value of about 5nM (3). Zinc ions bind to the enzyme in the closed conformation when additional metal-binding ligands are brought into the vicinity of the active site. In contrast, redox reactions target cysteines in the active sites of PTPs in the open conformation. This work provides a molecular basis how hydrogen peroxide and free zinc ions generated by growth factor signalling stimulate phosphorylation signalling differentially. (Supported by the Biotechnology and Biological Sciences Research Council UK, grant BB/K001442/1.). PMID:26461422

  16. Relationships between Signaling Pathway Usage and Sensitivity to a Pathway Inhibitor: Examination of Trametinib Responses in Cultured Breast Cancer Lines

    Science.gov (United States)

    Leung, Euphemia Y.; Kim, Ji Eun; Askarian-Amiri, Marjan; Rewcastle, Gordon W.; Finlay, Graeme J.; Baguley, Bruce C.

    2014-01-01

    Cellular signaling pathways involving mTOR, PI3K and ERK have dominated recent studies of breast cancer biology, and inhibitors of these pathways have formed a focus of numerous clinical trials. We have chosen trametinib, a drug targeting MEK in the ERK pathway, to address two questions. Firstly, does inhibition of a signaling pathway, as measured by protein phosphorylation, predict the antiproliferative activity of trametinib? Secondly, do inhibitors of the mTOR and PI3K pathways synergize with trametinib in their effects on cell proliferation? A panel of 30 human breast cancer cell lines was chosen to include lines that could be classified according to whether they were ER and PR positive, HER2 over-expressing, and “triple negative”. Everolimus (targeting mTOR), NVP-BEZ235 and GSK2126458 (both targeting PI3K/mTOR) were chosen for combination experiments. Inhibition of cell proliferation was measured by IC50 values and pathway utilization was measured by phosphorylation of signaling kinases. Overall, no correlation was found between trametinib IC50 values and inhibition of ERK signaling. Inhibition of ERK phosphorylation was observed at trametinib concentrations not affecting proliferation, and sensitivity of cell proliferation to trametinib was found in cell lines with low ERK phosphorylation. Evidence was found for synergy between trametinib and either everolimus, NVP-BEZ235 or GSK2126458, but this was cell line specific. The results have implications for the clinical application of PI3K/mTOR and MEK inhibitors. PMID:25170609

  17. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria

    OpenAIRE

    Han, Derick; Dara, Lily; Win, Sanda; Than, Tin Aung; Yuan, Liyun; Abbasi, Sadeea Q; Liu, Zhang-Xu; Kaplowitz, Neil

    2013-01-01

    Drugs that cause liver injury often “stress” mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Due to adaptation, drugs alone rarely cause liver injury, with acetaminophen being the notable excep...

  18. Sox17 regulates the Wnt/beta-catenin signaling pathway in oligodendrocyte progenitor cells

    OpenAIRE

    Chew, Li-Jin; Shen, Weiping; Ming, Xiaotian; Senatorov, Vladimir V.; Chen, Hui-Ling; Ying CHENG; Hong, Elim; Knoblach, Susan; Gallo, Vittorio

    2011-01-01

    The SRY-box (Sox) transcription factors regulate oligodendrocyte differentiation, but their signaling targets are largely unknown. We have identified a major signal transduction pathway regulated by Sox17 in the oligodendrocyte lineage. Microarray analysis in oligodendrocyte progenitor cells (OPCs) after Sox17 attenuation revealed upregulated genes associated with cell cycle control and activation of the Wnt/beta-catenin-pathway. Sox17 knockdown also increases the levels of cyclinD1, Axin2 an...

  19. Regulation of Cell Wall Biogenesis in Saccharomyces cerevisiae: The Cell Wall Integrity Signaling Pathway

    OpenAIRE

    Levin, David E.

    2011-01-01

    The yeast cell wall is a strong, but elastic, structure that is essential not only for the maintenance of cell shape and integrity, but also for progression through the cell cycle. During growth and morphogenesis, and in response to environmental challenges, the cell wall is remodeled in a highly regulated and polarized manner, a process that is principally under the control of the cell wall integrity (CWI) signaling pathway. This pathway transmits wall stress signals from the cell surface to...

  20. Teaching the Toolkit: A Laboratory Series to Demonstrate the Evolutionary Conservation of Metazoan Cell Signaling Pathways

    Science.gov (United States)

    LeClair, Elizabeth E.

    2008-01-01

    A major finding of comparative genomics and developmental genetics is that metazoans share certain conserved, embryonically deployed signaling pathways that instruct cells as to their ultimate fate. Because the DNA encoding these pathways predates the evolutionary split of most animal groups, it should in principle be possible to clone…

  1. A SNARE-protein has opposing functions in penetration resistance and defence signalling pathways

    DEFF Research Database (Denmark)

    Zhang, Ziguo; Feechan, Angela; Pedersen, Carsten;

    2007-01-01

    Penetration resistance is often the first line of defence against fungal pathogens. Subsequently induced defences are mediated by the programmed cell death (PCD) reaction pathway and the salicylic acid (SA), jasmonic acid (JA) and ethylene (ET) signalling pathways. We previously demonstrated...

  2. Medullary Thyroid Carcinoma: Molecular Signaling Pathways and Emerging Therapies

    Directory of Open Access Journals (Sweden)

    Karen Gómez

    2011-01-01

    Full Text Available Research on medullary thyroid carcinoma (MTC over the last 55 years has led to a good understanding of the genetic defects and altered molecular pathways associated with its development. Currently, with the use of genetic testing, patients at high risk for MTC can be identified before the disease develops and offered prophylactic treatment. In cases of localized neck disease, surgery can be curative. However, once MTC has spread beyond the neck, systemic therapy may be necessary. Conventional chemotherapy has been shown to be ineffective; however, multikinase inhibitors have shown promise in stabilizing disease, and this year will probably see the approval of a drug (Vandetanib for advanced unresectable or metastatic disease, which represents a new chapter in the history of MTC. In this paper, we explore newly understood molecular pathways and the most promising emerging therapies that may change the management of MTC.

  3. DMPD: Signal transduction pathways mediated by the interaction of CpG DNA withToll-like receptor 9. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14751759 Signal transduction pathways mediated by the interaction of CpG DNA withTo...;16(1):17-22. (.png) (.svg) (.html) (.csml) Show Signal transduction pathways mediated by the interaction of... CpG DNA withToll-like receptor 9. PubmedID 14751759 Title Signal transduction pa

  4. NO-DEPENDENT SIGNALING PATHWAYS IN UNLOADED SKELETAL MUSCLE

    Directory of Open Access Journals (Sweden)

    Boris Stivovich Shenkman

    2015-10-01

    Full Text Available The main focus of the current review is the nitric oxide (NO-mediated signaling mechanism in unloaded skeletal. Review of the published data describing muscles during physical activity and inactivity demonstrates that NO is an essential trigger of signaling processes, which leads to structural and metabolic changes of the muscle fibers. The experiments with modulation of NO-synthase (NOS activity during muscle unloading demonstrate the ability of an activated enzyme to stabilize degradation processes and prevent development of muscle atrophy. Various forms of muscle mechanical activity, i.e plantar afferent stimulation, resistive exercise and passive chronic stretch increase the content of neural NOS (nNOS and thus may facilitate an increase in NO production. Recent studies demonstrate that NO-synthase participates in the regulation of protein and energy metabolism in skeletal muscle by fine-tuning and stabilizing complex signaling systems which regulate protein synthesis and degradation in the fibers of inactive muscle.

  5. The crosstalk between EGF, IGF, and Insulin cell signaling pathways - computational and experimental analysis

    Directory of Open Access Journals (Sweden)

    Przytycka Teresa M

    2009-09-01

    Full Text Available Abstract Background Cellular response to external stimuli requires propagation of corresponding signals through molecular signaling pathways. However, signaling pathways are not isolated information highways, but rather interact in a number of ways forming sophisticated signaling networks. Since defects in signaling pathways are associated with many serious diseases, understanding of the crosstalk between them is fundamental for designing molecularly targeted therapy. Unfortunately, we still lack technology that would allow high throughput detailed measurement of activity of individual signaling molecules and their interactions. This necessitates developing methods to prioritize selection of the molecules such that measuring their activity would be most informative for understanding the crosstalk. Furthermore, absence of the reaction coefficients necessary for detailed modeling of signal propagation raises the question whether simple parameter-free models could provide useful information about such pathways. Results We study the combined signaling network of three major pro-survival signaling pathways: Epidermal Growth Factor Receptor (EGFR, Insulin-like Growth Factor-1 Receptor (IGF-1R, and Insulin Receptor (IR. Our study involves static analysis and dynamic modeling of this network, as well as an experimental verification of the model by measuring the response of selected signaling molecules to differential stimulation of EGF, IGF and insulin receptors. We introduced two novel measures of the importance of a node in the context of such crosstalk. Based on these measures several molecules, namely Erk1/2, Akt1, Jnk, p70S6K, were selected for monitoring in the network simulation and for experimental studies. Our simulation method relies on the Boolean network model combined with stochastic propagation of the signal. Most (although not all trends suggested by the simulations have been confirmed by experiments. Conclusion The simple model

  6. Signaling pathways and stem cells in uterus and fallopian tubes

    NARCIS (Netherlands)

    Y. Wang (Yongqian)

    2012-01-01

    textabstractDuring her fertile years, the endometrium of fertile women undergoes regular cycles of regeneration, differentiation and shedding, driven by changing concentrations of the steroid hormones estradiol and progesterone. In the present study, the role of Wnt/β-catenin signaling in relation t

  7. Identification of photoperception and light signal transduction pathways in citrus

    Directory of Open Access Journals (Sweden)

    Vera Quecini

    2007-01-01

    Full Text Available Studies employing model species have elucidated several aspects of photoperception and light signal transduction that control plant development. However, the information available for economically important crops is scarce. Citrus genome databases of expressed sequence tags (EST were investigated in order to identify genes coding for functionally characterized proteins responsible for light-regulated developmental control in model plants. Approximately 176,200 EST sequences from 53 libraries were queried and all bona fide and putative photoreceptor gene families were found in citrus species. We have identified 53 orthologs for several families of transcriptional regulators and cytoplasmic proteins mediating photoreceptor-induced responses although some important Arabidopsis phytochrome- and cryptochrome-signaling components are absent from citrus sequence databases. The main gene families responsible for phototropin-mediated signal transduction were present in citrus transcriptome, including general regulatory factors (14-3-3 proteins, scaffolding elements and auxin-responsive transcription factors and transporters. A working model of light perception, signal transduction and response-eliciting in citrus is proposed based on the identified key components. These results demonstrate the power of comparative genomics between model systems and economically important crop species to elucidate several aspects of plant physiology and metabolism.

  8. Understanding and Targeting the Wnt/β-Catenin Signaling Pathway in Chronic Leukemia

    Directory of Open Access Journals (Sweden)

    S. Thanendrarajan

    2011-01-01

    Full Text Available It has been revealed that the Wnt/β-catenin signaling pathway plays an important role in the development of solid tumors and hematological malignancies, particularly in B-cell neoplasia and leukemia. In the last decade there have been made experimental approaches targeting the Wnt pathway in chronic leukemia. In this paper we provide an overview about the current state of knowledge regarding the Wnt/β-catenin signaling pathway in chronic leukemia with special focus on therapeutic options and strategies.

  9. Curcumin and emodin down-regulate TGF-β signaling pathway in human cervical cancer cells.

    Directory of Open Access Journals (Sweden)

    Pooja Chandrakant Thacker

    Full Text Available Cervical cancer is the major cause of cancer related deaths in women, especially in developing countries and Human Papilloma Virus infection in conjunction with multiple deregulated signaling pathways leads to cervical carcinogenesis. TGF-β signaling in later stages of cancer is known to induce epithelial to mesenchymal transition promoting tumor growth. Phytochemicals, curcumin and emodin, are effective as chemopreventive and chemotherapeutic compounds against several cancers including cervical cancer. The main objective of this work was to study the effect of curcumin and emodin on TGF-β signaling pathway and its functional relevance to growth, migration and invasion in two cervical cancer cell lines, SiHa and HeLa. Since TGF-β and Wnt/β-catenin signaling pathways are known to cross talk having common downstream targets, we analyzed the effect of TGF-β on β-catenin (an important player in Wnt/β-catenin signaling and also studied whether curcumin and emodin modulate them. We observed that curcumin and emodin effectively down regulate TGF-β signaling pathway by decreasing the expression of TGF-β Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-β by inhibiting the TGF-β-induced migration and invasion. Expression of downstream effectors of TGF-β signaling pathway, cyclinD1, p21 and Pin1, was inhibited along with the down regulation of key mesenchymal markers (Snail and Slug upon curcumin and emodin treatment. Curcumin and emodin were also found to synergistically inhibit cell population and migration in SiHa and HeLa cells. Moreover, we found that TGF-β activates Wnt/β-catenin signaling pathway in HeLa cells, and curcumin and emodin down regulate the pathway by inhibiting β-catenin. Taken together our data provide a mechanistic basis for the use of curcumin and emodin in the treatment of cervical cancer.

  10. Conservation of early odontogenic signaling pathways in Aves

    OpenAIRE

    Chen, Yiping; Zhang, Yanding; Jiang, Ting-Xing; Barlow, Amanda J.; St Amand, Tara R; Hu, Yueping; Heaney, Shaun; Francis-West, Philippa; Chuong, Cheng-Ming; Maas, Richard

    2000-01-01

    Teeth have been missing from birds (Aves) for at least 60 million years. However, in the chick oral cavity a rudiment forms that resembles the lamina stage of the mammalian molar tooth germ. We have addressed the molecular basis for this secondary loss of tooth formation in Aves by analyzing in chick embryos the status of molecular pathways known to regulate mouse tooth development. Similar to the mouse dental lamina, expression of Fgf8, Pitx2, Barx1, and Pax9 defines a potential chick odonto...

  11. Interleukin-2 signaling pathway analysis by quantitative phosphoproteomics

    DEFF Research Database (Denmark)

    Osinalde, Nerea; Moss, Helle; Arrizabalaga, Onetsine;

    2011-01-01

    by IL-2, we aimed to define the global tyrosine-phosphoproteome of IL-2 pathway in human T cell line Kit225 using high resolution mass spectrometry combined with phosphotyrosine immunoprecipitation and SILAC. The molecular snapshot at 5min of IL-2 stimulation resulted in identification of 172...... proteins among which 79 were found with increased abundance in the tyrosine-phosphorylated complexes, including several previously not reported IL-2 downstream effectors. Combinatorial site-specific phosphoproteomic analysis resulted in identification of 99 phosphorylated sites mapping to the identified...

  12. Pulsating fluid flow modulates gene expression of proteins involved in Wnt signaling pathways in osteocytes

    NARCIS (Netherlands)

    A. Santos; A.D. Bakker; B. Zandieh-Doulabi; C.M. Semeins; J. Klein-Nulend

    2009-01-01

    Strain-derived flow of interstitial fluid activates signal transduction pathways in osteocytes that regulate bone mechanical adaptation. Wnts are involved in this process, but whether mechanical loading modulates Wnt signaling in osteocytes is unclear. We assessed whether mechanical stimulation by p

  13. Involvement of Jasmonate- signaling pathway in the herbivore-induced rice plant defense

    Institute of Scientific and Technical Information of China (English)

    XU Tao; ZHOU Qiang; CHEN Wei; ZHANG Guren; HE Guofeng; GU Dexiang; ZHANG Wenqing

    2003-01-01

    The expression patterns of eight defense- related genes in the herbivore-infested and jasmonate- treated (jasmonic acid, JA and its derivative MeJA) rice leaves were analyzed using RT-PCR. The results showed that Spodoptera litura Fabricius (Lepidoptera: Noctuidae) herbivory induced the expression of lipoxygenase (LOX) and allene oxide synthase (AOS) genes that are involved in the jasmonate-signaling pathway. Moreover, S. Litura damage resulted in the expression of farnesyl pyrophosphate synthase (FPS), Bowman-birk proteinase inhibitor (BBPI), phenylalanine ammonia-lyase (PAL) and other rice defense- related genes that were also induced by aqueous JA treatment or gaseous MeJA treatment. These indicated that in rice leaves, the JA-related signaling pathway was involved in the S. Litura-induced chemical defense. Mechanical damage and brown planthopper (BPH), Nilaparvata lugens (Stal) (Homoptera: Delphacidae) damage induced the expression of LOX gene, but both treatments did not induce the expression of AOS gene. However, BPH damage induced the expression of acidic pathogen-related protein 1 (PR-1a), Chitinase (PR-3), and PAL genes, which is involved in the salicylate- signaling pathway. It was suggested that salicylate-related signaling pathway or other pathways, rather than jasmonate-signaling pathway was involved in the BPH-induced rice plant defense.

  14. Identification of photoperception and light signal transduction pathways in citrus

    OpenAIRE

    Vera Quecini

    2007-01-01

    Studies employing model species have elucidated several aspects of photoperception and light signal transduction that control plant development. However, the information available for economically important crops is scarce. Citrus genome databases of expressed sequence tags (EST) were investigated in order to identify genes coding for functionally characterized proteins responsible for light-regulated developmental control in model plants. Approximately 176,200 EST sequences from 53 libraries...

  15. Phytohormones Signaling Pathways and ROS Involvement in Seed Germination

    Science.gov (United States)

    Oracz, Krystyna; Karpiński, Stanisław

    2016-01-01

    Phytohormones and reactive oxygen species (ROS) are major determinants of the regulation of development and stress responses in plants. During life cycle of these organisms, signaling networks of plant growth regulators and ROS interact in order to render an appropriate developmental and environmental response. In plant’s photosynthetic (e.g., leaves) and non-photosynthetic (e.g., seeds) tissues, enhanced and suboptimal ROS production is usually associated with stress, which in extreme cases can be lethal to cells, a whole organ or even an organism. However, controlled production of ROS is appreciated for cellular signaling. Despite the current progress that has been made in plant biology and increasing number of findings that have revealed roles of ROS and hormonal signaling in germination, some questions still arise, e.g., what are the downstream protein targets modified by ROS enabling stimulus-specific cellular responses of the seed? Or which molecular regulators allow ROS/phytohormones interactions and what is their function in seed life? In this particular review the role of some transcription factors, kinases and phosphatases is discussed, especially those which usually known to be involved in ROS and hormonal signal transduction under stress in plants, may also play a role in the regulation of processes occurring in seeds. The summarized recent findings regarding particular ROS- and phytohormones-related regulatory proteins, as well as their integration, allowed to propose a novel, possible model of action of LESION SIMULATING DISEASE 1, ENHANCED DISEASE SUSCEPTIBILITY 1, and PHYTOALEXIN DEFICIENT 4 functioning during seeds life. PMID:27379144

  16. β1 Integrins Mediate Mechanosensitive Signaling Pathways in Osteocytes

    OpenAIRE

    Litzenberger, Julie B.; Tummala, Padmaja; Kim, Jae-Beom; Jacobs, Christopher R.

    2010-01-01

    Integrins are cell-substrate adhesion proteins that initiate intracellular signaling and may serve as mechanosensors in bone. MLO-Y4 cells were stably transfected with a dominant negative form of the β1 integrin subunit (β1DN) containing the transmembrane domain and cytoplasmic tail of β1 integrin. Cells expressing β1DN had reduced vinculin localization to focal contacts but no change in intracellular actin organization. When exposed to oscillatory fluid flow, β1DN cells exhibited a significa...

  17. WDR26 is a new partner of Axin1 in the canonical Wnt signaling pathway.

    Science.gov (United States)

    Goto, Toshiyasu; Matsuzawa, Junhei; Iemura, Shun-Ichiro; Natsume, Tohru; Shibuya, Hiroshi

    2016-05-01

    The stability of β-catenin is very important for canonical Wnt signaling. A protein complex including Axin/APC/GSK3β phosphorylates β-catenin to be degraded by ubiquitination with β-TrCP. In the recent study, we isolated WDR26, a protein that binds to Axin. Here, we found that WDR26 is a negative regulator of the canonical Wnt signaling pathway, and that WDR26 affected β-catenin levels. In addition, WDR26/Axin binding is involved in the ubiquitination of β-catenin. These results suggest that WDR26 plays a negative role in β-catenin degradation in the Wnt signaling pathway. PMID:27098453

  18. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria.

    Science.gov (United States)

    Han, Derick; Dara, Lily; Win, Sanda; Than, Tin Aung; Yuan, Liyun; Abbasi, Sadeea Q; Liu, Zhang-Xu; Kaplowitz, Neil

    2013-04-01

    Drugs that cause liver injury often 'stress' mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and nuclear factor erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Owing to adaptation, drugs alone rarely cause liver injury, with acetaminophen (APAP) being the notable exception. Drug-induced liver injury (DILI) usually involves other extrinsic factors, such as the adaptive immune system, that cause 'stressed' hepatocytes to become injured, leading to idiosyncratic DILI, the rare and unpredictable adverse drug reaction in the liver. Hepatocyte injury, due to drug and extrinsic insult, causes a second wave of signaling changes associated with adaptation, cell death, and repair. If the stress and injury reach a critical threshold, then death signaling pathways such as c-Jun N-terminal kinase (JNK) become dominant and hepatocytes enter a failsafe mode to undergo self-destruction. DILI can be seen as an active process involving recruitment of death signaling pathways that mediate cell death rather than a passive process due to overwhelming biochemical injury. In this review, we highlight the role of signal transduction pathways, which frequently involve mitochondria, in the development of DILI. PMID:23453390

  19. From fruitflies to mammals: mechanisms of signalling via the Sonic hedgehog pathway in lung development

    OpenAIRE

    Tuyl, Minke; Post, Martin

    2000-01-01

    The hedgehog signalling pathway has been implicated in many different processes in fly and vertebrate development. It is now known that the hedgehog cascade is crucial for the patterning of the early respiratory system. Hedgehog signalling in the lung involves Gli transcription proteins, but their potential downstream target genes have yet to be identified. Bmp4 and Fgf10 have been shown to regulate lung branching morphogenesis but seem not to be targets of hedgehog signalling.

  20. Novel Modeling of Cancer Cell Signaling Pathways Enables Systematic Drug Repositioning for Distinct Breast Cancer Metastases

    OpenAIRE

    Zhao, Hong; Jin, Guangxu; Cui, Kemi; Ren, Ding; Liu, Timothy; Chen, Peikai; Wong, Solomon; Li, Fuhai; Fan, Yubo; Rodriguez, Angel; Chang, Jenny; Wong, Stephen TC.

    2013-01-01

    A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to ...

  1. Applications Of Selected Reaction Monitoring (SRM)-Mass Spectrometry (MS) For Quantitative Measurement Of Signaling Pathways

    OpenAIRE

    Zhao, Yingxin; Allan R. Brasier

    2013-01-01

    Quantitative measurement of the major regulatory proteins in signaling networks poses several technical challenges, including low abundance, the presence of post-translational modifications (PTMs), and the lack of suitable affinity detection reagents. Using the innate immune response (IIR) as a model signaling pathway, we illustrate the approach of stable isotopic dilution (SID)-selected reaction monitoring (SRM)-mass spectrometry (MS) assays for quantification of low abundance signaling prot...

  2. Development of Drugs Targeting the PI3K Signalling Pathway in Leukaemias and Lymphomas

    OpenAIRE

    Alexandre Arcaro

    2015-01-01

    The phosphoinositide 3-kinase (PI3K) family of signalling enzymes play a key role in the transduction of signals from activated cell surface receptors controlling cell growth and proliferation, survival, metabolism, and migration. The intracellular signalling pathway from activated receptors to PI3K and its downstream targets v-akt murine thymoma viral oncogene homolog (Akt) and mechanistic target of rapamycin (mTOR) is very frequently deregulated by genetic and epigenetic mechanisms in human...

  3. Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways.

    OpenAIRE

    Sengupta, T K; Schmitt, E M; Ivashkiv, L B

    1996-01-01

    An important component of cytokine regulation of cell growth and differentiation is rapid transcriptional activation of genes by the JAK-STAT (signal transducer and activator of transcription) signaling pathway. Ligation of cytokine receptors results in tyrosine phosphorylation and activation of receptor-associated Jak protein tyrosine kinases and cytoplasmic STAT transcription factors, which then translocate to the nucleus. We describe the interruption of cytokine triggered JAK-STAT signals ...

  4. The ubiquitin–proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer

    Directory of Open Access Journals (Sweden)

    Voutsadakis Ioannis A

    2012-07-01

    Full Text Available Abstract Epithelial to Mesenchymal transition (EMT in cancer, a process permitting cancer cells to become mobile and metastatic, has a signaling hardwire forged from development. Multiple signaling pathways that regulate carcinogenesis enabling characteristics in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis are also the main players in EMT. These pathways, as almost all cellular processes, are in their turn regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS. Ubiquitination is the covalent link of target proteins with the small protein ubiquitin and serves as a signal to target protein degradation by the proteasome or to other outcomes such as endocytosis, degradation by the lysosome or specification of cellular localization. This paper reviews signal transduction pathways regulating EMT and being regulated by ubiquitination.

  5. Modular and Stochastic Approaches to Molecular Pathway Models of ATM, TGF beta, and WNT Signaling

    Science.gov (United States)

    Cucinotta, Francis A.; O'Neill, Peter; Ponomarev, Artem; Carra, Claudio; Whalen, Mary; Pluth, Janice M.

    2009-01-01

    Deterministic pathway models that describe the biochemical interactions of a group of related proteins, their complexes, activation through kinase, etc. are often the basis for many systems biology models. Low dose radiation effects present a unique set of challenges to these models including the importance of stochastic effects due to the nature of radiation tracks and small number of molecules activated, and the search for infrequent events that contribute to cancer risks. We have been studying models of the ATM, TGF -Smad and WNT signaling pathways with the goal of applying pathway models to the investigation of low dose radiation cancer risks. Modeling challenges include introduction of stochastic models of radiation tracks, their relationships to more than one substrate species that perturb pathways, and the identification of a representative set of enzymes that act on the dominant substrates. Because several pathways are activated concurrently by radiation the development of modular pathway approach is of interest.

  6. Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy.

    Science.gov (United States)

    Juan, Wen Chun; Hong, Wanjin

    2016-01-01

    The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators that are negatively regulated by the Hippo signaling pathway. By binding to transcription factors, especially the TEA domain transcription factors (TEADs), YAP and TAZ induce the expression of growth-promoting genes, which can promote organ regeneration after injury. Therefore, controlled activation of YAP and TAZ can be useful for regenerative medicine. However, aberrant activation of YAP and TAZ due to deregulation of the Hippo pathway or overexpression of YAP/TAZ and TEADs can promote cancer development. Hence, pharmacological inhibition of YAP and TAZ may be a useful approach to treat tumors with high YAP and/or TAZ activity. In this review, we present the mechanisms regulating the Hippo pathway, the role of the Hippo pathway in tissue repair and cancer, as well as a detailed analysis of the different strategies to target the Hippo signaling pathway and the genes regulated by YAP and TAZ for regenerative medicine and cancer therapy. PMID:27589805

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

    International Nuclear Information System (INIS)

    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

  8. 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.

  9. Liposomal lipopolysaccharide initiates TRIF-dependent signaling pathway independent of CD14.

    Directory of Open Access Journals (Sweden)

    Sachiko Watanabe

    Full Text Available Lipopolysaccharide (LPS is recognized by CD14 with Toll-like receptor 4 (TLR4, and initiates 2 major pathways of TLR4 signaling, the MyD88-dependent and TRIF-dependent signaling pathways. The MyD88-dependent pathway induces inflammatory responses such as the production of TNF-α, IL-6, and IL-12 via the activation of NFκB and MAPK. The TRIF-dependent pathway induces the production of type-I IFN, and RANTES via the activation of IRF-3 and NFκB, and is also important for the induction of adaptive immune responses. CD14 plays a critical role in initiating the TRIF-dependent signaling pathway response to LPS, to support the internalization of LPS via endocytosis. Here, we clearly demonstrate that intracellular delivery of LPS by LPS-formulated liposomes (LPS-liposomes initiate only TRIF-dependent signaling via clathrin-mediated endocytosis, independent of CD14. In fact, LPS-liposomes do not induce the production of TNF-α and IL-6 but induce RANTES production in peritoneal macrophages. Additionally, LPS-liposomes could induce adaptive immune responses effectively in CD14-deficient mice. Collectively, our results strongly suggest that LPS-liposomes are useful as a TRIF-dependent signaling-based immune adjuvant without inducing unnecessary inflammation.

  10. Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways

    Institute of Scientific and Technical Information of China (English)

    Michael J Nemeth; David M Bodine

    2007-01-01

    Hematopoietic stem cells (HSCs) are a rare population of cells that are responsible for life-long generation of blood cells of all lineages. In order to maintain their numbers, HSCs must establish a balance between the opposing cell fates of self-renewal (in which the ability to function as HSCs is retained) and initiation of hematopoietic differentiation. Multiple signaling pathways have been implicated in the regulation of HSC cell fate. One such set of pathways are those activated by the Wnt family of ligands. Wnt signaling pathways play a crucial role during embryogenesis and deregulation of these pathways has been implicated in the formation of solid tumors. Wnt signaling also plays a role in the regulation of stem cells from multiple tissues, such as embryonic, epidermal, and intestinal stem cells. However, the function of Wnt signaling in HSC biology is still controversial. In this review, we will discuss the basic characteristics of the adult HSC and its regulatory microenvironment, the "niche", focusing on the regulation of the HSC and its niche by the Wnt signaling pathways.

  11. Constraint-based modeling and kinetic analysis of the Smad dependent TGF-beta signaling pathway.

    Directory of Open Access Journals (Sweden)

    Zhike Zi

    Full Text Available BACKGROUND: Investigation of dynamics and regulation of the TGF-beta signaling pathway is central to the understanding of complex cellular processes such as growth, apoptosis, and differentiation. In this study, we aim at using systems biology approach to provide dynamic analysis on this pathway. METHODOLOGY/PRINCIPAL FINDINGS: We proposed a constraint-based modeling method to build a comprehensive mathematical model for the Smad dependent TGF-beta signaling pathway by fitting the experimental data and incorporating the qualitative constraints from the experimental analysis. The performance of the model generated by constraint-based modeling method is significantly improved compared to the model obtained by only fitting the quantitative data. The model agrees well with the experimental analysis of TGF-beta pathway, such as the time course of nuclear phosphorylated Smad, the subcellular location of Smad and signal response of Smad phosphorylation to different doses of TGF-beta. CONCLUSIONS/SIGNIFICANCE: The simulation results indicate that the signal response to TGF-beta is regulated by the balance between clathrin dependent endocytosis and non-clathrin mediated endocytosis. This model is useful to be built upon as new precise experimental data are emerging. The constraint-based modeling method can also be applied to quantitative modeling of other signaling pathways.

  12. Interactions between Trypanosoma cruzi Secreted Proteins and Host Cell Signaling Pathways

    Science.gov (United States)

    Watanabe Costa, Renata; da Silveira, Jose F.; Bahia, Diana

    2016-01-01

    Chagas disease is one of the prevalent neglected tropical diseases, affecting at least 6–7 million individuals in Latin America. It is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to vertebrate hosts by blood-sucking insects. After infection, the parasite invades and multiplies in the myocardium, leading to acute myocarditis that kills around 5% of untreated individuals. T. cruzi secretes proteins that manipulate multiple host cell signaling pathways to promote host cell invasion. The primary secreted lysosomal peptidase in T. cruzi is cruzipain, which has been shown to modulate the host immune response. Cruzipain hinders macrophage activation during the early stages of infection by interrupting the NF-kB P65 mediated signaling pathway. This allows the parasite to survive and replicate, and may contribute to the spread of infection in acute Chagas disease. Another secreted protein P21, which is expressed in all of the developmental stages of T. cruzi, has been shown to modulate host phagocytosis signaling pathways. The parasite also secretes soluble factors that exert effects on host extracellular matrix, such as proteolytic degradation of collagens. Finally, secreted phospholipase A from T. cruzi contributes to lipid modifications on host cells and concomitantly activates the PKC signaling pathway. Here, we present a brief review of the interaction between secreted proteins from T. cruzi and the host cells, emphasizing the manipulation of host signaling pathways during invasion. PMID:27065960

  13. Proinflammatory Cytokines Regulate Cementogenic Differentiation of Periodontal Ligament Cells by Wnt/Ca(2+) Signaling Pathway.

    Science.gov (United States)

    Han, Pingping; Lloyd, Tain; Chen, Zetao; Xiao, Yin

    2016-05-01

    Periodontal inflammation can inhibit cell differentiation of periodontal ligament cells (PDLCs), resulting in decreased bone/cementum regeneration ability. The Wnt signaling pathway, including canonical Wnt/β-catenin signaling and noncanonical Wnt/Ca(2+) signaling, plays essential roles in cell proliferation and differentiation during tooth development. However, little is still known whether noncanonical Wnt/Ca(2+) signaling cascade could regulate cementogenic/osteogenic differentiation capability of PDLCs within an inflammatory environment. Therefore, in this study, human PDLCs (hPDLCs) and their cementogenic differentiation potential were investigated in the presence of cytokines. The data demonstrated that both cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) inhibited cell proliferation, relative alkaline phosphatase activity, bone/cementum-related gene/protein expression, and canonical Wnt pathway-related gene/protein expression in hPDLCs. Interestingly, both cytokines upregulated the noncanonical Wnt/Ca(2+) signaling-related gene and protein expression in hPDLCs. When the Wnt/Ca(2+) pathway was blocked by Ca(2+)/calmodulin-dependent protein kinase II inhibitor KN93, even in the presence of IL-6 and TNF-α, cementogenesis could be stimulated in hPDLCs. Our data indicate that the Wnt/Ca(2+) pathway plays an inhibitory role on PDLC cementogenic differentiation in inflammatory microenvironments. Therefore, targeting the Wnt/Ca(2+) pathway may provide a novel therapeutic approach to improve periodontal regeneration for periodontal diseases. PMID:27074616

  14. Crosstalk between signaling pathways of adrenoreceptors and signal transducers and activators of transcription 3 (STAT3) in heart

    Institute of Scientific and Technical Information of China (English)

    Kai-zheng GONG; Hui ZHANG; Jian-hai DU; You-yi ZHANG

    2007-01-01

    Recently, there have been important advancements in our understanding of the signaling mechanisms of adrenoreceptors (AR) and signal transducers and activators of transcription 3 (STAT3). While their crucial roles in the pathological processes of the heart are well established, accumulating evidence suggests there is a complex pattern of crosstalk between these 2 signaling pathways. Moreover, the potential for crosstalk occurs at multiple levels in each signaling cascade and involves receptor transactivation, G proteins, small GTPases, cyclic adenosine 3',5'-monophosphate/protein kinase A, protein kinase C, scaffold/adaptor proteins, protein tyrosine kinases, and mitogen-activated protein kinases. In addition, post-translational modification (eg acetylation) of STAT3 may provide a link betweenSTAT3 and AR signaling. In particular, crosstalk between these 2 systems in the heart would appear to be dependent upon the species/tissue studied, develop-mental stage, and eliciting stimulus. This at least partly accounts for the epigenetic effects on biological function that is mediated by the 2 signaling pathways. Elucidation of these mechanisms will provide new targets in the development of novel clinical strategies for heart disorders.

  15. Down-regulation of HIV-1 Infection by Inhibition of the MAPK Signaling Pathway

    Institute of Scientific and Technical Information of China (English)

    Jian Gong; Xi-hui Shen; Chao Chen; Hui Qiu; Rong-ge Yang

    2011-01-01

    The human immunodeficiency virus type 1(HIV-1)can interact with and exploit the host cellular machinery to replicate and propagate itself.Numerous studies have shown that the Mitogen-activated protein kinase(MAPK)signal pathway can positively regulate the replication of HIV-1,but exactly how each MAPK pathway affects HIV-1 infection and replication is not understood.In this study,we used the Extracellular signal-regulated kinase(ERK)pathway inhibitor,PD98059,the Jun N-terminal kinase(JNK)pathway inhibitor,SP600125,and the p38 pathway inhibitor,SB203580,to investigate the roles of these pathways in HIV-1replication.We found that application of PD98059 results in a strong VSV-G pseudotyped HIV-1NL4-3 luciferase reporter virus and HIV-1NL4-3 virus inhibition activity.In addition,SB203580 and SP600125 also elicited marked VSV-G pseudotyped HIV-1NL4-3 luciferase reporter virus inhibition activity but no HIV-1NL4-3 virus inhibition activity.We also found that SB203580 and SP600125 can enhance the HIV-1 inhibition activity of PD98059when cells were treated with all three MAPK pathway inhibitors in combination.Finally,we show that HIV-1virus inhibition activity of the MAPK pathway inhibitors was the result of the negative regulation of HIV-1 LTR promoter activity.

  16. Remote activation of the Wnt/β-catenin signalling pathway using functionalised magnetic particles.

    Directory of Open Access Journals (Sweden)

    Michael Rotherham

    Full Text Available Wnt signalling pathways play crucial roles in developmental biology, stem cell fate and tissue patterning and have become an attractive therapeutic target in the fields of tissue engineering and regenerative medicine. Wnt signalling has also been shown to play a role in human Mesenchymal Stem Cell (hMSC fate, which have shown potential as a cell therapy in bone and cartilage tissue engineering. Previous work has shown that biocompatible magnetic nanoparticles (MNP can be used to stimulate specific mechanosensitive membrane receptors and ion channels in vitro and in vivo. Using this strategy, we determined the effects of mechano-stimulation of the Wnt Frizzled receptor on Wnt pathway activation in hMSC. Frizzled receptors were tagged using anti-Frizzled functionalised MNP (Fz-MNP. A commercially available oscillating magnetic bioreactor (MICA Biosystems was used to mechanically stimulate Frizzled receptors remotely. Our results demonstrate that Fz-MNP can activate Wnt/β-catenin signalling at key checkpoints in the signalling pathway. Immunocytochemistry indicated nuclear localisation of the Wnt intracellular messenger β-catenin after treatment with Fz-MNP. A Wnt signalling TCF/LEF responsive luciferase reporter transfected into hMSC was used to assess terminal signal activation at the nucleus. We observed an increase in reporter activity after treatment with Fz-MNP and this effect was enhanced after mechano-stimulation using the magnetic array. Western blot analysis was used to probe the mechanism of signalling activation and indicated that Fz-MNP signal through an LRP independent mechanism. Finally, the gene expression profiles of stress response genes were found to be similar when cells were treated with recombinant Wnt-3A or Fz-MNP. This study provides proof of principle that Wnt signalling and Frizzled receptors are mechanosensitive and can be remotely activated in vitro. Using magnetic nanoparticle technology it may be possible to modulate

  17. Role of Notch signalling pathway in cancer and its association with DNA methylation

    Indian Academy of Sciences (India)

    Madhuri G. S. Aithal; Narayanappa Rajeswari

    2013-12-01

    The Notch signalling pathway is an evolutionarily conserved cell signalling pathway involved in the development of organisms as diverse as humans and fruit flies. It plays a pivotal role in cell fate determination. Dysregulated Notch signalling is oncogenic, inhibits apoptosis and promotes cell survival. Abnormal Notch signalling is seen in many cancers like T-cell acute lymphoblastic leukaemia, acute myeloid leukaemia and cancers of the breast, cervix, colon, pancreas, skin and brain. Inhibition of Notch signalling leads to growth arrest and differentiation in those cells in which Notch pathway is activated and this represents a new target for cancer therapy. Cancer develops from genome defects, including both genetic and epigenetic alterations. Epigenetics deals with heritable changes in gene function that occur without a change in the DNA sequence. Among various epigenetic alterations such as acetylation, phosphorylation, ubiquitylation and sumoylation, promoter region methylation is considered as an important component in cancer development. Epigenetic alterations can be used as biomarkers in screening, detection, diagnosis, staging and risk stratification of various cancers. DNA methylation can be therapeutically reversed and demethylating drugs have proven to be promising in cancer treatment. This review focusses on the methylation status of genes in Notch signalling pathway from various cancers and how this epigenetic alteration can be used as a biomarker for cancer diagnosis and subsequent treatment.

  18. The PI3K signaling pathway as a pharmacological target in Autism related disorders and Schizophrenia.

    Science.gov (United States)

    Enriquez-Barreto, Lilian; Morales, Miguel

    2016-01-01

    This review is focused in PI3K's involvement in two widespread mental disorders: Autism and Schizophrenia. A large body of evidence points to synaptic dysfunction as a cause of these diseases, either during the initial phases of brain synaptic circuit's development or later modulating synaptic function and plasticity. Autism related disorders and Schizophrenia are complex genetic conditions in which the identification of gene markers has proved difficult, although the existence of single-gene mutations with a high prevalence in both diseases offers insight into the role of the PI3K signaling pathway. In the brain, components of the PI3K pathway regulate synaptic formation and plasticity; thus, disruption of this pathway leads to synapse dysfunction and pathological behaviors. Here, we recapitulate recent evidences that demonstrate the imbalance of several PI3K elements as leading causes of Autism and Schizophrenia, together with the plausible new pharmacological paths targeting this signaling pathway. PMID:26877878

  19. Signaling Pathways in Exosomes Biogenesis, Secretion and Fate

    Directory of Open Access Journals (Sweden)

    Carla Emiliani

    2013-03-01

    Full Text Available Exosomes are small extracellular vesicles (30–100 nm derived from the endosomal system, which have raised considerable interest in the last decade. Several studies have shown that they mediate cell-to-cell communication in a variety of biological processes. Thus, in addition to cell-to-cell direct interaction or secretion of active molecules, they are now considered another class of signal mediators. Exosomes can be secreted by several cell types and retrieved in many body fluids, such as blood, urine, saliva and cerebrospinal fluid. In addition to proteins and lipids, they also contain nucleic acids, namely mRNA and miRNA. These features have prompted extensive research to exploit them as a source of biomarkers for several pathologies, such as cancer and neurodegenerative disorders. In this context, exosomes also appear attractive as gene delivery vehicles. Furthermore, exosome immunomodulatory and regenerative properties are also encouraging their application for further therapeutic purposes. Nevertheless, several issues remain to be addressed: exosome biogenesis and secretion mechanisms have not been clearly understood, and physiological functions, as well as pathological roles, are far from being satisfactorily elucidated.

  20. PKC and MAPK signalling pathways regulate vascular endothelin receptor expression

    DEFF Research Database (Denmark)

    Nilsson, David; Wackenfors, Angelica; Gustafsson, Lotta; Ugander, Martin; Ingemansson, Richard; Edvinsson, Lars; Malmsjö, Malin

    immunofluorescence techniques. Sarafotoxin 6c and endothelin ET-1 were used to examine the endothelin ET(A) and ET(B) receptor effects. The involvement of PKC and MAPK in the receptor regulation was examined by culture in the presence of antagonists. Organ culture resulted in increased sarafotoxin 6c and endothelin......-1 contractions, endothelin ET(A) and ET(B) receptor immunofluorescence staining intensities and endothelin ET(B), but not ET(A), receptor mRNA levels. The general PKC inhibitors, bisindolylmaleimide I (10 microM) or Ro-32-0432 (10 microM), inhibited these effects. Also, the increase in sarafotoxin 6......c contraction, endothelin ET(B) receptor and mRNA levels and endothelin ET(A) and ET(B) immunofluorescence staining intensities were inhibited by MAPK inhibitors for extracellular signal related kinases 1 and 2 (ERK1/2), PD98059 (10 microM), C-jun terminal kinase (JNK), SP600125 (10 microM), but not...

  1. Targeting key signalling pathways in oesophageal adenocarcinoma: A reality for personalised medicine?

    Institute of Scientific and Technical Information of China (English)

    Richard R Keld; Yeng S Ang

    2011-01-01

    Cancer treatments are rapidly changing. Curative treatment for oesophageal adenocarcinoma currently involves surgery and cytotoxic chemotherapy or chemoradiotherapy.Outcomes for both regimes are generally poor as a result of tumor recurrence. We have reviewed the key signalling pathways associated with oesophageal adenocarcinomas and discussed the recent trials of novel agents that attempt to target these pathways. There are many trials underway with the aim of improving survival in oesophageal cancer. Currently,phase 2 and 3 trials are focused on MAP kinase inhibition, either through inhibition of growth factor receptors or signal transducer proteins. In order to avoid tumor resistance, it appears to be clear that targeted therapy will be needed to combat the multiple signalling pathways that are in operation in oesophageal adenocarcinomas. This may be achievable in the future with the advent of gene signatures and a combinatorial approach.

  2. The role of MAPK signalling pathways in acetic acid-induced cell death of Saccharomyces cerevisiae

    OpenAIRE

    Azevedo, Flávio Humberto Torres Dias Feio de

    2011-01-01

    Dissertação de mestrado em Genética Molecular Mitogenic Activated Protein Kinase (MAPK) cascades are important signalling pathways that allow yeast cells to swiftly adapt to changing environmental conditions. Previous studies suggested that the High Osmolarity Glycerol (HOG) MAPK pathway and ceramide production are involved in acetic-acid induced apoptosis in yeast. Evidence that changes in the levels of endogenous ceramides can affect yeast cell fate has also been put forth...

  3. Advances of Targeted Therapy Based on Estrogen Receptor Signaling Pathway 
in Lung Cancer

    OpenAIRE

    Xu, Liqiang; Liao, Yongde; Hexiao TANG; Zhang, Chao; Liu, Zhaoguo

    2011-01-01

    Increasing evidence indicates that estrogen promotes tumor growth in both estrogen target organs and non-target organs. Estrogen regulates cell proliferation and differentiation via two different receptors, estrogen receptors α and β (ERα and ERβ). In recent decades, with the clarification of the ERα-mediated signaling pathways in breast cancer, targeted therapy through these pathways have successfully been used in clinical application. Tamoxifen, the classic representative, is a selective es...

  4. Cellular regulation of dinoflagellate bioluminescence : characterizing mechanosensitive ion channels in the signaling pathway

    OpenAIRE

    Jin, Kelly

    2012-01-01

    Dinoflagellate bioluminescence represents a dramatic response to mechanical stress found in nature. The cellular mechanisms that govern this pathway, however, are not completely understood. The objective of this thesis is to build and expand from previous studies to explore the mechanosensitive properties of dinoflagellate bioluminescence. Chapter I tests the hypothesis that the signaling pathway involves a stretch-activated component. Chapter I uses two separate, measurable types of biolumin...

  5. Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Jin; Lee, Yi Sle; Seo, Kyo Won; Bae, Jin Ung; Kim, Gyu Hee; Park, So Youn; Kim, Chi Dae, E-mail: chidkim@pusan.ac.kr

    2012-04-01

    Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways. -- Highlights: ► Homocysteine (Hcy) induced MMP-9 production in murine macrophages. ► Hcy induced MMP-9 production through ERK and Akt signaling pathways. ► ERK and Akt signaling pathways were activated by Hcy in murine macrophages. ► ERK and Akt pathways were additively act on Hcy-induced MMP-9 production. ► Hcy enhances MMP-9 production in macrophages via activation of ERK and Akt signaling pathways in an independent manner.

  6. Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways

    International Nuclear Information System (INIS)

    Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways. -- Highlights: ► Homocysteine (Hcy) induced MMP-9 production in murine macrophages. ► Hcy induced MMP-9 production through ERK and Akt signaling pathways. ► ERK and Akt signaling pathways were activated by Hcy in murine macrophages. ► ERK and Akt pathways were additively act on Hcy-induced MMP-9 production. ► Hcy enhances MMP-9 production in macrophages via activation of ERK and Akt signaling pathways in an independent manner.

  7. Identification of Major Signaling Pathways in Prion Disease Progression Using Network Analysis.

    Science.gov (United States)

    Newaz, Khalique; Sriram, K; Bera, Debajyoti

    2015-01-01

    Prion diseases are transmissible neurodegenerative diseases that arise due to conformational change of normal, cellular prion protein (PrPC) to protease-resistant isofrom (rPrPSc). Deposition of misfolded PrpSc proteins leads to an alteration of many signaling pathways that includes immunological and apoptotic pathways. As a result, this culminates in the dysfunction and death of neuronal cells. Earlier works on transcriptomic studies have revealed some affected pathways, but it is not clear which is (are) the prime network pathway(s) that change during the disease progression and how these pathways are involved in crosstalks with each other from the time of incubation to clinical death. We perform network analysis on large-scale transcriptomic data of differentially expressed genes obtained from whole brain in six different mouse strain-prion strain combination models to determine the pathways involved in prion diseases, and to understand the role of crosstalks in disease propagation. We employ a notion of differential network centrality measures on protein interaction networks to identify the potential biological pathways involved. We also propose a crosstalk ranking method based on dynamic protein interaction networks to identify the core network elements involved in crosstalk with different pathways. We identify 148 DEGs (differentially expressed genes) potentially related to the prion disease progression. Functional association of the identified genes implicates a strong involvement of immunological pathways. We extract a bow-tie structure that is potentially dysregulated in prion disease. We also propose an ODE model for the bow-tie network. Predictions related to diseased condition suggests the downregulation of the core signaling elements (PI3Ks and AKTs) of the bow-tie network. In this work, we show using transcriptomic data that the neuronal dysfunction in prion disease is strongly related to the immunological pathways. We conclude that these

  8. Identification of Major Signaling Pathways in Prion Disease Progression Using Network Analysis.

    Directory of Open Access Journals (Sweden)

    Khalique Newaz

    Full Text Available Prion diseases are transmissible neurodegenerative diseases that arise due to conformational change of normal, cellular prion protein (PrPC to protease-resistant isofrom (rPrPSc. Deposition of misfolded PrpSc proteins leads to an alteration of many signaling pathways that includes immunological and apoptotic pathways. As a result, this culminates in the dysfunction and death of neuronal cells. Earlier works on transcriptomic studies have revealed some affected pathways, but it is not clear which is (are the prime network pathway(s that change during the disease progression and how these pathways are involved in crosstalks with each other from the time of incubation to clinical death. We perform network analysis on large-scale transcriptomic data of differentially expressed genes obtained from whole brain in six different mouse strain-prion strain combination models to determine the pathways involved in prion diseases, and to understand the role of crosstalks in disease propagation. We employ a notion of differential network centrality measures on protein interaction networks to identify the potential biological pathways involved. We also propose a crosstalk ranking method based on dynamic protein interaction networks to identify the core network elements involved in crosstalk with different pathways. We identify 148 DEGs (differentially expressed genes potentially related to the prion disease progression. Functional association of the identified genes implicates a strong involvement of immunological pathways. We extract a bow-tie structure that is potentially dysregulated in prion disease. We also propose an ODE model for the bow-tie network. Predictions related to diseased condition suggests the downregulation of the core signaling elements (PI3Ks and AKTs of the bow-tie network. In this work, we show using transcriptomic data that the neuronal dysfunction in prion disease is strongly related to the immunological pathways. We conclude that

  9. The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease.

    Science.gov (United States)

    Berridge, Michael J

    2016-10-01

    Many cellular functions are regulated by calcium (Ca(2+)) signals that are generated by different signaling pathways. One of these is the inositol 1,4,5-trisphosphate/calcium (InsP3/Ca(2+)) signaling pathway that operates through either primary or modulatory mechanisms. In its primary role, it generates the Ca(2+) that acts directly to control processes such as metabolism, secretion, fertilization, proliferation, and smooth muscle contraction. Its modulatory role occurs in excitable cells where it modulates the primary Ca(2+) signal generated by the entry of Ca(2+) through voltage-operated channels that releases Ca(2+) from ryanodine receptors (RYRs) on the internal stores. In carrying out this modulatory role, the InsP3/Ca(2+) signaling pathway induces subtle changes in the generation and function of the voltage-dependent primary Ca(2+) signal. Changes in the nature of both the primary and modulatory roles of InsP3/Ca(2+) signaling are a contributory factor responsible for the onset of a large number human diseases. PMID:27512009

  10. Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways.

    Directory of Open Access Journals (Sweden)

    Kapil Dev Singh

    Full Text Available Complex traits, including common disease-related traits, are affected by many different genes that function in multiple pathways and networks. The apoptosis, MAPK, Notch, and Wnt signalling pathways play important roles in development and disease progression. At the moment we have a poor understanding of how allelic variation affects gene expression in these pathways at the level of translation. Here we report the effect of natural genetic variation on transcript and protein abundance involved in developmental signalling pathways in Caenorhabditis elegans. We used selected reaction monitoring to analyse proteins from the abovementioned four pathways in a set of recombinant inbred lines (RILs generated from the wild-type strains N2 (Bristol and CB4856 (Hawaii to enable quantitative trait locus (QTL mapping. About half of the cases from the 44 genes tested showed a statistically significant change in protein abundance between various strains, most of these were however very weak (below 1.3-fold change. We detected a distant QTL on the left arm of chromosome II that affected protein abundance of the phosphatidylserine receptor protein PSR-1, and two separate QTLs that influenced embryonic and ionizing radiation-induced apoptosis on chromosome IV. Our results demonstrate that natural variation in C. elegans is sufficient to cause significant changes in signalling pathways both at the gene expression (transcript and protein abundance and phenotypic levels.

  11. Epigenetic regulator Lid maintains germline stem cells through regulating JAK-STAT signaling pathway activity

    Directory of Open Access Journals (Sweden)

    Lama Tarayrah

    2015-11-01

    Full Text Available Signaling pathways and epigenetic mechanisms have both been shown to play essential roles in regulating stem cell activity. While the role of either mechanism in this regulation is well established in multiple stem cell lineages, how the two mechanisms interact to regulate stem cell activity is not as well understood. Here we report that in the Drosophila testis, an H3K4me3-specific histone demethylase encoded by little imaginal discs (lid maintains germline stem cell (GSC mitotic index and prevents GSC premature differentiation. Lid is required in germ cells for proper expression of the Stat92E transcription factor, the downstream effector of the Janus kinase signal transducer and activator of transcription (JAK-STAT signaling pathway. Our findings support a germ cell autonomous role for the JAK-STAT pathway in maintaining GSCs and place Lid as an upstream regulator of this pathway. Our study provides new insights into the biological functions of a histone demethylase in vivo and sheds light on the interaction between epigenetic mechanisms and signaling pathways in regulating stem cell activities.

  12. Role of insulin/insulin-like growth factor 1 signaling pathway in longevity

    Institute of Scientific and Technical Information of China (English)

    Chun-Lei Cheng; Tian-Qin Gao; Zhen Wang; Dian-Dong Li

    2005-01-01

    The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway is evolutionary conserved in diverse species including C.elegans, saccharomyces cerevisiae, Drosophila melanogaster, rodents and humans, which is involved in many interrelated functions that are necessary for metabolism, growth and reproduction. Interestingly,more and more research has revealed that insulin/IGF-1 signaling pathway plays a pivotal role in the regulation of longevity. Generally, disruption of the power of this pathway will extend longevity in species ranging from C.elegansto humans. The role of insulin/IGF-1 in longevity is probably related to stress resistance. Although the underlying mechanisms of longevity are not fully understood,the Insulin/IGF-1 signaling pathway has attracted substantial attention and it will be a novel target to prevent or postpone age-related diseases and extend life span.In this review, we mainly focus on the similar constitution and role of insulin/IGF-1 signaling pathway in C.elegans,saccharomyces cerevisiae, rodents and humans.

  13. Dopamine D1-D2 receptor heteromer signaling pathway in the brain: emerging physiological relevance

    Directory of Open Access Journals (Sweden)

    Hasbi Ahmed

    2011-06-01

    Full Text Available Abstract Dopamine is an important catecholamine neurotransmitter modulating many physiological functions, and is linked to psychopathology of many diseases such as schizophrenia and drug addiction. Dopamine D1 and D2 receptors are the most abundant dopaminergic receptors in the striatum, and although a clear segregation between the pathways expressing these two receptors has been reported in certain subregions, the presence of D1-D2 receptor heteromers within a unique subset of neurons, forming a novel signaling transducing functional entity has been shown. Recently, significant progress has been made in elucidating the signaling pathways activated by the D1-D2 receptor heteromer and their potential physiological relevance.

  14. Aberrant Wnt signaling pathway in medial temporal lobe structures of Alzheimer's disease

    DEFF Research Database (Denmark)

    Riise, Jesper; Plath, Niels; Pakkenberg, Bente;

    2015-01-01

    hippocampus exhibiting most pronounced changes. Furthermore, the Wnt pathway constituents Wnt7b and Tcf7l1/Tcf3 showed overlapping gene expression alterations across both medial temporal lobe structures, while β-catenin was inversely expressed between brain regions. We also identified total protein......-targeted hyperphosphorylation at specific tau epitope in soluble pretangles and prominent tau aggregation exclusively in insoluble neurofibrillary tangles of AD subjects. The Wnt pathway-focused approach confirms altered Wnt signaling in the neurodegenerative AD brain and highlights the potential role of the pathway as a...

  15. Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway

    International Nuclear Information System (INIS)

    Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H:quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism

  16. Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Maayah, Zaid H. [Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451 (Saudi Arabia); Ghebeh, Hazem [Stem Cell & Tissue Re-Engineering, King Faisal Specialist Hospital and Research Center, Riyadh 11211 (Saudi Arabia); Alhaider, Abdulqader A. [Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451 (Saudi Arabia); Camel Biomedical Research Unit, College of Pharmacy and Medicine, King Saud University, Riyadh 11451 (Saudi Arabia); El-Kadi, Ayman O.S. [Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton (Canada); Soshilov, Anatoly A.; Denison, Michael S. [Department of Environmental Toxicology, University of California at Davis, Davis, CA 95616 (United States); Ansari, Mushtaq Ahmad [Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451 (Saudi Arabia); Korashy, Hesham M., E-mail: hkorashy@ksu.edu.sa [Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451 (Saudi Arabia)

    2015-04-15

    Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H:quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism

  17. Induction of Cancer Cell Death by Isoflavone: The Role of Multiple Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Fazlul H. Sarkar

    2011-10-01

    Full Text Available Soy isoflavones have been documented as dietary nutrients broadly classified as “natural agents” which plays important roles in reducing the incidence of hormone-related cancers in Asian countries, and have shown inhibitory effects on cancer development and progression in vitro and in vivo, suggesting the cancer preventive or therapeutic activity of soy isoflavones against cancers. Emerging experimental evidence shows that isoflavones could induce cancer cell death by regulating multiple cellular signaling pathways including Akt, NF-κB, MAPK, Wnt, androgen receptor (AR, p53 and Notch signaling, all of which have been found to be deregulated in cancer cells. Therefore, homeostatic regulation of these important cellular signaling pathways by isoflavones could be useful for the activation of cell death signaling, which could result in the induction of apoptosis of both pre-cancerous and/or cancerous cells without affecting normal cells. In this article, we have attempted to summarize the current state-of-our-knowledge regarding the induction of cancer cell death pathways by isoflavones, which is believed to be mediated through the regulation of multiple cellular signaling pathways. The knowledge gained from this article will provide a comprehensive view on the molecular mechanism(s by which soy isoflavones may exert their effects on the prevention of tumor progression and/or treatment of human malignancies, which would also aid in stimulating further in-depth mechanistic research and foster the initiation of novel clinical trials.

  18. Investigations on Inhibitors of Hedgehog Signal Pathway: A Quantitative Structure-Activity Relationship Study

    Directory of Open Access Journals (Sweden)

    Zhiwei Cao

    2011-05-01

    Full Text Available The hedgehog signal pathway is an essential agent in developmental patterning, wherein the local concentration of the Hedgehog morphogens directs cellular differentiation and expansion. Furthermore, the Hedgehog pathway has been implicated in tumor/stromal interaction and cancer stem cell. Nowadays searching novel inhibitors for Hedgehog Signal Pathway is drawing much more attention by biological, chemical and pharmological scientists. In our study, a solid computational model is proposed which incorporates various statistical analysis methods to perform a Quantitative Structure-Activity Relationship (QSAR study on the inhibitors of Hedgehog signaling. The whole QSAR data contain 93 cyclopamine derivatives as well as their activities against four different cell lines (NCI-H446, BxPC-3, SW1990 and NCI-H157. Our extensive testing indicated that the binary classification model is a better choice for building the QSAR model of inhibitors of Hedgehog signaling compared with other statistical methods and the corresponding in silico analysis provides three possible ways to improve the activity of inhibitors by demethylation, methylation and hydroxylation at specific positions of the compound scaffold respectively. From these, demethylation is the best choice for inhibitor structure modifications. Our investigation also revealed that NCI-H466 served as the best cell line for testing the activities of inhibitors of Hedgehog signal pathway among others.

  19. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells.

    Science.gov (United States)

    Justilien, Verline; Fields, Alan P

    2015-02-01

    The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation, including the maintenance of the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors, including a lack of patient stratification in early trials, cross-talk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anticancer therapy. PMID:25646180

  20. A dominant negative zebrafish Ahr2 partially protects developing zebrafish from dioxin toxicity.

    Directory of Open Access Journals (Sweden)

    Kevin A Lanham

    Full Text Available The toxicity by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD is thought to be caused by activation of the aryl hydrocarbon receptor (AHR. However, our understanding of how AHR activation by TCDD leads to toxic effects is poor. Ideally we would like to manipulate AHR activity in specific tissues and at specific times. One route to this is expressing dominant negative AHRs (dnAHRs. This work describes the construction and characterization of dominant negative forms of the zebrafish Ahr2 in which the C-terminal transactivation domain was either removed, or replaced with the inhibitory domain from the Drosophila engrailed repressor protein. One of these dnAhr2s was selected for expression from the ubiquitously active e2fα promoter in transgenic zebrafish. We found that these transgenic zebrafish expressing dnAhr2 had reduced TCDD induction of the Ahr2 target gene cyp1a, as measured by 7-ethoxyresorufin-O-deethylase activity. Furthermore, the cardiotoxicity produced by TCDD, pericardial edema, heart malformation, and reduced blood flow, were all mitigated in the zebrafish expressing the dnAhr2. These results provide in vivo proof-of-principle results demonstrating the effectiveness of dnAHRs in manipulating AHR activity in vivo, and demonstrating that this approach can be a means for blocking TCDD toxicity.

  1. File list: Oth.Bld.50.Ahr.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.50.Ahr.AllCell mm9 TFs and others Ahr Blood SRX122384,SRX122382,SRX122385,S...RX122383 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.50.Ahr.AllCell.bed ...

  2. File list: Oth.Bld.20.Ahr.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.20.Ahr.AllCell mm9 TFs and others Ahr Blood SRX122382,SRX122384,SRX122385,S...RX122383 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.20.Ahr.AllCell.bed ...

  3. File list: Oth.ALL.50.Ahr.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  4. File list: Oth.Bld.10.Ahr.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.10.Ahr.AllCell mm9 TFs and others Ahr Blood SRX122382,SRX122385,SRX122384,S...RX122383 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.10.Ahr.AllCell.bed ...

  5. File list: Oth.ALL.10.Ahr.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  6. Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases

    Science.gov (United States)

    Arakelyan, Arsen; Nersisyan, Lilit; Petrek, Martin; Löffler-Wirth, Henry; Binder, Hans

    2016-01-01

    Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent. PMID:27200087

  7. Analysis of corkscrew signaling in the Drosophila epidermal growth factor receptor pathway during myogenesis.

    OpenAIRE

    Johnson Hamlet, M R; Perkins, L A

    2001-01-01

    The Drosophila nonreceptor protein tyrosine phosphatase, Corkscrew (Csw), functions positively in multiple receptor tyrosine kinase (RTK) pathways, including signaling by the epidermal growth factor receptor (EGFR). Detailed phenotypic analyses of csw mutations have revealed that Csw activity is required in many of the same developmental processes that require EGFR function. However, it is still unclear where in the signaling hierarchy Csw functions relative to other proteins whose activities...

  8. The BMP signaling pathway at the Drosophila neuromuscular junction and its links to neurodegenerative diseases

    OpenAIRE

    Bayat, Vafa; Jaiswal, Manish; Bellen, Hugo J

    2010-01-01

    The Drosophila neuromuscular junction (NMJ) has recently provided new insights into the roles of various proteins in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Multiple Sclerosis (MS) Hereditary Spastic Paraplegia (HSP), and Huntington’s Disease (HD). Several developmental signaling pathways including WNT, MAPK and BMP/TGF-β signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of the fly homolog...

  9. Conditions and constraints for astrocyte calcium signaling in the hippocampal mossy fiber pathway

    OpenAIRE

    Haustein, Martin D.; Kracun, Sebastian; Lu, Xiao-Hong; Shih, Tiffany; Jackson-Weaver, Olan; Tong, Xiaoping; Xu, Ji; Yang, X William; O'Dell, Thomas J.; Marvin, Jonathan S.; Ellisman, Mark H.; Bushong, Eric A.; Looger, Loren L.; Khakh, Baljit S.

    2014-01-01

    The spatiotemporal activities of astrocyte Ca2+ signaling in mature neuronal circuits remain unclear. We used genetically encoded Ca2+ and glutamate indicators as well as pharmacogenetic and electrical control of neurotransmitter release to explore astrocyte activity in the hippocampal mossy fiber pathway. Our data revealed numerous localised spontaneous Ca2+ signals in astrocyte branches and territories, but these were not driven by neuronal activity or glutamate. Moreover, evoked astrocyte ...

  10. Cell death and signal transduction pathways in Alzheimer's disease : The role of presenilin 1

    OpenAIRE

    Popescu, Bogdan O

    2004-01-01

    Mutated presenilins (PSs) may cause familial Alzheimer's disease (FAD) by altering neuronal signal transduction pathways, by increasing AP production or by triggering a number of proapoptotic mechanisms. The present thesis explores mechanisms by which PSs regulate signal transduction and cell death with relevance to AD. Paper I explored the complex proteolytic processing of wild-type (WT) and FAD presenilin 1 (PS1) exon 9 deleted mutant (deltaE9 PS1) during apoptosis. PS...

  11. Targeting Notch signaling pathway in cancer: Clinical development advances and challenges

    OpenAIRE

    Takebe, Naoko; Nguyen, Dat; Yang, Sherry X

    2013-01-01

    Notch signaling plays an important role in development and cell fate determination, and it is deregulated in human hematologic malignancies and solid tumors. This review includes a brief introduction of the relevant pathophysiology of Notch signaling pathway and primarily focuses on the clinical development of promising agents that either obstruct Notch receptor cleavages such as γ-secretase inhibitors (GSIs) or interfere with the Notch ligand–receptor interaction by monoclonal antibodies (mA...

  12. Signaling pathway-based identification of extensive prognostic gene signatures for lung adenocarcinoma

    OpenAIRE

    Wan, Ying-Wooi; Beer, David G.; Guo, Nancy Lan

    2011-01-01

    Tumor recurrence is the major cause of death in lung cancer treatment. To date, there is no clinically applied gene expression-based model to predict the risk for tumor recurrence in non-small cell lung cancer (NSCLC). We sought to embed crosstalk with major signaling pathways into biomarker identification. Three approaches were used to identify prognostic gene signatures from 442 lung adenocarcinoma samples. Candidate genes co-expressed with 6 or 7 major NSCLC signaling hallmarks were identi...

  13. MAPK signal pathways in the regulation of cell proliferation in mammalian cells

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    MAPK families play an important role in complex cellular programs like proliferation, differentiation,development, transformation, and apoptosis. At least three MAPK families have been characterized: extracellular signal-regulated kinase (ERK), Jun kinase (JNK/SAPK) and p38 MAPK. The above effects are fulfilled by regulation of cell cycle engine and other cell proliferation related proteins. In this paper we discussed their functions and cooperation with other signal pathways in regulation of cell proliferation.

  14. Two distinct signaling pathways participate in auxin-induced swelling of pea epidermal protoplasts.

    Science.gov (United States)

    Yamagami, Mutsumi; Haga, Ken; Napier, Richard M; Iino, Moritoshi

    2004-02-01

    Protoplast swelling was used to investigate auxin signaling in the growth-limiting stem epidermis. The protoplasts of epidermal cells were isolated from elongating internodes of pea (Pisum sativum). These protoplasts swelled in response to auxin, providing the clearest evidence that the epidermis can directly perceive auxin. The swelling response to the natural auxin IAA showed a biphasic dose response curve but that to the synthetic auxin 1-naphthalene acetic acid (NAA) showed a simple bell-shaped dose response curve. The responses to IAA and NAA were further analyzed using antibodies raised against ABP1 (auxin-binding protein 1), and their dependency on extracellular ions was investigated. Two signaling pathways were resolved for IAA, an ABP1-dependent pathway and an ABP1-independent pathway that is much more sensitive to IAA than the former. The response by the ABP1 pathway was eliminated by anti-ABP1 antibodies, had a higher sensitivity to NAA, and did not depend on extracellular Ca(2+). In contrast, the response by the non-ABP1 pathway was not affected by anti-ABP1 antibodies, had no sensitivity to NAA, and depended on extracellular Ca(2+). The swelling by either pathway required extracellular K(+) and Cl(-). The auxin-induced growth of pea internode segments showed similar response patterns, including the occurrence of two peaks in the dose response curve for IAA and the difference in Ca(2+) requirements. It is suggested that two signaling pathways participate in auxin-induced internode growth and that the non-ABP1 pathway is more likely to be involved in the control of growth by constitutive concentrations of endogenous auxin. PMID:14764902

  15. Ca2+ signal is generated only once in the mating pheromone response pathway in Saccharomyces cerevisiae.

    Science.gov (United States)

    Nakajima-Shimada, J; Sakaguchi, S; Tsuji, F I; Anraku, Y; Iida, H

    2000-04-01

    The mating pheromone, alpha-factor, of the yeast Saccharomyces cerevisiae binds to the heterotrimeric G protein-coupled cell surface receptor of MATa cells and induces cellular responses necessary for mating. In higher eukaryotic cells, many hormones and growth factors rapidly mobilize a second messenger, Ca2+, by means of receptor-G protein signaling. Although striking similarities between the mechanisms of the receptor-G protein signaling in yeast and higher eukaryotes have long been known, it is still uncertain whether the pheromone rapidly mobilizes Ca2+ necessary for early events of the pheromone response. Here we reexamine this problem using sensitive methods for detecting Ca2+ fluxes and mobilization, and find no evidence that there is rapid Ca2+ influx leading to a rapid increase in the cytosolic free Ca2+ concentration. In addition, the yeast PLC1 deletion mutant lacking phosphoinositide-specific phospholipase C, a key enzyme for generating Ca2+ signals in higher eukaryotic cells, responds normally to the pheromone. These findings suggest that the receptor-G protein signaling does not utilize Ca2+ as a second messenger in the early stage of the pheromone response pathway. Since the receptor-G protein signaling does stimulate Ca2+ influx after early events have finished and this stimulation is essential for late events in the pheromone response pathway [Iida et al., (1990) J. Biol. Chem., 265: 13391-13399] Ca2+ may be used only once in the signal transduction pathway in unicellular eukaryotes such as yeast. PMID:10885582

  16. Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

    OpenAIRE

    Jin, Un-Ho; Lee, Syng-Ook; Safe, Stephen

    2012-01-01

    Leflunomide, flutamide, nimodipine, mexiletine, sulindac, tranilast, 4-hydroxytamoxifen, and omeprazole are pharmaceuticals previously characterized as aryl hydrocarbon receptor (AHR) agonists in various cell lines and animal models. In this study, the eight AHR-active pharmaceuticals were investigated in highly aggressive aryl hydrocarbon (Ah)-responsive BT474 and MDA-MB-468 breast cancer cell lines, and their effects on AHR protein, CYP1A1 (protein and mRNA), CYP1B1 (mRNA), and cell migrati...

  17. A model invalidation-based approach for elucidating biological signalling pathways, applied to the chemotaxis pathway in R. sphaeroides

    Directory of Open Access Journals (Sweden)

    Hamadeh Abdullah

    2009-10-01

    Full Text Available Abstract Background Developing methods for understanding the connectivity of signalling pathways is a major challenge in biological research. For this purpose, mathematical models are routinely developed based on experimental observations, which also allow the prediction of the system behaviour under different experimental conditions. Often, however, the same experimental data can be represented by several competing network models. Results In this paper, we developed a novel mathematical model/experiment design cycle to help determine the probable network connectivity by iteratively invalidating models corresponding to competing signalling pathways. To do this, we systematically design experiments in silico that discriminate best between models of the competing signalling pathways. The method determines the inputs and parameter perturbations that will differentiate best between model outputs, corresponding to what can be measured/observed experimentally. We applied our method to the unknown connectivities in the chemotaxis pathway of the bacterium Rhodobacter sphaeroides. We first developed several models of R. sphaeroides chemotaxis corresponding to different signalling networks, all of which are biologically plausible. Parameters in these models were fitted so that they all represented wild type data equally well. The models were then compared to current mutant data and some were invalidated. To discriminate between the remaining models we used ideas from control systems theory to determine efficiently in silico an input profile that would result in the biggest difference in model outputs. However, when we applied this input to the models, we found it to be insufficient for discrimination in silico. Thus, to achieve better discrimination, we determined the best change in initial conditions (total protein concentrations as well as the best change in the input profile. The designed experiments were then performed on live cells and the resulting

  18. Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DAN damage in rats

    Energy Technology Data Exchange (ETDEWEB)

    Wei, Min; Yamada, Takanori; Yamano, Shotaro; Kato, Minoru; Kakehashi, Anna; Fujioka, Masaki; Tago, Yoshiyuki; Kitano, Mistuaki; Wanibuchi, Hideki, E-mail: wani@med.osaka-cu.ac.jp

    2013-11-15

    Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. Inorganic arsenic is carcinogenic in humans and its organic arsenic metabolites are carcinogenic in animal studies, raising serious concerns about the carcinogenicity of DPAA. However, the carcinogenic potential of DPAA has not yet been evaluated. In the present study we found that DPAA significantly enhanced the development of diethylnitrosamine-induced preneoplastic lesions in the liver in a medium-term rat liver carcinogenesis assay. Evaluation of the expression of cytochrome P450 (CYP) enzymes in the liver revealed that DPAA induced the expression of CYP1B1, but not any other CYP1, CYP2, or CYP3 enzymes, suggesting that CYP1B1 might be the enzyme responsible for the metabolic activation of DPAA. We also found increased oxidative DNA damage, possibly due to elevated CYP1B1 expression. Induction of CYP1B1 has generally been linked with the activation of AhR, and we found that DPAA activates the aryl hydrocarbon receptor (AhR). Importantly, the promotion effect of DPAA was observed only at a dose that activated the AhR, suggesting that activation of AhR and consequent induction of AhR target genes and oxidative DNA damage plays a vital role in the promotion effects of DPAA. The present study provides, for the first time, evidence regarding the carcinogenicity of DPAA and indicates the necessity of comprehensive evaluation of its carcinogenic potential using long-term carcinogenicity studies. - Highlights: • DPAA, an environmental neurotoxicant, promotes liver carcinogenesis in rats. • DPAA is an activator of AhR signaling pathway. • DPAA promoted oxidative DNA damage in rat livers. • AhR target gene CYP 1B1 might be involved in the metabolism of DPAA.

  19. Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DAN damage in rats

    International Nuclear Information System (INIS)

    Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. Inorganic arsenic is carcinogenic in humans and its organic arsenic metabolites are carcinogenic in animal studies, raising serious concerns about the carcinogenicity of DPAA. However, the carcinogenic potential of DPAA has not yet been evaluated. In the present study we found that DPAA significantly enhanced the development of diethylnitrosamine-induced preneoplastic lesions in the liver in a medium-term rat liver carcinogenesis assay. Evaluation of the expression of cytochrome P450 (CYP) enzymes in the liver revealed that DPAA induced the expression of CYP1B1, but not any other CYP1, CYP2, or CYP3 enzymes, suggesting that CYP1B1 might be the enzyme responsible for the metabolic activation of DPAA. We also found increased oxidative DNA damage, possibly due to elevated CYP1B1 expression. Induction of CYP1B1 has generally been linked with the activation of AhR, and we found that DPAA activates the aryl hydrocarbon receptor (AhR). Importantly, the promotion effect of DPAA was observed only at a dose that activated the AhR, suggesting that activation of AhR and consequent induction of AhR target genes and oxidative DNA damage plays a vital role in the promotion effects of DPAA. The present study provides, for the first time, evidence regarding the carcinogenicity of DPAA and indicates the necessity of comprehensive evaluation of its carcinogenic potential using long-term carcinogenicity studies. - Highlights: • DPAA, an environmental neurotoxicant, promotes liver carcinogenesis in rats. • DPAA is an activator of AhR signaling pathway. • DPAA promoted oxidative DNA damage in rat livers. • AhR target gene CYP 1B1 might be involved in the metabolism of DPAA

  20. Narrative-based computational modelling of the Gp130/JAK/STAT signalling pathway

    Directory of Open Access Journals (Sweden)

    Heath John K

    2009-04-01

    Full Text Available Abstract Background Appropriately formulated quantitative computational models can support researchers in understanding the dynamic behaviour of biological pathways and support hypothesis formulation and selection by "in silico" experimentation. An obstacle to widespread adoption of this approach is the requirement to formulate a biological pathway as machine executable computer code. We have recently proposed a novel, biologically intuitive, narrative-style modelling language for biologists to formulate the pathway which is then automatically translated into an executable format and is, thus, usable for analysis via existing simulation techniques. Results Here we use a high-level narrative language in designing a computational model of the gp130/JAK/STAT signalling pathway and show that the model reproduces the dynamic behaviour of the pathway derived by biological observation. We then "experiment" on the model by simulation and sensitivity analysis to define those parameters which dominate the dynamic behaviour of the pathway. The model predicts that nuclear compartmentalisation and phosphorylation status of STAT are key determinants of the pathway and that alternative mechanisms of signal attenuation exert their influence on different timescales. Conclusion The described narrative model of the gp130/JAK/STAT pathway represents an interesting case study showing how, by using this approach, researchers can model biological systems without explicitly dealing with formal notations and mathematical expressions (typically used for biochemical modelling, nevertheless being able to obtain simulation and analysis results. We present the model and the sensitivity analysis results we have obtained, that allow us to identify the parameters which are most sensitive to perturbations. The results, which are shown to be in agreement with existing mathematical models of the gp130/JAK/STAT pathway, serve us as a form of validation of the model and of the

  1. Sorting and targeting of melanosomal membrane proteins: signals, pathways, and mechanisms.

    Science.gov (United States)

    Setaluri, V

    2000-06-01

    Newly synthesized melanosomal proteins, like many other cellular proteins, traverse through a series of intracellular compartments en route to melanosomes. Entry and exit of proteins through these compartments is orchestrated by cellular sorting machinery that recognize specific sorting signals. Melanosomal membrane proteins begin their intracellular journey upon co-translational importation into the endoplasmic reticulum (ER). The biosynthetic output of tyrosinase, the key melanogenic enzyme, appears to be regulated by quality-control events at the ER, the 'port of entry' to the secretory pathway. Following maturation in the ER and through the Golgi, the sorting of these proteins in the trans-Golgi network for intracellular retention and transport along endosome/lysosome pathway requires cytoplasmically exposed signals. A di-leucine motif, present in the cytoplasmic tails of most melanosomal proteins, and its interaction with adaptor protein (AP) complexes, specifically AP-3, are critical for these events. Defects in sorting signals and the cytosolic components that interact with these signals result in a number of murine coat color phenotypes and cause human pigmentary disorders. Thus, missense or frame-shift mutations that produce truncated tyrosinase lacking the melanosomal sorting signal(s) appear to be responsible for murine platinum coat color phenotypes and a proportion of human oculocutaneous albinism-1; mutations in AP-3 appear to be responsible for the mocha phenotype in mice and Hermansky-Pudlak-like syndrome in man. Additional signals and sorting steps downstream of AP-3 appear to be required for endosomal sorting and targeting proteins to melanosomes. Signals and mechanisms that sequester melanosomal proteins from endosomes/lysosomes are not understood. Potential candidates that mediate such processes include proteins encoded by lyst and pallid genes. The common occurrence of abnormalities in melanosomes in many storage-pool disorders suggests that

  2. Human aging mechanisms and radiation exposure related to the mTOR signaling pathway

    International Nuclear Information System (INIS)

    The search for human aging mechanisms has been guided by a paradigm: Aging and age-related diseases are mainly attributable to the accumulation of damage at the molecular level. Exposure to ionizing radiation is observed to increase risks of age-related diseases, including cancer and cardiovascular disease. Such radiation effects are also viewed and investigated from the perspective of molecular damage. Recently, another aging mechanism theory has been proposed from an entirely different perspective. The 'hyperfunction' theory (Blagosklonny, 2006) views aging where anabolic processes, such as protein synthesis, which contribute to cell proliferation and tissue formation in developmental phases, continue in later life at too high a level, leading to hypertrophy and hyperplasia. In these activities, nutrient and growth factor-sensing pathways, typically the mechanistic target of rapamycin (mTOR), are known to play pivotal roles. In fact, inhibition of the mTOR signaling pathway expands lifespan in model animals, and the mTOR signaling is activated in human cancer cells. Interestingly enough, recent studies revealed that activity of the mTOR signaling pathway is altered by irradiation and that mTOR activity is involved in cellular responses to radiation exposure. In this paper, I discuss human aging mechanisms and radiation exposure in terms of the mTOR signaling pathway. (author)

  3. Primary cilia and signaling pathways in mammalian development, health and disease

    DEFF Research Database (Denmark)

    Veland, Iben R; Awan, Aashir; Pedersen, Lotte B;

    2009-01-01

    surface of most growth-arrested or differentiated mammalian cells, and defects in their assembly or function are tightly coupled to many developmental defects, diseases and disorders. In normal tissues, the primary cilium coordinates a series of signal transduction pathways, including Hedgehog, Wnt...

  4. Involvement of wnt signaling pathways in the metamorphosis of the bryozoan bugula neritina

    KAUST Repository

    Wong, Yue Him

    2012-03-20

    In this study, we analyzed the metamorphosis of the marine bryozoan Bugula neritina. We observed the morphogenesis of the ancestrula. We defined three distinct pre-ancestrula stages based on the anatomy of the developing polypide and the overall morphology of pre-ancestrula. We then used an annotation based enrichment analysis tool to analyze the B. neritina transcriptome and identified over-representation of genes related to Wnt signaling pathways, suggesting its involvement in metamorphosis. Finally, we studied the temporal-spatial gene expression studies of several Wnt pathway genes. We found that one of the Wnt ligand, BnWnt10, was expressed spatially opposite to the Wnt antagonist BnsFRP within the blastemas, which is the presumptive polypide. Down-stream components of the canonical Wnt signaling pathway were exclusively expressed in the blastemas. Bn?catenin and BnFz5/8 were exclusively expressed in the blastemas throughout the metamorphosis. Based on the genes expression patterns, we propose that BnWnt10 and BnsFRP may relate to the patterning of the polypide, in which the two genes served as positional signals and contributed to the polarization of the blastemas. Another Wnt ligand, BnWnt6, was expressed in the apical part of the pre-ancestrula epidermis. Overall, our findings suggest that the Wnt signaling pathway may be important to the pattern formation of polypide and the development of epidermis. © 2012 Wong et al.

  5. Signaling pathways involved in PDGF-evoked cellular responses in human RPE cells

    International Nuclear Information System (INIS)

    We examined whether PDGF may directly stimulate the expression of VEGF by retinal pigment epithelial (RPE) cells in vitro, and the involvement of three signal transduction pathways in the regulation of PDGF-evoked cell proliferation, migration, and production of VEGF-A was investigated. PDGF stimulated the gene and protein expression of VEGF-A by RPE cells, and increased cell proliferation and chemotaxis. PDGF activated all signaling pathways investigated, as determined by increased phosphorylation levels of ERK1/2, p38, and Akt proteins. The three signaling pathways were involved in the mediation of PDGF-evoked cell proliferation, while p38 and PI3K mediated cell migration, and PI3K mediated secretion of VEGF-A. In addition to VEGF-A, the cells expressed mRNAs for various members of the VEGF family and for their receptors, including VEGF-B, -C, -D, flt-1, and KDR. The data indicate that PDGF selectively stimulates the expression of VEGF-A in RPE cells. PDGF evokes at least three signal transduction pathways which are differentially involved in various cellular responses

  6. Signaling Pathways Used by Ergot Alkaloids to Inhibit Bovine Sperm Motility

    Science.gov (United States)

    Ergot alkaloids exert their toxic or pharmaceutical effects through membrane receptor-mediated activities. This study investigated the signaling pathways involved in the in vitro inhibitory effects of both ergotamine (ET) and dihydroergotamine (DEHT) on bovine sperm motility using specific inhibitor...

  7. Protein conservation and variation suggest mechanisms of cell type-specific modulation of signaling pathways.

    Directory of Open Access Journals (Sweden)

    Martin H Schaefer

    2014-06-01

    Full Text Available Many proteins and signaling pathways are present in most cell types and tissues and yet perform specialized functions. To elucidate mechanisms by which these ubiquitous pathways are modulated, we overlaid information about cross-cell line protein abundance and variability, and evolutionary conservation onto functional pathway components and topological layers in the pathway hierarchy. We found that the input (receptors and the output (transcription factors layers evolve more rapidly than proteins in the intermediary transmission layer. In contrast, protein expression variability decreases from the input to the output layer. We observed that the differences in protein variability between the input and transmission layer can be attributed to both the network position and the tendency of variable proteins to physically interact with constitutively expressed proteins. Differences in protein expression variability and conservation are also accompanied by the tendency of conserved and constitutively expressed proteins to acquire somatic mutations, while germline mutations tend to occur in cell type-specific proteins. Thus, conserved core proteins in the transmission layer could perform a fundamental role in most cell types and are therefore less tolerant to germline mutations. In summary, we propose that the core signal transmission machinery is largely modulated by a variable input layer through physical protein interactions. We hypothesize that the bow-tie organization of cellular signaling on the level of protein abundance variability contributes to the specificity of the signal response in different cell types.

  8. Tyrosinase kinetics in epidermal melanocytes: analysis of DAG-PKC-dependent signaling pathway

    Science.gov (United States)

    Stolnitz, Mikhail M.; Peshkova, Anna Y.

    2001-05-01

    Tyrosinase is the key enzyme of melanogenesis with unusual enzyme kinetics. Protein kinase C plays an important role in regulating of tyrosinase activity. In the paper the mathematical model of PKC-DAG-dependent signal transduction pathway for UV-radiation is presented.

  9. Protein conservation and variation suggest mechanisms of cell type-specific modulation of signaling pathways.

    Science.gov (United States)

    Schaefer, Martin H; Yang, Jae-Seong; Serrano, Luis; Kiel, Christina

    2014-06-01

    Many proteins and signaling pathways are present in most cell types and tissues and yet perform specialized functions. To elucidate mechanisms by which these ubiquitous pathways are modulated, we overlaid information about cross-cell line protein abundance and variability, and evolutionary conservation onto functional pathway components and topological layers in the pathway hierarchy. We found that the input (receptors) and the output (transcription factors) layers evolve more rapidly than proteins in the intermediary transmission layer. In contrast, protein expression variability decreases from the input to the output layer. We observed that the differences in protein variability between the input and transmission layer can be attributed to both the network position and the tendency of variable proteins to physically interact with constitutively expressed proteins. Differences in protein expression variability and conservation are also accompanied by the tendency of conserved and constitutively expressed proteins to acquire somatic mutations, while germline mutations tend to occur in cell type-specific proteins. Thus, conserved core proteins in the transmission layer could perform a fundamental role in most cell types and are therefore less tolerant to germline mutations. In summary, we propose that the core signal transmission machinery is largely modulated by a variable input layer through physical protein interactions. We hypothesize that the bow-tie organization of cellular signaling on the level of protein abundance variability contributes to the specificity of the signal response in different cell types. PMID:24922536

  10. The role of CXCL12-CXCR4 signaling pathway in pancreatic development

    DEFF Research Database (Denmark)

    Katsumoto, Keiichi; Kume, Shoen

    2013-01-01

    , cell chemotaxis and apoptosis [1, 2]. The expression of CXCR4 is observed in embryonic stem cells, blood cells, haematopoietic stem cells, endothelial cells, angioblasts and smooth muscle cells [3-9]. The CXCL12-CXCR4 signaling pathway has very important roles in the embryonic development. Mutant mice...

  11. Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo.

    Science.gov (United States)

    Dowling, James E; Alimzhanov, Marat; Bao, Larry; Chuaqui, Claudio; Denz, Christopher R; Jenkins, Emma; Larsen, Nicholas A; Lyne, Paul D; Pontz, Timothy; Ye, Qing; Holdgate, Geoff A; Snow, Lindsay; O'Connell, Nichole; Ferguson, Andrew D

    2016-03-10

    The Wnt pathway is an evolutionarily conserved and tightly regulated signaling network with important roles in embryonic development and adult tissue regeneration. Impaired Wnt pathway regulation, arising from mutations in Wnt signaling components, such as Axin, APC, and β-catenin, results in uncontrolled cell growth and triggers oncogenesis. To explore the reported link between CK2 kinase activity and Wnt pathway signaling, we sought to identify a potent, selective inhibitor of CK2 suitable for proof of concept studies in vivo. Starting from a pyrazolo[1,5-a]pyrimidine lead (2), we identified compound 7h, a potent CK2 inhibitor with picomolar affinity that is highly selectivity against other kinase family enzymes and inhibits Wnt pathway signaling (IC50 = 50 nM) in DLD-1 cells. In addition, compound 7h has physicochemical properties that are suitable for formulation as an intravenous solution, has demonstrated good pharmacokinetics in preclinical species, and exhibits a high level of activity as a monotherapy in HCT-116 and SW-620 xenografts. PMID:26985319

  12. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors

    Directory of Open Access Journals (Sweden)

    Tadas K. Rimkus

    2016-02-01

    Full Text Available The sonic hedgehog (Shh signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO and glioma-associated oncogene homolog (GLI family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials.

  13. Dicer-2-dependent activation of Culex Vago occurs via the TRAF-Rel2 signaling pathway.

    Directory of Open Access Journals (Sweden)

    Prasad N Paradkar

    2014-04-01

    Full Text Available Despite their importance as vectors of human and livestock diseases, relatively little is known about innate antiviral immune pathways in mosquitoes and other insects. Previous work has shown that Culex Vago (CxVago, which is induced and secreted from West Nile virus (WNV-infected mosquito cells, acts as a functional homolog of interferon, by activating Jak-STAT pathway and limiting virus replication in neighbouring cells. Here we describe the Dicer-2-dependent pathway leading to WNV-induced CxVago activation. Using a luciferase reporter assay, we show that a NF-κB-like binding site in CxVago promoter region is conserved in mosquito species and is responsible for induction of CxVago expression following WNV infection. Using dsRNA-based gene knockdown, we show that the NF-κB ortholog, Rel2, plays significant role in the signaling pathway that activates CxVago in mosquito cells in vitro and in vivo. Using similar approaches, we also show that TRAF, but not TRAF-3, is involved in activation of Rel2 after viral infection. Overall the study shows that a conserved signaling pathway, which is similar to mammalian interferon activation pathway, is responsible for the induction and antiviral activity of CxVago.

  14. Make Yourself at Home: Viral Hijacking of the PI3K/Akt Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Nora Diehl

    2013-12-01

    Full Text Available As viruses do not possess genes encoding for proteins required for translation, energy metabolism or membrane biosynthesis, they are classified as obligatory intracellular parasites that depend on a host cell to replicate. This genome limitation forces them to gain control over cellular processes to ensure their successful propagation. A diverse spectrum of virally encoded proteins tackling a broad spectrum of cellular pathways during most steps of the viral life cycle ranging from the host cell entry to viral protein translation has evolved. Since the host cell PI3K/Akt signaling pathway plays a critical regulatory role in many cellular processes including RNA processing, translation, autophagy and apoptosis, many viruses, in widely varying ways, target it. This review focuses on a number of remarkable examples of viral strategies, which exploit the PI3K/Akt signaling pathway for effective viral replication.

  15. Advances of Targeted Therapy Based on Estrogen Receptor Signaling Pathway 
in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Liqiang XU

    2011-09-01

    Full Text Available Increasing evidence indicates that estrogen promotes tumor growth in both estrogen target organs and non-target organs. Estrogen regulates cell proliferation and differentiation via two different receptors, estrogen receptors α and β (ERα and ERβ. In recent decades, with the clarification of the ERα-mediated signaling pathways in breast cancer, targeted therapy through these pathways have successfully been used in clinical application. Tamoxifen, the classic representative, is a selective estrogen receptor modulator (SERM. Along with the elucidation of the role of estrogen in the pathophysiology of lung cancer, targeted lung cancer treatment based on the ER signaling pathways is also gradually being applied and it could become an important part of the comprehensive treatment for lung cancer.

  16. Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling.

    Science.gov (United States)

    Rosen, Ezra Y; Wexler, Eric M; Versano, Revital; Coppola, Giovanni; Gao, Fuying; Winden, Kellen D; Oldham, Michael C; Martens, Lauren Herl; Zhou, Ping; Farese, Robert V; Geschwind, Daniel H

    2011-09-22

    Progranulin (GRN) mutations cause frontotemporal dementia (FTD), but GRN's function in the CNS remains largely unknown. To identify the pathways downstream of GRN, we used weighted gene coexpression network analysis (WGCNA) to develop a systems-level view of transcriptional alterations in a human neural progenitor model of GRN-deficiency. This highlighted key pathways such as apoptosis and ubiquitination in GRN deficient human neurons, while revealing an unexpected major role for the Wnt signaling pathway, which was confirmed by analysis of gene expression data from postmortem FTD brain. Furthermore, we observed that the Wnt receptor Fzd2 was one of only a few genes upregulated at 6 weeks in a GRN knockout mouse, and that FZD2 reduction caused increased apoptosis, while its upregulation promoted neuronal survival in vitro. Together, these in vitro and in vivo data point to an adaptive role for altered Wnt signaling in GRN deficiency-mediated FTD, representing a potential therapeutic target. PMID:21943601

  17. Arrestin development: emerging roles for beta-arrestins in developmental signaling pathways.

    Science.gov (United States)

    Kovacs, Jeffrey J; Hara, Makoto R; Davenport, Chandra L; Kim, Jihee; Lefkowitz, Robert J

    2009-10-01

    Arrestins were identified as mediators of G protein-coupled receptor (GPCR) desensitization and endocytosis. However, it is now clear that they scaffold many intracellular signaling networks to modulate the strength and duration of signaling by diverse types of receptors--including those relevant to the Hedgehog, Wnt, Notch, and TGFbeta pathways--and downstream kinases such as the MAPK and Akt/PI3K cascades. The involvement of arrestins in many discrete developmental signaling events suggests an indispensable role for these multifaceted molecular scaffolds. PMID:19853559

  18. A cGMP-signaling pathway in a subset of olfactory sensory neurons

    OpenAIRE

    Meyer, M.R.; Angele, A.; Kremmer, E; Kaupp, U B; F. Müller

    2000-01-01

    It is well established that signal transduction in sensory neurons of the rat olfactory epithelium involves a cAMP-signaling pathway. However, a small number of olfactory neurons specifically express cGMP-signaling components, namely a guanylyl cyclase (GC-D) and a cGMP-stimulated phosphodiesterase (PDE2). Here, we show that this subset of olfactory neurons expressing GC-D and PDE2 does also express the subunit of a cGMP-selective cyclic nucleotide-gated (CNG) channel that has been previously...

  19. Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer.

    Science.gov (United States)

    Fan, Cong; Wang, Yunshan; Liu, Ziming; Sun, Ying; Wang, Xiuwen; Wei, Guangwei; Wei, Junmin

    2015-07-01

    Metformin, a widely prescribed antidiabetic drug, has previously been shown to lower the risk of certain types of cancer, including that of breast cancer, and to improve prognosis. Its anticancer effects, which are mediated by the activation of AMP-activated protein kinase (AMPK), have become notable. The Sonic hedgehog (Shh) signaling pathway is involved in changes in mammary ducts and malignant transformation. The aim of the present study was to elucidate the role of the Shh pathway in mediating the anticancer effects of metformin and the correlation between AMPK and the Shh pathway. We investigated the effectiveness of metformin in inhibiting the proliferation, migration, invasion and stemness of breast cancer cells in vitro using RNA extraction and reverse transcription‑polymerase chain reaction (RT-PCR), western blot analysis, cell proliferation assay, scratch-wound assay (cell migration assay), cell invasion assay, mammosphere culture and flow cytometry. In in vivo experiments, a tumor xenograft model was used to detect the effects of metformin on cancer cell proliferation. The results revealed that the treatment of breast cancer cells with metformin led to the inhibition of the Shh signaling pathway. Importantly, metformin inhibited recombinant human Shh (rhShh)‑induced cell migration, invasion, and stemness, and impaired cell proliferation both in vitro and in vivo. Furthermore, the small interfering RNA (siRNA)‑mediated downregulation of AMPK reversed the inhibitory effects of metformin on rhShh‑induced Gli-1 expression and stemness. Our findings identified a role of the Shh signaling pathway in the anticancer effects of metformin in breast cancer. Furthermore, we revealed that the metformin-mediated inhibition of the Shh signaling pathway may be dependent on AMPK. PMID:25999130

  20. Directed random walks and constraint programming reveal active pathways in hepatocyte growth factor signaling.

    Science.gov (United States)

    Kittas, Aristotelis; Delobelle, Aurélien; Schmitt, Sabrina; Breuhahn, Kai; Guziolowski, Carito; Grabe, Niels

    2016-01-01

    An effective means to analyze mRNA expression data is to take advantage of established knowledge from pathway databases, using methods such as pathway-enrichment analyses. However, pathway databases are not case-specific and expression data could be used to infer gene-regulation patterns in the context of specific pathways. In addition, canonical pathways may not always describe the signaling mechanisms properly, because interactions can frequently occur between genes in different pathways. Relatively few methods have been proposed to date for generating and analyzing such networks, preserving the causality between gene interactions and reasoning over the qualitative logic of regulatory effects. We present an algorithm (MCWalk) integrated with a logic programming approach, to discover subgraphs in large-scale signaling networks by random walks in a fully automated pipeline. As an exemplary application, we uncover the signal transduction mechanisms in a gene interaction network describing hepatocyte growth factor-stimulated cell migration and proliferation from gene-expression measured with microarray and RT-qPCR using in-house perturbation experiments in a keratinocyte-fibroblast co-culture. The resulting subgraphs illustrate possible associations of hepatocyte growth factor receptor c-Met nodes, differentially expressed genes and cellular states. Using perturbation experiments and Answer Set programming, we are able to select those which are more consistent with the experimental data. We discover key regulator nodes by measuring the frequency with which they are traversed when connecting signaling between receptors and significantly regulated genes and predict their expression-shift consistently with the measured data. The Java implementation of MCWalk is publicly available under the MIT license at: https://bitbucket.org/akittas/biosubg. PMID:26518250

  1. Association of single nucleotide polymorphisms in Wnt signaling pathway genes with breast cancer in Saudi patients.

    Directory of Open Access Journals (Sweden)

    Mohammad Saud Alanazi

    Full Text Available Breast cancer is a complex heterogeneous disease involving genetic and epigenetic alterations in genes encoding proteins that are components of various signaling pathways. Candidate gene approach have identified association of genetic variants in the Wnt signaling pathway genes and increased susceptibility to several diseases including breast cancer. Due to the rarity of somatic mutations in key genes of Wnt pathway, we investigated the association of genetic variants in these genes with predisposition to breast cancers. We performed a case-control study to identify risk variants by examining 15 SNPs located in 8 genes associated with Wnt signaling. Genotypic analysis of individual locus showed statistically significant association of five SNPs located in β-catenin, AXIN2, DKK3, SFRP3 and TCF7L2 with breast cancers. Increased risk was observed only with the SNP in β-catenin while the other four SNPs conferred protection against breast cancers. Majority of these associations persisted after stratification of the cases based on estrogen receptor status and age of on-set of breast cancer. The rs7775 SNP in exon 6 of SFRP3 gene that codes for either arginine or glycine exhibited very strong association with breast cancer, even after Bonferroni's correction. Apart from these five variants, rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. This is the first study to utilize pathway based approach to identify association of risk variants in the Wnt signaling pathway genes with breast cancers. Confirmation of our findings in larger populations of different ethnicities would provide evidence for the role of Wnt pathway as well as screening markers for early detection of breast carcinomas.

  2. Wnt-signalling pathways and microRNAs network in carcinogenesis: experimental and bioinformatics approaches.

    Science.gov (United States)

    Onyido, Emenike K; Sweeney, Eloise; Nateri, Abdolrahman Shams

    2016-01-01

    Over the past few years, microRNAs (miRNAs) have not only emerged as integral regulators of gene expression at the post-transcriptional level but also respond to signalling molecules to affect cell function(s). miRNAs crosstalk with a variety of the key cellular signalling networks such as Wnt, transforming growth factor-β and Notch, control stem cell activity in maintaining tissue homeostasis, while if dysregulated contributes to the initiation and progression of cancer. Herein, we overview the molecular mechanism(s) underlying the crosstalk between Wnt-signalling components (canonical and non-canonical) and miRNAs, as well as changes in the miRNA/Wnt-signalling components observed in the different forms of cancer. Furthermore, the fundamental understanding of miRNA-mediated regulation of Wnt-signalling pathway and vice versa has been significantly improved by high-throughput genomics and bioinformatics technologies. Whilst, these approaches have identified a number of specific miRNA(s) that function as oncogenes or tumour suppressors, additional analyses will be necessary to fully unravel the links among conserved cellular signalling pathways and miRNAs and their potential associated components in cancer, thereby creating therapeutic avenues against tumours. Hence, we also discuss the current challenges associated with Wnt-signalling/miRNAs complex and the analysis using the biomedical experimental and bioinformatics approaches. PMID:27590724

  3. Long-distance plant signaling pathways in response to multiple stressors: the gap in knowledge.

    Science.gov (United States)

    Huber, Annika E; Bauerle, Taryn L

    2016-03-01

    Plants require the capacity for quick and precise recognition of external stimuli within their environment for survival. Upon exposure to biotic (herbivores and pathogens) or abiotic stressors (environmental conditions), plants can activate hydraulic, chemical, or electrical long-distance signals to initiate systemic stress responses. A plant's stress reactions can be highly precise and orchestrated in response to different stressors or stress combinations. To date, an array of information is available on plant responses to single stressors. However, information on simultaneously occurring stresses that represent either multiple, within, or across abiotic and biotic stress types is nascent. Likewise, the crosstalk between hydraulic, chemical, and electrical signaling pathways and the importance of each individual signaling type requires further investigation in order to be fully understood. The overlapping presence and speed of the signals upon plant exposure to various stressors makes it challenging to identify the signal initiating plant systemic stress/defense responses. Furthermore, it is thought that systemic plant responses are not transmitted by a single pathway, but rather by a combination of signals enabling the transmission of information on the prevailing stressor(s) and its intensity. In this review, we summarize the mode of action of hydraulic, chemical, and electrical long-distance signals, discuss their importance in information transmission to biotic and abiotic stressors, and suggest future research directions. PMID:26944636

  4. Signaling pathways regulating Homer1a expression: implications for antidepressant therapy.

    Science.gov (United States)

    Serchov, Tsvetan; Heumann, Rolf; van Calker, Dietrich; Biber, Knut

    2016-03-01

    Homer1a is upregulated by several different antidepressant measures, including non-pharmacological treatments, like sleep deprivation (SD) and electroconvulsive therapy (ECT) and antidepressant drugs, such as imipramine, fluoxetine and ketamine. Homer1a induction might thus be a crucial joint mechanism for antidepressant therapy in general. However, the upstream signaling pathways that regulate or induce Homer1a expression are still not well understood. The main focus of the present review is to offer an overview of the current knowledge about the potential role of Homer1a in depression and the signaling pathways responsible for Homer1a regulation. It is suggested here that a detailed characterization of the signaling mechanisms leading to Homer1a expression might provide novel therapeutic targets for antidepressant drug development. PMID:26641965

  5. Emerging Roles for Intersectin (ITSN in Regulating Signaling and Disease Pathways

    Directory of Open Access Journals (Sweden)

    John P. O'Bryan

    2013-04-01

    Full Text Available Intersectins (ITSNs represent a family of multi-domain adaptor proteins that regulate endocytosis and cell signaling. ITSN genes are highly conserved and present in all metazoan genomes examined thus far. Lower eukaryotes have only one ITSN gene, whereas higher eukaryotes have two ITSN genes. ITSN was first identified as an endocytic scaffold protein, and numerous studies reveal a conserved role for ITSN in endocytosis. Subsequently, ITSNs were found to regulate multiple signaling pathways including receptor tyrosine kinases (RTKs, GTPases, and phosphatidylinositol 3-kinase Class 2beta (PI3KC2β. ITSN has also been implicated in diseases such as Down Syndrome (DS, Alzheimer Disease (AD, and other neurodegenerative disorders. This review summarizes the evolutionary conservation of ITSN, the latest research on the role of ITSN in endocytosis, the emerging roles of ITSN in regulating cell signaling pathways, and the involvement of ITSN in human diseases such as DS, AD, and cancer.

  6. The EBI2 signalling pathway plays a role in cellular crosstalk between astrocytes and macrophages.

    Science.gov (United States)

    Rutkowska, Aleksandra; O'Sullivan, Sinead A; Christen, Isabelle; Zhang, Juan; Sailer, Andreas W; Dev, Kumlesh K

    2016-01-01

    EBI2 is a G protein-coupled receptor activated by oxysterol 7α, 25-dihydroxycholesterol (7α25HC) and regulates T cell-dependant antibody response and B cell migration. We recently found EBI2 is expressed in human astrocytes, regulates intracellular signalling and modulates astrocyte migration. Here, we report that LPS treatment of mouse astrocytes alters mRNA levels of EBI2 and oxysterols suggesting that the EBI2 signalling pathway is sensitive to LPS-mediated immune challenge. We also find that conditioned media obtained from LPS-stimulated mouse astrocytes induces macrophage migration, which is inhibited by the EBI2 antagonist NIBR189. These results demonstrate a role for the EBI2 signalling pathway in astrocytes as a sensor for immune challenge and for communication with innate immune cells such as macrophages. PMID:27166278

  7. Inhibitory mechanisms of two Uncaria tomentosa extracts affecting the Wnt-signaling pathway.

    Science.gov (United States)

    Gurrola-Díaz, Carmen Magdalena; García-López, Pedro Macedonio; Gulewicz, Krzysztof; Pilarski, Radoslaw; Dihlmann, Susanne

    2011-06-15

    Uncaria tomentosa ("uña de gato"; "cat's claw"), a woody vine native to the Amazon rainforest, is commonly used in South American traditional medicine to treat a broad spectrum of diseases. Although recent studies have reported anti-inflammatory and anti-proliferative properties of different alkaloids extracted from this plant, the underlying molecular mechanisms of these effects have not been elucidated yet. Our study investigates the inhibitory mechanisms of Uncaria tomentosa extracts on the Wnt-signaling pathway, a central regulator of development and tissue homoeostasis. A modified cell-based luciferase assay for screening inhibitors of the Wnt-pathway was used for analysis. Three cancer cell lines displaying different levels of aberrant Wnt-signaling activity were transfected with Wnt-signaling responsive Tcf-reporter plasmids and treated with increasing concentrations of two Uncaria tomentosa bark extracts. Wnt-signaling activity was assessed by luciferase activity and by expression of Wnt-responsive target genes. We show that both, an aqueous and an alkaloid-enriched extract specifically inhibit Wnt-signaling activity in HeLa, HCT116 and SW480 cancer cells resulting in reduced expression of the Wnt-target gene: c-Myc. The alkaloid-enriched extract (B/S(rt)) was found to be more effective than the aqueous extract (B/W(37)). The strongest effect was observed in SW480 cells, displaying the highest endogenous Wnt-signaling activity. Downregulation of Wnt-signaling by a dominant negative-TCF-4 variant in non-cancer cells rendered the cells insensitive towards treatment with B/S(rt). B/Srt was less toxic in non-cancer cells than in cancer cells. Our data suggest that the broad spectrum of pharmacological action of Uncaria tomentosa involves inhibition of the Wnt-signaling pathway, downstream of beta-Catenin activity. PMID:21156346

  8. Schisantherin A suppresses osteoclast formation and wear particle-induced osteolysis via modulating RANKL signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    He, Yi; Zhang, Qing; Shen, Yi; Chen, Xia; Zhou, Feng; Peng, Dan, E-mail: xyeypd@163.com

    2014-07-04

    Highlights: • Schisantherin A suppresses osteoclasts formation and function in vitro. • Schisantherin A impairs RANKL signaling pathway. • Schisantherin A suppresses osteolysis in vivo. • Schisantherin A may be used for treating osteoclast related diseases. - Abstract: Receptor activator of NF-κB ligand (RANKL) plays critical role in osteoclastogenesis. Targeting RANKL signaling pathways has been a promising strategy for treating osteoclast related bone diseases such as osteoporosis and aseptic prosthetic loosening. Schisantherin A (SA), a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera, has been used as an antitussive, tonic, and sedative agent, but its effect on osteoclasts has been hitherto unknown. In the present study, SA was found to inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, SA inhibited OSCAR, cathepsin K and TRAP in a dose dependent manner. Further signal transduction studies revealed that SA down-regulate RANKL-induced nuclear factor-kappaB (NF-κB) signaling activation by suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the NF-κB transcriptional activity. Moreover, SA also decreased the RANKL-induced MAPKs signaling pathway, including JNK and ERK1/2 posphorylation while had no obvious effects on p38 activation. Finally, SA suppressed the NF-κB and MAPKs subsequent gene expression of NFATc1 and c-Fos. In vivo studies, SA inhibited osteoclast function and exhibited bone protection effect in wear-particle-induced bone erosion model. Taken together, SA could attenuate osteoclast formation and wear particle-induced osteolysis by mediating RANKL signaling pathways. These data indicated that SA is a promising therapeutic natural compound for the treatment of osteoclast-related prosthesis loosening.

  9. Signal Propagation in the Human Visual Pathways: An Effective Connectivity Analysis.

    Science.gov (United States)

    Youssofzadeh, Vahab; Prasad, Girijesh; Fagan, Andrew J; Reilly, Richard B; Martens, Sven; Meaney, James F; Wong-Lin, KongFatt

    2015-09-30

    Although the visual system has been extensively investigated, an integrated account of the spatiotemporal dynamics of long-range signal propagation along the human visual pathways is not completely known or validated. In this work, we used dynamic causal modeling approach to provide insights into the underlying neural circuit dynamics of pattern reversal visual-evoked potentials extracted from concurrent EEG-fMRI data. A recurrent forward-backward connectivity model, consisting of multiple interacting brain regions identified by EEG source localization aided by fMRI spatial priors, best accounted for the data dynamics. Sources were first identified in the thalamic area, primary visual cortex, as well as higher cortical areas along the ventral and dorsal visual processing streams. Consistent with hierarchical early visual processing, the model disclosed and quantified the neural temporal dynamics across the identified activity sources. This signal propagation is dominated by a feedforward process, but we also found weaker effective feedback connectivity. Using effective connectivity analysis, the optimal dynamic causal modeling revealed enhanced connectivity along the dorsal pathway but slightly suppressed connectivity along the ventral pathway. A bias was also found in favor of the right hemisphere consistent with functional attentional asymmetry. This study validates, for the first time, the long-range signal propagation timing in the human visual pathways. A similar modeling approach can potentially be used to understand other cognitive processes and dysfunctions in signal propagation in neurological and neuropsychiatric disorders. Significance statement: An integrated account of long-range visual signal propagation in the human brain is currently incomplete. Using computational neural modeling on our acquired concurrent EEG-fMRI data under a visual evoked task, we found not only a substantial forward propagation toward "higher-order" brain regions but also a

  10. Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling

    Directory of Open Access Journals (Sweden)

    Smeets Ruben L

    2012-03-01

    Full Text Available Abstract Background T lymphocytes are orchestrators of adaptive immunity. Naïve T cells may differentiate into Th1, Th2, Th17 or iTreg phenotypes, depending on environmental co-stimulatory signals. To identify genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we performed comprehensive transcriptome analyses of Jurkat T cells stimulated with various stimuli and pathway inhibitors. Results from these experiments were validated in a human experimental setting using whole blood and purified CD4+ Tcells. Results Calcium-dependent activation of T cells using CD3/CD28 and PMA/CD3 stimulation induced a Th1 expression profile reflected by increased expression of T-bet, RUNX3, IL-2, and IFNγ, whereas calcium-independent activation via PMA/CD28 induced a Th2 expression profile which included GATA3, RXRA, CCL1 and Itk. Knock down with siRNA and gene expression profiling in the presence of selective kinase inhibitors showed that proximal kinases Lck and PKCθ are crucial signaling hubs during T helper cell activation, revealing a clear role for Lck in Th1 development and for PKCθ in both Th1 and Th2 development. Medial signaling via MAPkinases appeared to be less important in these pathways, since specific inhibitors of these kinases displayed a minor effect on gene expression. Translation towards a primary, whole blood setting and purified human CD4+ T cells revealed that PMA/CD3 stimulation induced a more pronounced Th1 specific, Lck and PKCθ dependent IFNγ production, whereas PMA/CD28 induced Th2 specific IL-5 and IL-13 production, independent of Lck activation. PMA/CD3-mediated skewing towards a Th1 phenotype was also reflected in mRNA expression of the master transcription factor Tbet, whereas PMA/CD28-mediated stimulation enhanced GATA3 mRNA expression in primary human CD4+ Tcells. Conclusions This study identifies stimulatory pathways and gene expression profiles for in vitro skewing of T helper cell

  11. Hedgehog信号通路与乳腺癌%Hedgehog Signal Pathway in the Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    屈超; 陈茜; 黄慧芳; 崔玉影; 邹伟

    2012-01-01

    The Hedgehog signaling pathway is considered to be involved in the molecular mechanism of the invasion and metastasis of the tumors. Mutations or abnormal expression in components of this pathway lead to the growth of breast tumors. Hedgehog signaling pathway interacts with Wnt, MAPK to regulate the progress of tumors. To better understand the molecular mechanism on the growth and progress of breast cancer, the vital role of Hedgehog signaling pathway on the growth and development of breast cancers was briefly reviewed.%近年来的研究表明,Hedgehog信号通路在肿瘤的发生发展中具有重要的作用,该通路基因突变或异常表达将导致多种器官肿瘤的发生,并与Wnt、MAPK等信号通路相互作用,共同调节肿瘤的发生发展.我们简要综述了Hedgehog信号通路在乳腺癌发生发展中的重要作用,旨在了解乳腺癌发生、发展的分子机制.

  12. Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

    Institute of Scientific and Technical Information of China (English)

    Yan Xiong; Zhenqian Hu; Xiaofan Han; Beibei Jiang; Rongli Zhang; Xiaoyu Zhang; Yao Lu

    2013-01-01

    Regulated endothelial exocytosis of Weibel-Palade bodies (WPBs),the first stage in leukocyte trafficking,plays a pivotal role in inflammation and injury.Acute mechanical stretch has been closely associated with vascular inflammation,although the precise mechanism is unknown.Here,we show that hypertensive stretch regulates the exocytosis of WPBs of endothelial ceils (ECs) through VEGF receptor 2 (VEGFR2) signaling pathways.Stretch triggers a rapid release (within minutes) of von Willebrand factor and interleukin-8 from WPBs in cultured human ECs,promoting the interaction between leukocytes and ECs through the translocation of P-selectin to the cell membrane.We further show that hypertensive stretch significantly induces P-selectin translocation of intact ECs and enhances leukocyte adhesion both ex vivo and in vivo.Stretch-induced endothelial exocytosis is mediated via a VEGFR2/PLCy1/calcium pathway.Interestingly,stretch also induces a negative feedback via a VEGFR2/Akt/nitric oxide pathway.Such dual effects are confirmed using pharmacological and genetic approaches in carotid artery segments,as well as in acute hypertensive mouse models.These studies reveal mechanical stretch as a potent agonist for endothelial exocytosis,which is modulated by VEGFR2 signaling.Thus,VEGFR2 signaling pathways may represent novel therapeutic targets in limiting hypertensive stretch-related inflammation.

  13. Drosophila Cyclin G Is a Regulator of the Notch Signalling Pathway during Wing Development

    Science.gov (United States)

    Nagel, Anja C.; Szawinski, Jutta; Zimmermann, Mirjam; Preiss, Anette

    2016-01-01

    Notch signalling regulates a multitude of differentiation processes during Drosophila development. For example, Notch activity is required for proper wing vein differentiation which is hampered in mutants of either the receptor Notch, the ligand Delta or the antagonist Hairless. Moreover, the Notch pathway is involved in several aspects of Drosophila oogenesis as well. We have identified Drosophila Cyclin G (CycG) as a molecular interaction partner of Hairless, the major antagonist in the Notch signalling pathway, in vitro and in vivo. Loss of CycG was shown before to cause female sterility and to disturb the architecture of the egg shell. Nevertheless, Notch dependent processes during oogenesis appeared largely unaffected in cycG mutant egg chambers. Loss of CycG modified the dominant wing phenotypes of Notch, Delta and Hairless mutants. Whereas the Notch loss of function phenotype was ameliorated by a loss of CycG, the phenotypes of either Notch gain of function or of Delta or Hairless loss of function were enhanced. In contrast, loss of CycG had only a minor effect on the wing vein phenotype of mutants affecting the EGFR signalling pathway emphasizing the specificity of the interaction of CycG and Notch pathway members. PMID:26963612

  14. Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks

    Directory of Open Access Journals (Sweden)

    Kirouac Daniel C

    2012-05-01

    Full Text Available Abstract Background Understanding the information-processing capabilities of signal transduction networks, how those networks are disrupted in disease, and rationally designing therapies to manipulate diseased states require systematic and accurate reconstruction of network topology. Data on networks central to human physiology, such as the inflammatory signalling networks analyzed here, are found in a multiplicity of on-line resources of pathway and interactome databases (Cancer CellMap, GeneGo, KEGG, NCI-Pathway Interactome Database (NCI-PID, PANTHER, Reactome, I2D, and STRING. We sought to determine whether these databases contain overlapping information and whether they can be used to construct high reliability prior knowledge networks for subsequent modeling of experimental data. Results We have assembled an ensemble network from multiple on-line sources representing a significant portion of all machine-readable and reconcilable human knowledge on proteins and protein interactions involved in inflammation. This ensemble network has many features expected of complex signalling networks assembled from high-throughput data: a power law distribution of both node degree and edge annotations, and topological features of a “bow tie” architecture in which diverse pathways converge on a highly conserved set of enzymatic cascades focused around PI3K/AKT, MAPK/ERK, JAK/STAT, NFκB, and apoptotic signaling. Individual pathways exhibit “fuzzy” modularity that is statistically significant but still involving a majority of “cross-talk” interactions. However, we find that the most widely used pathway databases are highly inconsistent with respect to the actual constituents and interactions in this network. Using a set of growth factor signalling networks as examples (epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, and wingless, we find a multiplicity of network topologies in which receptors couple to downstream

  15. The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

    International Nuclear Information System (INIS)

    To better understand the role of the canonical Wnt signaling pathway in cartilage development, we adenovirally expressed a constitutively active (Canada) or a dominant negative (dn) form of lymphoid enhancer factor-1 (LEF-1), the main nuclear effector of the pathway, in undifferentiated mesenchymal cells, chondrogenic cells, and primary chondrocytes, and examined the expression of markers for chondrogenic differentiation and hypertrophy. caLEF-1 and LiCl, an activator of the canonical pathway, promoted both chondrogenic differentiation and hypertrophy, whereas dnLEF-1 and the gene silencing of β-catenin suppressed LiCl-promoted effects. To investigate whether these effects were dependent on Sox9, a master regulator of cartilage development, we stimulated Sox9-deficient ES cells with the pathway. caLEF-1 and LiCl promoted both chondrogenic differentiation and hypertrophy in wild-type, but not in Sox9-deficient, cells. The response of Sox9-deficient cells was restored by the adenoviral expression of Sox9. Thus, the canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

  16. A Trichoderma atroviride stress-activated MAPK pathway integrates stress and light signals.

    Science.gov (United States)

    Esquivel-Naranjo, Edgardo Ulises; García-Esquivel, Mónica; Medina-Castellanos, Elizabeth; Correa-Pérez, Víctor Alejandro; Parra-Arriaga, Jorge Luis; Landeros-Jaime, Fidel; Cervantes-Chávez, José Antonio; Herrera-Estrella, Alfredo

    2016-06-01

    Cells possess stress-activated protein kinase (SAPK) signalling pathways, which are activated practically in response to any cellular insult, regulating responses for survival and adaptation to harmful environmental changes. To understand the function of SAPK pathways in T. atroviride, mutants lacking the MAPKK Pbs2 and the MAPK Tmk3 were analysed under several cellular stresses, and in their response to light. All mutants were highly sensitive to cellular insults such as osmotic and oxidative stress, cell wall damage, high temperature, cadmium, and UV irradiation. Under oxidative stress, the Tmk3 pathway showed specific roles during development, which in conidia are essential for tolerance to oxidant agents and appear to play a minor role in mycelia. The function of this pathway was more evident in Δpbs2 and Δtmk3 mutant strains when combining oxidative stress or cell wall damage with light. Light stimulates tolerance to osmotic stress through Tmk3 independently of the photoreceptor Blr1. Strikingly, photoconidiation and expression of blue light regulated genes was severally affected in Δtmk3 and Δpbs2 strains, indicating that this pathway regulates light responses. Furthermore, Tmk3 was rapidly phosphorylated upon light exposure. Thus, our data indicate that Tmk3 signalling cooperates with the Blr photoreceptor complex in the activation of gene expression. PMID:26878111

  17. Pollutants in particulate and gaseous fractions of ambient air interfere with multiple signaling pathways in vitro.

    Science.gov (United States)

    Novák, Jirí; Jálová, Veronika; Giesy, John P; Hilscherová, Klára

    2009-01-01

    Traditionally, contamination of air has been evaluated primarily by chemical analyses of indicator contaminants and these studies have focused mainly on compounds associated with particulates. Some reports have shown that air contaminants can produce specific biological effects such as toxicity mediated by the aryl hydrocarbon receptor (AhR) or modulation of the endocrine system. This study assessed the dioxin-like toxicity, anti-/estrogenicity, anti-/androgenicity and anti-/retinoic activity of both the particulate and gas phase fractions of air in two regions with different types of pollution sources and a background locality situated in an agricultural area of Central Europe. The first region (A) is known to be significantly contaminated by organochlorine pesticides and chemical industry. The other region (B) has been polluted by historical releases of PCBs, but the major current sources of contamination are probably combustion sources from local traffic and heating. Samples of both particle and gas fractions produced dioxin-like (AhR-mediated) activity, anti-estrogenic and antiandrogenic effects, but none had any effect on retinoid signaling. AhR-mediated activities were observed in all samples and the TEQ values were comparable in both fractions in region A, but significantly greater in the particulate fraction in region B. The greater AhR-mediated activity corresponded to a greater coincident antiestrogenicity of both phases in region B. Our study is the first report of antiestrogenicity and antiandrogenicity in ambient air. Anti-androgenicity was observed in the gas phase of all regions, while in the particulate phase only in one region due to the specific type of pollution in that area. Even though based on concentrations of individual compounds, except for the OCPs, the level of contamination of the two regions was similar, there were strong differences in responses in the bioassays between the two regions. Moreover, AhR-mediated activity and

  18. The nuclear factor-kappaB-interleukin-6 signalling pathway mediating vascular inflammation.

    Science.gov (United States)

    Brasier, Allan R

    2010-05-01

    Vascular inflammation is a common pathophysiological response to diverse cardiovascular disease processes, including atherosclerosis, myocardial infarction, congestive heart failure, and aortic aneurysms/dissection. Inflammation is an ordered process initiated by vascular injury that produces enhanced leucocyte adherence, chemotaxis, and finally activation in situ. This process is coordinated by local secretion of adhesion molecules, chemotactic factors, and cytokines whose expression is the result of vascular injury-induced signal transduction networks. A wide variety of mediators of the vascular injury response have been identified; these factors include vasoactive peptides (angiotensin II, Ang II), CD40 ligands, oxidized cholesterol, and advanced glycation end-products. Downstream, the nuclear factor-kappaB (NF-kappaB) transcription factor performs an important signal integration step, responding to mediators of vascular injury in a stimulus-dependent and cell type-specific manner. The ultimate consequence of NF-kappaB signalling is the activation of inflammatory genes including adhesion molecules and chemotaxins. However, clinically, the hallmark of vascular NF-kappaB activation is the production of interleukin-6 (IL-6), whose local role in vascular inflammation is relatively unknown. The recent elucidation for the role of the IL-6 signalling pathway in Ang II-induced vascular inflammation as one that controls monocyte activation as well as its diverse signalling mechanism will be reviewed. These new discoveries further our understanding for the important role of the NF-kappaB-IL-6 signalling pathway in the process of vascular inflammation. PMID:20202975

  19. Hydrogen peroxide induces activation of insulin signaling pathway via AMP-dependent kinase in podocytes

    International Nuclear Information System (INIS)

    Highlights: ► H2O2 activates the insulin signaling pathway and glucose uptake in podocytes. ► H2O2 induces time-dependent changes in AMPK phosphorylation. ► H2O2 enhances insulin signaling pathways via AMPK activation. ► H2O2 stimulation of glucose uptake is AMPK-dependent. -- Abstract: Podocytes are cells that form the glomerular filtration barrier in the kidney. Insulin signaling in podocytes is critical for normal kidney function. Insulin signaling is regulated by oxidative stress and intracellular energy levels. We cultured rat podocytes to investigate the effects of hydrogen peroxide (H2O2) on the phosphorylation of proximal and distal elements of insulin signaling. We also investigated H2O2-induced intracellular changes in the distribution of protein kinase B (Akt). Western blots showed that H2O2 (100 μM) induced rapid, transient phosphorylation of the insulin receptor (IR), the IR substrate-1 (IRS1), and Akt with peak activities at 5 min (Δ 183%, P 2O2>. Furthermore, H2O2 inhibited phosphorylation of the phosphatase and tensin homologue (PTEN; peak activity at 10 min; Δ −32%, P 2O2 on IR phosphorylation by about 40% (from 2.07 ± 0.28 to 1.28 ± 0.12, P 2O2 increased glucose uptake in podocytes (from 0.88 ± 0.04 to 1.29 ± 0.12 nmol/min/mg protein, P 2O2 activated the insulin signaling pathway and glucose uptake via AMPK in cultured rat podocytes. This signaling may play a potential role in the prevention of insulin resistance under conditions associated with oxidative stress.

  20. Utilizing ras signaling pathway to direct selective replication of herpes simplex virus-1.

    Directory of Open Access Journals (Sweden)

    Weihong Pan

    Full Text Available Re-engineering the tropism of viruses is an attractive translational strategy for targeting cancer cells. The Ras signal transduction pathway is a central hub for a variety of pro-oncogenic events with a fundamental role in normal and neoplastic physiology. In this work we were interested in linking Ras activation to HSV-1 replication in a direct manner in order to generate a novel oncolytic herpes virus which can target cancer cells. To establish such link, we developed a mutant HSV-1 in which the expression of ICP4 (infected cell protein-4, a viral protein necessary for replication is controlled by activation of ELK, a transcription factor down-stream of the Ras pathway and mainly activated by ERK (extracellular signal-regulated kinase, an important Ras effector pathway. This mutant HSV-1 was named as Signal-Smart 1 (SS1. A series of prostate cells were infected with the SS1 virus. Cells with elevated levels of ELK activation were preferentially infected by the SS1 virus, as demonstrated by increased levels of viral progeny, herpetic glycoprotein C and overall SS1 viral protein production. Upon exposure to SS1, the proliferation, invasiveness and colony formation capabilities of prostate cancer cells with increased ELK activation were significantly decreased (p<0.05, while the rate of apoptosis/necrosis in these cells was increased. Additionally, high Ras signaling cells infected with SS1 showed a prominent arrest in the G1 phase of the cell cycle as compared to cells exposed to parental HSV-1. The results of this study reveal the potential for re-modeling the host-herpes interaction to specifically interfere with the life of cancer cells with increased Ras signaling. SS1 also serves as a "prototype" for development of a family of signal-smart viruses which can target cancer cells on the basis of their signaling portfolio.

  1. Improved Protein Arrays for Quantitative Systems Analysis of the Dynamics of Signaling Pathway Interactions

    Energy Technology Data Exchange (ETDEWEB)

    YANG, CHIN-RANG [NHLBI, NIH

    2013-12-11

    Astronauts and workers in nuclear plants who repeatedly exposed to low doses of ionizing radiation (IR, <10 cGy) are likely to incur specific changes in signal transduction and gene expression in various tissues of their body. Remarkable advances in high throughput genomics and proteomics technologies enable researchers to broaden their focus from examining single gene/protein kinetics to better understanding global gene/protein expression profiling and biological pathway analyses, namely Systems Biology. An ultimate goal of systems biology is to develop dynamic mathematical models of interacting biological systems capable of simulating living systems in a computer. This Glue Grant is to complement Dr. Boothman’s existing DOE grant (No. DE-FG02-06ER64186) entitled “The IGF1/IGF-1R-MAPK-Secretory Clusterin (sCLU) Pathway: Mediator of a Low Dose IR-Inducible Bystander Effect” to develop sensitive and quantitative proteomic technology that suitable for low dose radiobiology researches. An improved version of quantitative protein array platform utilizing linear Quantum dot signaling for systematically measuring protein levels and phosphorylation states for systems biology modeling is presented. The signals are amplified by a confocal laser Quantum dot scanner resulting in ~1000-fold more sensitivity than traditional Western blots and show the good linearity that is impossible for the signals of HRP-amplification. Therefore this improved protein array technology is suitable to detect weak responses of low dose radiation. Software is developed to facilitate the quantitative readout of signaling network activities. Kinetics of EGFRvIII mutant signaling was analyzed to quantify cross-talks between EGFR and other signaling pathways.

  2. Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway.

    Science.gov (United States)

    Fu, Ying-Zi; Yan, Yuan-Yuan; He, Miao; Xiao, Qing-Huan; Yao, Wei-Fan; Zhao, Lin; Wu, Hui-Zhe; Yu, Zhao-Jin; Zhou, Ming-Yi; Lv, Mu-Tian; Zhang, Shan-Shan; Chen, Jian-Jun; Wei, Min-Jie

    2016-02-01

    Breast cancer stem cells (BCSCs) are believed to be responsible for tumor chemoresistance, recurrence, and metastasis formation. Salinomycin (SAL), a carboxylic polyether ionophore, has been reported to act as a selective breast CSC inhibitor. However, the molecular mechanisms underlying SAL-induced cytotoxicity on BCSCs remain unclear. The Hedgehog (Hh) signaling pathway plays an important role in CSC maintenance and carcinogenesis. Here, we investigated whether SAL induces cytotoxicity on BCSCs through targeting Hh pathway. In the present study, we cultured breast cancer MCF-7 cells in suspension in serum-free medium to obtain breast CSC-enriched MCF-7 mammospheres (MCF-7 MS). MCF-7 MS cells possessed typical BCSC properties, such as CD44+CD24-/low phenotype, high expression of OCT4 (a stem cell marker), increased colony-forming ability, strong migration and invasion capabilities, differentiation potential, and strong tumorigenicity in xenografted mice. SAL exhibited selective cytotoxicity to MCF-7 MS cells relative to MCF-7 cells. The Hh pathway was highly activated in BCSC-enriched MCF-7 MS cells and SAL inhibited Hh signaling activation by downregulating the expression of critical components of the Hh pathway such as PTCH, SMO, Gli1, and Gli2, and subsequently repressing the expression of their essential downstream targets including C-myc, Bcl-2, and Snail (but not cyclin D1). Conversely, Shh-induced Hh signaling activation could largely reverse SAL-mediated inhibitory effects. These findings suggest that SAL-induced selective cytotoxicity against MCF-7 MS cells is associated with the inhibition of Hh signaling activation and the expression of downstream targets and the Hh pathway is an important player and a possible drug target in the pathogenesis of BCSCs. PMID:26718029

  3. TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling

    OpenAIRE

    Zhong, Jun; Sharma, Jyoti; Raju, Rajesh; Palapetta, Shyam Mohan; Prasad, T. S. Keshava; Huang, Tai-Chung; Yoda, Akinori; Tyner, Jeffrey W; van Bodegom, Diederik; Weinstock, David M.; Ziegler, Steven F.; Pandey, Akhilesh

    2014-01-01

    Thymic stromal lymphopoietin (TSLP) is a four-helix bundle cytokine that plays a critical role in the regulation of immune responses and in the differentiation of hematopoietic cells. TSLP signals through a heterodimeric receptor complex consisting of an interleukin-7 receptor α chain and a unique TSLP receptor (TSLPR) [also known as cytokine receptor-like factor 2 (CRLF2)]. Cellular targets of TSLP include dendritic cells, B cells, mast cells, regulatory T (Treg) cells and CD4+ and CD8+ T ce...

  4. Semantic Mining based on graph theory and ontologies. Case Study: Cell Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Carlos R. Rangel

    2016-08-01

    Full Text Available In this paper we use concepts from graph theory and cellular biology represented as ontologies, to carry out semantic mining tasks on signaling pathway networks. Specifically, the paper describes the semantic enrichment of signaling pathway networks. A cell signaling network describes the basic cellular activities and their interactions. The main contribution of this paper is in the signaling pathway research area, it proposes a new technique to analyze and understand how changes in these networks may affect the transmission and flow of information, which produce diseases such as cancer and diabetes. Our approach is based on three concepts from graph theory (modularity, clustering and centrality frequently used on social networks analysis. Our approach consists into two phases: the first uses the graph theory concepts to determine the cellular groups in the network, which we will call them communities; the second uses ontologies for the semantic enrichment of the cellular communities. The measures used from the graph theory allow us to determine the set of cells that are close (for example, in a disease, and the main cells in each community. We analyze our approach in two cases: TGF-ß and the Alzheimer Disease.

  5. The Role of CXCL12-CXCR4 Signaling Pathway in Pancreatic Development

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    Keiichi Katsumoto, Shoen Kume

    2013-01-01

    Full Text Available Chemokine (C-X-C motif receptor 4 (CXCR4 is the receptor for chemokine (C-X-C motif ligand 12 (CXCL12, also known as stromal derived factor-1, Sdf1. CXCR4, a protein consisting 352 amino acids, is known to transduce various signals such as cell differentiation, cell survival, cell proliferation, cell chemotaxis and apoptosis [1, 2]. The expression of CXCR4 is observed in embryonic stem cells, blood cells, haematopoietic stem cells, endothelial cells, angioblasts and smooth muscle cells [3-9]. The CXCL12-CXCR4 signaling pathway has very important roles in the embryonic development. Mutant mice for CXCL12 or CXCR4 genes showed lethality due to defects in neurogenesis, angiogenesis, cardiogenesis, myelopoiesis, lymphopoiesis and germ cell development [10-13]. Recently, we reported that CXCL12-CXCR4 signaling pathway has a crucial role in regional specification of the gut endoderm during early development [14]. Here, we would like to focus on the role of CXCL12-CXCR4 signaling pathway in pancreatic development and summarize recent findings of its role in the induction of the pancreatic progenitor cells.

  6. Signaling cross-talk between TGF-β/BMP and other path-ways

    Institute of Scientific and Technical Information of China (English)

    Xing Guo; Xiao-Fan Wang

    2009-01-01

    Transforming growth factor-beta(TGF-β)/bone morphogenic protein(BMP)signaling is involved in the vast majority of cellular processes and is fundamentally important during the entire life of alI metazoans.Deregulation of TGF-β/BMP activity almost invariably leads to developmental defects and/or diseases.including cancer.The proper functioning of the TGF-β/BMP pathway depends on its constitutive and extensive communication with other signaling pathways,leading to synergistic or antagonistic effects and eventually desirable biological outcomes.The nature of such signaling cross-talk iS overwhelmingly complex and highly context-dependent.Here we review the difierent modes of cross-talk between TGF-β/BMP and the signaling pathways of Mitogen-activated protein kinase,phosphatidyIinositoI-3 kinase/Akt,Wnt,Hedgehog,Notch,and the interleukin/interferon-gamma/tumor necrosis factor-alpha cytokines,with an emphasis on the underlying molecular mechanisms.

  7. Necroptotic Cell Death Signaling and Execution Pathway: Lessons from Knockout Mice

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    José Belizário

    2015-01-01

    Full Text Available Under stress conditions, cells in living tissue die by apoptosis or necrosis depending on the activation of the key molecules within a dying cell that either transduce cell survival or death signals that actively destroy the sentenced cell. Multiple extracellular (pH, heat, oxidants, and detergents or intracellular (DNA damage and Ca2+ overload stress conditions trigger various types of the nuclear, endoplasmic reticulum (ER, cytoplasmatic, and mitochondrion-centered signaling events that allow cells to preserve the DNA integrity, protein folding, energetic, ionic and redox homeostasis, thus escaping from injury. Along the transition from reversible to irreversible injury, death signaling is highly heterogeneous and damaged cells may engage autophagy, apoptotic, or necrotic cell death programs. Studies on multiple double- and triple- knockout mice identified caspase-8, flip, and fadd genes as key regulators of embryonic lethality and inflammation. Caspase-8 has a critical role in pro- and antinecrotic signaling pathways leading to the activation of receptor interacting protein kinase 1 (RIPK1, RIPK3, and the mixed kinase domain-like (MLKL for a convergent execution pathway of necroptosis or regulated necrosis. Here we outline the recent discoveries into how the necrotic cell death execution pathway is engaged in many physiological and pathological outcome based on genetic analysis of knockout mice.

  8. Deoxynivalenol: signaling pathways and human exposure risk assessment--an update.

    Science.gov (United States)

    Wang, Zhonghong; Wu, Qinghua; Kuča, Kamil; Dohnal, Vlastimil; Tian, Zhihong

    2014-11-01

    Deoxynivalenol (DON) is a group B trichothecene and a common contaminant of crops worldwide. This toxin is known to cause a spectrum of diseases in animals and humans such as vomiting and gastroenteritis. Importantly, DON could inhibit the synthesis of protein and nucleonic acid and induce cell apoptosis in eukaryote cells. The transduction of signaling pathways is involved in the underlying mechanism of the cytotoxicity of DON. Mitogen-activated protein kinase and Janus kinase/signal transducer and activator of transcription seem to be two important signaling pathways and induce the inflammatory response by modulating the binding activates of specific transcription factors. This review mainly discussed the toxic mechanism of DON from the vantage point of signaling pathways and also assessed the profiles of DON and its metabolites in humans. Importantly, we conducted a human exposure risk assessment of DON from cereals, cereal-based foods, vegetables, water, and animal-derived foods in different countries. Some regular patterns of DON occurrence in these countries are suggested based on an analysis of global contamination with DON. This review should provide further insight for the toxic mechanism study of DON and human exposure risk assessment, thereby facilitating mycotoxin control strategies. PMID:25199684

  9. Human cytomegalovirus infection dysregulates the canonical Wnt/β-catenin signaling pathway.

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    Magdalena Angelova

    Full Text Available Human Cytomegalovirus (HCMV is a ubiquitous herpesvirus that currently infects a large percentage of the world population. Although usually asymptomatic in healthy individuals, HCMV infection during pregnancy may cause spontaneous abortions, premature delivery, or permanent neurological disabilities in infants infected in utero. During infection, the virus exerts control over a multitude of host signaling pathways. Wnt/β-catenin signaling, an essential pathway involved in cell cycle control, differentiation, embryonic development, placentation and metastasis, is frequently dysregulated by viruses. How HCMV infection affects this critical pathway is not currently known. In this study, we demonstrate that HCMV dysregulates Wnt/β-catenin signaling in dermal fibroblasts and human placental extravillous trophoblasts. Infection inhibits Wnt-induced transcriptional activity of β-catenin and expression of β-catenin target genes in these cells. HCMV infection leads to β-catenin protein accumulation in a discrete juxtanuclear region. Levels of β-catenin in membrane-associated and cytosolic pools, as well as nuclear β-catenin, are reduced after infection; while transcription of the β-catenin gene is unchanged, suggesting enhanced degradation. Given the critical role of Wnt/β-catenin signaling in cellular processes, these findings represent a novel and important mechanism whereby HCMV disrupts normal cellular function.

  10. SPIKE – a database, visualization and analysis tool of cellular signaling pathways

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    Blekhman Ran

    2008-02-01

    Full Text Available Abstract Background Biological signaling pathways that govern cellular physiology form an intricate web of tightly regulated interlocking processes. Data on these regulatory networks are accumulating at an unprecedented pace. The assimilation, visualization and interpretation of these data have become a major challenge in biological research, and once met, will greatly boost our ability to understand cell functioning on a systems level. Results To cope with this challenge, we are developing the SPIKE knowledge-base of signaling pathways. SPIKE contains three main software components: 1 A database (DB of biological signaling pathways. Carefully curated information from the literature and data from large public sources constitute distinct tiers of the DB. 2 A visualization package that allows interactive graphic representations of regulatory interactions stored in the DB and superposition of functional genomic and proteomic data on the maps. 3 An algorithmic inference engine that analyzes the networks for novel functional interplays between network components. SPIKE is designed and implemented as a community tool and therefore provides a user-friendly interface that allows registered users to upload data to SPIKE DB. Our vision is that the DB will be populated by a distributed and highly collaborative effort undertaken by multiple groups in the research community, where each group contributes data in its field of expertise. Conclusion The integrated capabilities of SPIKE make it a powerful platform for the analysis of signaling networks and the integration of knowledge on such networks with omics data.

  11. Activation of Sonic Hedgehog Signaling Pathway in S-type Neuroblastoma Cell Lines

    Institute of Scientific and Technical Information of China (English)

    周昱男; 戴若连; 毛玲; 夏远鹏; 姚玉芳; 杨雪; 胡波

    2010-01-01

    The effects of Sonic hedgehog(Shh) signaling pathway activation on S-type neuroblastoma(NB) cell lines and its role in NB tumorigenesis were investigated.Immunohistochemistry was used to detect the expression of Shh pathway components- Patched1(PTCH1) and Gli1 in 40 human primary NB samples.Western blotting and RT-PCR were used to examine the protein expression and mRNA levels of PTCH1 and Gli1 in three kinds of S-type NB cell lines(SK-N-AS,SK-N-SH and SHEP1),respectively.Exogenous Shh was administrated to ...

  12. Synthesis and evaluation of novel benzylphthalazine derivatives as hedgehog signaling pathway inhibitors.

    Science.gov (United States)

    Bao, Xiaolong; Peng, Yuanqiu; Lu, Xiuhong; Yang, Jun; Zhao, Weili; Tan, Wenfu; Dong, Xiaochun

    2016-07-01

    We report herein the design and synthesis of a series of novel benzylphthalazine derivatives as hedgehog signaling pathway inhibitors. Gli-luciferase assay demonstrated that changing piperazine ring of Anta XV to different four, five or six-membered heterocyclic building blocks afforded significant influences on Hh pathway inhibition. In particular, compound 10e with piperidin-4-amine moiety was found to possess 12-fold higher Hh inhibitory activities comparing to the lead compound in vitro. In vivo efficacy of 10e in a ptch(+/-)p53(-/-) mouse medulloblastoma allograft model also indicated encouraging results. PMID:27180012

  13. Signal transduction pathways in the pentameric ligand-gated ion channels.

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    David Mowrey

    Full Text Available The mechanisms of allosteric action within pentameric ligand-gated ion channels (pLGICs remain to be determined. Using crystallography, site-directed mutagenesis, and two-electrode voltage clamp measurements, we identified two functionally relevant sites in the extracellular (EC domain of the bacterial pLGIC from Gloeobacter violaceus (GLIC. One site is at the C-loop region, where the NQN mutation (D91N, E177Q, and D178N eliminated inter-subunit salt bridges in the open-channel GLIC structure and thereby shifted the channel activation to a higher agonist concentration. The other site is below the C-loop, where binding of the anesthetic ketamine inhibited GLIC currents in a concentration dependent manner. To understand how a perturbation signal in the EC domain, either resulting from the NQN mutation or ketamine binding, is transduced to the channel gate, we have used the Perturbation-based Markovian Transmission (PMT model to determine dynamic responses of the GLIC channel and signaling pathways upon initial perturbations in the EC domain of GLIC. Despite the existence of many possible routes for the initial perturbation signal to reach the channel gate, the PMT model in combination with Yen's algorithm revealed that perturbation signals with the highest probability flow travel either via the β1-β2 loop or through pre-TM1. The β1-β2 loop occurs in either intra- or inter-subunit pathways, while pre-TM1 occurs exclusively in inter-subunit pathways. Residues involved in both types of pathways are well supported by previous experimental data on nAChR. The direct coupling between pre-TM1 and TM2 of the adjacent subunit adds new insight into the allosteric signaling mechanism in pLGICs.

  14. Mutational analysis of hedgehog signaling pathway genes in human malignant mesothelioma.

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    Chuan Bian Lim

    Full Text Available BACKGROUND: The Hedgehog (HH signaling pathway is critical for embryonic development and adult homeostasis. Recent studies have identified regulatory roles for this pathway in certain cancers with mutations in the HH pathway genes. The extent to which mutations of the HH pathway genes are involved in the pathogenesis of malignant mesothelioma (MMe is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Real-time PCR analysis of HH pathway genes PTCH1, GLI1 and GLI2 were performed on 7 human MMe cell lines. Exon sequencing of 13 HH pathway genes was also performed in cell lines and human MMe tumors. In silico programs were used to predict the likelihood that an amino-acid substitution would have a functional effect. GLI1, GLI2 and PTCH1 were highly expressed in MMe cells, indicative of active HH signaling. PTCH1, SMO and SUFU mutations were found in 2 of 11 MMe cell lines examined. A non-synonymous missense SUFU mutation (p.T411M was identified in LO68 cells. In silico characterization of the SUFU mutant suggested that the p.T411M mutation might alter protein function. However, we were unable to demonstrate any functional effect of this mutation on Gli activity. Deletion of exons of the PTCH1 gene was found in JU77 cells, resulting in loss of one of two extracellular loops implicated in HH ligand binding and the intracellular C-terminal domain. A 3-bp insertion (69_70insCTG in SMO, predicting an additional leucine residue in the signal peptide segment of SMO protein was also identified in LO68 cells and a MMe tumour. CONCLUSIONS/SIGNIFICANCE: We identified the first novel mutations in PTCH1, SUFU and SMO associated with MMe. Although HH pathway mutations are relatively rare in MMe, these data suggest a possible role for dysfunctional HH pathway in the pathogenesis of a subgroup of MMe and help rationalize the exploration of HH pathway inhibitors for MMe therapy.

  15. Activation of ERK and JNK signaling pathways by mycotoxin citrinin in human cells

    International Nuclear Information System (INIS)

    Mycotoxin citrinin (CTN) is commonly found in foods and feeds that are contaminated/inoculated with Penicillium, Aspergillus and Monascus species. The exposure of human embryonic kidney (HEK293) and HeLa cells to CTN resulted in a dose-dependent increase in the phosphorylation of two major mitogen-activated protein kinases (MAPKs), ERK1/2 and JNK. In HEK293 cultures, the administering of CTN increased both the mRNA and protein levels of egr-1, c-fos and c-jun genes; additionally, the ERK1/2 pathway contributed to the upregulation of Egr-1 and c-Fos protein expression. CTN treatment also induced the transcription activity of Egr-1 and AP-1 proteins, as evidenced by luciferase reporter assays. Bioinformatic analyses indicated two genes Gadd45β and MMP3 have Egr-1 and AP-1 response elements in their promoters, respectively. Furthermore, co-exposure of HEK293 cells to CTN and MAPK pathway inhibitors demonstrated that CTN increased the levels of Gadd45β mRNA through ERK1/2 signaling pathway and up-regulated the MMP3 transcripts majorly via JNK pathway. Finally, CTN-triggered caspase 3 activity was significantly reduced in the presence of MAPK inhibitors. Our results suggest that CTN positively regulates ERK1/2 and JNK pathways as well as their downstream effectors in human cells; activated MAPK pathways are also involved in CTN-induced apoptosis.

  16. Regulatory Cross-Talks and Cascades in Rice Hormone Biosynthesis Pathways Contribute to Stress Signaling.

    Science.gov (United States)

    Deb, Arindam; Grewal, Rumdeep K; Kundu, Sudip

    2016-01-01

    Crosstalk among different hormone signaling pathways play an important role in modulating plant response to both biotic and abiotic stress. Hormone activity is controlled by its bio-availability, which is again influenced by its biosynthesis. Thus, independent hormone biosynthesis pathways must be regulated and co-ordinated to mount an integrated response. One of the possibilities is to use cis-regulatory elements to orchestrate expression of hormone biosynthesis genes. Analysis of CREs, associated with differentially expressed hormone biosynthesis related genes in rice leaf under Magnaporthe oryzae attack and drought stress enabled us to obtain insights about cross-talk among hormone biosynthesis pathways at the transcriptional level. We identified some master transcription regulators that co-ordinate different hormone biosynthesis pathways under stress. We found that Abscisic acid and Brassinosteroid regulate Cytokinin conjugation; conversely Brassinosteroid biosynthesis is affected by both Abscisic acid and Cytokinin. Jasmonic acid and Ethylene biosynthesis may be modulated by Abscisic acid through DREB transcription factors. Jasmonic acid or Salicylic acid biosynthesis pathways are co-regulated but they are unlikely to influence each others production directly. Thus, multiple hormones may modulate hormone biosynthesis pathways through a complex regulatory network, where biosynthesis of one hormone is affected by several other contributing hormones. PMID:27617021

  17. Regulation of mRNA export by the PI3 kinase/AKT signal transduction pathway.

    Science.gov (United States)

    Quaresma, Alexandre Jose Christino; Sievert, Rachel; Nickerson, Jeffrey A

    2013-04-01

    UAP56, ALY/REF, and NXF1 are mRNA export factors that sequentially bind at the 5' end of a nuclear mRNA but are also reported to associate with the exon junction complex (EJC). To screen for signal transduction pathways regulating mRNA export complex assembly, we used fluorescence recovery after photobleaching to measure the binding of mRNA export and EJC core proteins in nuclear complexes. The fraction of UAP56, ALY/REF, and NXF1 tightly bound in complexes was reduced by drug inhibition of the phosphatidylinositide 3-kinase (PI3 kinase)/AKT pathway, as was the tightly bound fraction of the core EJC proteins eIF4A3, MAGOH, and Y14. Inhibition of the mTOR mTORC1 pathway decreased the tight binding of MAGOH. Inhibition of the PI3 kinase/AKT pathway increased the export of poly(A) RNA and of a subset of candidate mRNAs. A similar effect of PI3 kinase/AKT inhibition was observed for mRNAs from both intron-containing and intronless histone genes. However, the nuclear export of mRNAs coding for proteins targeted to the endoplasmic reticulum or to mitochondria was not affected by the PI3 kinase/AKT pathway. These results show that the active PI3 kinase/AKT pathway can regulate mRNA export and promote the nuclear retention of some mRNAs. PMID:23427269

  18. Comprehensive Expression of Wnt Signaling Pathway Genes during Development and Maturation of the Mouse Cochlea.

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    Ruishuang Geng

    Full Text Available In the inner ear Wnt signaling is necessary for proliferation, cell fate determination, growth of the cochlear duct, polarized orientation of stereociliary bundles, differentiation of the periotic mesenchyme, and homeostasis of the stria vascularis. In neonatal tissue Wnt signaling can drive proliferation of cells in the sensory region, suggesting that Wnt signaling could be used to regenerate the sensory epithelium in the damaged adult inner ear. Manipulation of Wnt signaling for regeneration will require an understanding of the dynamics of Wnt pathway gene expression in the ear. We present a comprehensive screen for 84 Wnt signaling related genes across four developmental and postnatal time points.We identified 72 Wnt related genes expressed in the inner ear on embryonic day (E 12.5, postnatal day (P 0, P6 and P30. These genes included secreted Wnts, Wnt antagonists, intracellular components of canonical signaling and components of non-canonical signaling/planar cell polarity.A large number of Wnt signaling molecules were dynamically expressed during cochlear development and in the early postnatal period, suggesting complex regulation of Wnt transduction. The data revealed several potential key regulators for further study.

  19. Gene-Environment Interactions Target Mitogen-activated Protein 3 Kinase 1 (MAP3K1) Signaling in Eyelid Morphogenesis.

    Science.gov (United States)

    Mongan, Maureen; Meng, Qinghang; Wang, Jingjing; Kao, Winston W-Y; Puga, Alvaro; Xia, Ying

    2015-08-01

    Gene-environment interactions determine the biological outcomes through mechanisms that are poorly understood. Mouse embryonic eyelid closure is a well defined model to study the genetic control of developmental programs. Using this model, we investigated how exposure to dioxin-like environmental pollutants modifies the genetic risk of developmental abnormalities. Our studies reveal that mitogen-activated protein 3 kinase 1 (MAP3K1) signaling is a focal point of gene-environment cross-talk. Dioxin exposure, acting through the aryl hydrocarbon receptor (AHR), blocked eyelid closure in genetic mutants in which MAP3K1 signaling was attenuated but did not disturb this developmental program in either wild type or mutant mice with attenuated epidermal growth factor receptor or WNT signaling. Exposure also markedly inhibited c-Jun phosphorylation in Map3k1(+/-) embryonic eyelid epithelium, suggesting that dioxin-induced AHR pathways can synergize with gene mutations to inhibit MAP3K1 signaling. Our studies uncover a novel mechanism through which the dioxin-AHR axis interacts with the MAP3K1 signaling pathways during fetal development and provide strong empirical evidence that specific gene alterations can increase the risk of developmental abnormalities driven by environmental pollutant exposure. PMID:26109068

  20. CXCL12/CXCR4 signaling pathway regulates cochlear development in neonatal mice.

    Science.gov (United States)

    Zhang, Wen; Sun, Ji-Zhou; Han, Yu; Chen, Jun; Liu, Hui; Wang, Ye; Yue, Bo; Chen, Yang

    2016-05-01

    Chemotactic cytokines (chemokines) are a highly conserved class of secreted signaling molecules that are important in various cellular processes. CXC chemokine ligand 12 (CXCL12) and its receptor, CXC chemokine receptor 4 (CXCR4) have been previously reported to be crucial for the establishment of neural networks in different neuronal systems. However, it is unclear whether the CXCL12/CXCR4 signaling pathway regulates the development of the cochlea. The current study investigated the effects of the CXCL12/CXCR4 signaling pathway on cochlear development in neonatal mice. The expression levels of CXCL12 and CXCR4 were detected using immunofluorescence, reverse transcription‑quantitative polymerase chain reaction and western blot analysis demonstrating that CXCL12 and CXCR4 expression were significantly increased during cochlear development in neonatal mice. Treatment of spiral ganglion neurons with CXCL12 significantly decreased the protein expression levels of caspase‑3 and cleaved caspase‑3, indicating that CXCL12/CXCR4 signaling increased cell survival of spiral ganglion neurons. Furthermore, CXCL12 treatment significantly increased the number and length of neurites extending from spiral ganglion neurons. By contrast, the in vitro effects of CXCL12 were significantly abrogated by AMD100, a CXCR4 antagonist. Additionally, inhibiting CXCL12/CXCR4 signaling in neonatal mice significantly reduced the cell number and altered the morphology of spiral ganglion neurons in vivo. Thus, the present study indicates that the CXCL12/CXCR4 signaling pathway is important during the development of cochleae in neonatal mice. PMID:27052602

  1. Crosstalk among Jasmonate, Salicylate and Ethylene Signaling Pathways in Plant Disease and Immune Responses.

    Science.gov (United States)

    Yang, You-Xin; Ahammed, Golam J; Wu, Caijun; Fan, Shu-ying; Zhou, Yan-Hong

    2015-01-01

    Phytohormone crosstalk is crucial for plant defenses against pathogens and insects in which salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) play key roles. These low molecular mass signals critically trigger and modulate plant resistance against biotrophic as well as necrotrophic pathogens through a complex signaling network that even involves participation of other hormones. Crosstalk among SA, JA and ET is mediated by different molecular players, considered as integral part of these crosscommunicating signal transduction pathways. Recent progress has revealed that the positive versus negative interactions among those pathways ultimately enable a plant to fine-tune its defense against specific aggressors. On the other hand, pathogens have evolved strategies to manipulate the signaling network to their favour in order to intensify virulence on host plant. Here we review recent advances and current knowledge on the role of classical primary defense hormones SA, JA and ET as well as their synergistic and antagonistic interaction in plant disease and immune responses. Crosstalk with other hormones such as abscisic acid, auxin, brassinosteroids, cytokinins and melatonin is also discussed mainly in plant disease resistance. In addition to our keen focus on hormonal crosstalk, this review also highlights potential implication of positive and negative regulatory interactions for developing an efficient disease management strategy through manipulation of hormone signaling in plant. PMID:25824390

  2. Neuroendocrine Control of the Gut During Stress: Corticotropin-Releasing Factor Signaling Pathways in the Spotlight

    Science.gov (United States)

    Stengel, Andreas; Taché, Yvette

    2009-01-01

    Stress affects the gastrointestinal tract as part of the visceral response. Various stressors induce similar profiles of gut motor function alterations, including inhibition of gastric emptying, stimulation of colonic propulsive motility, and hypersensitivity to colorectal distension. In recent years, substantial progress has been made in our understanding of the underlying mechanisms of stress’s impact on gut function. Activation of corticotropin-releasing factor (CRF) signaling pathways mediates both the inhibition of upper gastrointestinal (GI) and the stimulation of lower GI motor function through interaction with different CRF receptor subtypes. Here, we review how various stressors affect the gut, with special emphasis on the central and peripheral CRF signaling systems. PMID:18928406

  3. Non-monotonic dynamics and crosstalk in signaling pathways and their implications for pharmacology

    Science.gov (United States)

    van Wijk, Roeland; Tans, Sander J.; Wolde, Pieter Rein Ten; Mashaghi, Alireza

    2015-06-01

    Currently, drug discovery approaches commonly assume a monotonic dose-response relationship. However, the assumption of monotonicity is increasingly being challenged. Here we show that for two simple interacting linear signaling pathways that carry two different signals with different physiological responses, a non-monotonic input-output relation can arise with simple network topologies including coherent and incoherent feed-forward loops. We show that non-monotonicity of the response functions has severe implications for pharmacological treatment. Fundamental constraints are imposed on the effectiveness and toxicity of any drug independent of its chemical nature and selectivity due to the specific network structure.

  4. Neuroendocrine control of the gut during stress: corticotropin-releasing factor signaling pathways in the spotlight.

    Science.gov (United States)

    Stengel, Andreas; Taché, Yvette

    2009-01-01

    Stress affects the gastrointestinal tract as part of the visceral response. Various stressors induce similar profiles of gut motor function alterations, including inhibition of gastric emptying, stimulation of colonic propulsive motility, and hypersensitivity to colorectal distension. In recent years, substantial progress has been made in our understanding of the underlying mechanisms of stress's impact on gut function. Activation of corticotropin-releasing factor (CRF) signaling pathways mediates both the inhibition of upper gastrointestinal (GI) and the stimulation of lower GI motor function through interaction with different CRF receptor subtypes. Here, we review how various stressors affect the gut, with special emphasis on the central and peripheral CRF signaling systems. PMID:18928406

  5. Partial Decay of Thiamine Signal Transduction Pathway Alters Growth Properties of Candida glabrata.

    Science.gov (United States)

    Iosue, Christine L; Attanasio, Nicholas; Shaik, Noor F; Neal, Erin M; Leone, Sarah G; Cali, Brian J; Peel, Michael T; Grannas, Amanda M; Wykoff, Dennis D

    2016-01-01

    The phosphorylated form of thiamine (Vitamin B1), thiamine pyrophosphate (TPP) is essential for the metabolism of amino acids and carbohydrates in all organisms. Plants and microorganisms, such as yeast, synthesize thiamine de novo whereas animals do not. The thiamine signal transduction (THI) pathway in Saccharomyces cerevisiae is well characterized. The ~10 genes required for thiamine biosynthesis and uptake are transcriptionally upregulated during thiamine starvation by THI2, THI3, and PDC2. Candida glabrata, a human commensal and opportunistic pathogen, is closely related to S. cerevisiae but is missing half of the biosynthetic pathway, which limits its ability to make thiamine. We investigated the changes to the THI pathway in C. glabrata, confirming orthologous functions. We found that C. glabrata is unable to synthesize the pyrimidine subunit of thiamine as well as the thiamine precursor vitamin B6. In addition, THI2 (the gene encoding a transcription factor) is not present in C. glabrata, indicating a difference in the transcriptional regulation of the pathway. Although the pathway is upregulated by thiamine starvation in both species, C. glabrata appears to upregulate genes involved in thiamine uptake to a greater extent than S. cerevisiae. However, the altered regulation of the THI pathway does not alter the concentration of thiamine and its vitamers in the two species as measured by HPLC. Finally, we demonstrate potential consequences to having a partial decay of the THI biosynthetic and regulatory pathway. When the two species are co-cultured, the presence of thiamine allows C. glabrata to rapidly outcompete S. cerevisiae, while absence of thiamine allows S. cerevisiae to outcompete C. glabrata. This simplification of the THI pathway in C. glabrata suggests its environment provides thiamine and/or its precursors to cells, whereas S. cerevisiae is not as reliant on environmental sources of thiamine. PMID:27015653

  6. Partial Decay of Thiamine Signal Transduction Pathway Alters Growth Properties of Candida glabrata

    Science.gov (United States)

    Shaik, Noor F.; Neal, Erin M.; Leone, Sarah G.; Cali, Brian J.; Peel, Michael T.; Grannas, Amanda M.; Wykoff, Dennis D.

    2016-01-01

    The phosphorylated form of thiamine (Vitamin B1), thiamine pyrophosphate (TPP) is essential for the metabolism of amino acids and carbohydrates in all organisms. Plants and microorganisms, such as yeast, synthesize thiamine de novo whereas animals do not. The thiamine signal transduction (THI) pathway in Saccharomyces cerevisiae is well characterized. The ~10 genes required for thiamine biosynthesis and uptake are transcriptionally upregulated during thiamine starvation by THI2, THI3, and PDC2. Candida glabrata, a human commensal and opportunistic pathogen, is closely related to S. cerevisiae but is missing half of the biosynthetic pathway, which limits its ability to make thiamine. We investigated the changes to the THI pathway in C. glabrata, confirming orthologous functions. We found that C. glabrata is unable to synthesize the pyrimidine subunit of thiamine as well as the thiamine precursor vitamin B6. In addition, THI2 (the gene encoding a transcription factor) is not present in C. glabrata, indicating a difference in the transcriptional regulation of the pathway. Although the pathway is upregulated by thiamine starvation in both species, C. glabrata appears to upregulate genes involved in thiamine uptake to a greater extent than S. cerevisiae. However, the altered regulation of the THI pathway does not alter the concentration of thiamine and its vitamers in the two species as measured by HPLC. Finally, we demonstrate potential consequences to having a partial decay of the THI biosynthetic and regulatory pathway. When the two species are co-cultured, the presence of thiamine allows C. glabrata to rapidly outcompete S. cerevisiae, while absence of thiamine allows S. cerevisiae to outcompete C. glabrata. This simplification of the THI pathway in C. glabrata suggests its environment provides thiamine and/or its precursors to cells, whereas S. cerevisiae is not as reliant on environmental sources of thiamine. PMID:27015653

  7. Partial Decay of Thiamine Signal Transduction Pathway Alters Growth Properties of Candida glabrata.

    Directory of Open Access Journals (Sweden)

    Christine L Iosue

    Full Text Available The phosphorylated form of thiamine (Vitamin B1, thiamine pyrophosphate (TPP is essential for the metabolism of amino acids and carbohydrates in all organisms. Plants and microorganisms, such as yeast, synthesize thiamine de novo whereas animals do not. The thiamine signal transduction (THI pathway in Saccharomyces cerevisiae is well characterized. The ~10 genes required for thiamine biosynthesis and uptake are transcriptionally upregulated during thiamine starvation by THI2, THI3, and PDC2. Candida glabrata, a human commensal and opportunistic pathogen, is closely related to S. cerevisiae but is missing half of the biosynthetic pathway, which limits its ability to make thiamine. We investigated the changes to the THI pathway in C. glabrata, confirming orthologous functions. We found that C. glabrata is unable to synthesize the pyrimidine subunit of thiamine as well as the thiamine precursor vitamin B6. In addition, THI2 (the gene encoding a transcription factor is not present in C. glabrata, indicating a difference in the transcriptional regulation of the pathway. Although the pathway is upregulated by thiamine starvation in both species, C. glabrata appears to upregulate genes involved in thiamine uptake to a greater extent than S. cerevisiae. However, the altered regulation of the THI pathway does not alter the concentration of thiamine and its vitamers in the two species as measured by HPLC. Finally, we demonstrate potential consequences to having a partial decay of the THI biosynthetic and regulatory pathway. When the two species are co-cultured, the presence of thiamine allows C. glabrata to rapidly outcompete S. cerevisiae, while absence of thiamine allows S. cerevisiae to outcompete C. glabrata. This simplification of the THI pathway in C. glabrata suggests its environment provides thiamine and/or its precursors to cells, whereas S. cerevisiae is not as reliant on environmental sources of thiamine.

  8. Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease

    Directory of Open Access Journals (Sweden)

    João Antonio Chaves de Souza

    2012-04-01

    Full Text Available Recently, new treatment approaches have been developed to target the host component of periodontal disease. This review aims at providing updated information on host-modulating therapies, focusing on treatment strategies for inhibiting signal transduction pathways involved in inflammation. Pharmacological inhibitors of MAPK, NFκB and JAK/STAT pathways are being developed to manage rheumatoid arthritis, periodontal disease and other inflammatory diseases. Through these agents, inflammatory mediators can be inhibited at cell signaling level, interfering on transcription factors activation and inflammatory gene expression. Although these drugs offer great potential to modulate host response, their main limitations are lack of specificity and developments of side effects. After overcoming these limitations, adjunctive host modulating drugs will provide new therapeutic strategies for periodontal treatment.

  9. Role of chemokine signaling pathways in pancreatic islet rejection during allo- and xenotransplantation.

    Science.gov (United States)

    Sigrist, S; Ebel, N; Langlois, A; Bosco, D; Toso, C; Kleiss, C; Mandes, K; Berney, T; Pinget, M; Belcourt, A; Kessler, L

    2005-10-01

    During transplantation, pancreatic islets release chemokines promoting macrophage attraction, hampering engraftment of islets. The aim of this work was to examine the mechanism of macrophage-pancreatic islets interaction that mediates islet rejection during transplantation. Human macrophages exposed to supernates of human and porcine pancreatic islets for the allogeneic and xenogeneic models, respectively, were evaluated for chemotaxis and expression of chemokine receptors (CCR-5). To modulate migration and identify the signaling pathway of macrophages, we tested pertussis toxin (PTX) to block Gi protein, and staurosporin and wortmannin to inhibit the protein kinase, and phosphoinositol-3 kinase, respectively. The addition of these agents significantly reduced macrophage migration induced by human islet supernates from 3.2 +/- 0.5 to 1.5 +/- 0.2, 0.9 +/- 0.1, and 1 +/- 0.1, respectively (P rejection even though the chemokine signaling pathways differ between allo- and xenotransplantation. Understanding the molecular mechanisms of islet rejection may improve graft survival. PMID:16298647

  10. Circadian period integrates network information through activation of the BMP signaling pathway.

    Directory of Open Access Journals (Sweden)

    Esteban J Beckwith

    2013-12-01

    Full Text Available Living organisms use biological clocks to maintain their internal temporal order and anticipate daily environmental changes. In Drosophila, circadian regulation of locomotor behavior is controlled by ∼150 neurons; among them, neurons expressing the PIGMENT DISPERSING FACTOR (PDF set the period of locomotor behavior under free-running conditions. To date, it remains unclear how individual circadian clusters integrate their activity to assemble a distinctive behavioral output. Here we show that the BONE MORPHOGENETIC PROTEIN (BMP signaling pathway plays a crucial role in setting the circadian period in PDF neurons in the adult brain. Acute deregulation of BMP signaling causes period lengthening through regulation of dClock transcription, providing evidence for a novel function of this pathway in the adult brain. We propose that coherence in the circadian network arises from integration in PDF neurons of both the pace of the cell-autonomous molecular clock and information derived from circadian-relevant neurons through release of BMP ligands.

  11. Circadian Period Integrates Network Information Through Activation of the BMP Signaling Pathway

    Science.gov (United States)

    Beckwith, Esteban J.; Gorostiza, E. Axel; Berni, Jimena; Rezával, Carolina; Pérez-Santángelo, Agustín; Nadra, Alejandro D.; Ceriani, María Fernanda

    2013-01-01

    Living organisms use biological clocks to maintain their internal temporal order and anticipate daily environmental changes. In Drosophila, circadian regulation of locomotor behavior is controlled by ∼150 neurons; among them, neurons expressing the PIGMENT DISPERSING FACTOR (PDF) set the period of locomotor behavior under free-running conditions. To date, it remains unclear how individual circadian clusters integrate their activity to assemble a distinctive behavioral output. Here we show that the BONE MORPHOGENETIC PROTEIN (BMP) signaling pathway plays a crucial role in setting the circadian period in PDF neurons in the adult brain. Acute deregulation of BMP signaling causes period lengthening through regulation of dClock transcription, providing evidence for a novel function of this pathway in the adult brain. We propose that coherence in the circadian network arises from integration in PDF neurons of both the pace of the cell-autonomous molecular clock and information derived from circadian-relevant neurons through release of BMP ligands. PMID:24339749

  12. Primary cilia and coordination of signaling pathways in heart development and tissue Homeostasis

    DEFF Research Database (Denmark)

    Clement, Christian Alexandro

    This thesis focuses on cilia and their sensory function in the mammalian organism. In particular, the Hedgehog (Hh) signaling pathway functions via the primary cilium and plays a unique role in development, differentiation, cancer and possibly in stem cell fate. Defects in primary cilia assembly or...... function are tightly coupled to developmental disorders and diseases in mammals termed "ciliopathies". The primary objective of this thesis was to investigate the role the primary cilium in coordinating Hh signaling in stem cell differentiation and heart development in the mouse. We show that human...... embryonic stem cells (hESC) and mouse embryonal carcinoma stem cells (P19.CL6 EC cells) have primary cilia that display ciliary localization of the essential Hh proteins; Gli2, Ptc1 and Smo. Inhibition of the Hh pathway by KAAD-cyclopamine in P19.CL6 cells hinder formation of synchronously beating clusters...

  13. Helicobacter pylori-Induced Signaling Pathways Contribute to Intestinal Metaplasia and Gastric Carcinogenesis

    OpenAIRE

    Soichiro Sue; Wataru Shibata; Shin Maeda

    2015-01-01

    Helicobacter pylori (H. pylori) induces chronic gastric inflammation, atrophic gastritis, intestinal metaplasia, and cancer. Although the risk of gastric cancer increases exponentially with the extent of atrophic gastritis, the precise mechanisms of gastric carcinogenesis have not been fully elucidated. H. pylori induces genetic and epigenetic changes in gastric epithelial cells through activating intracellular signaling pathways in a cagPAI-dependent manner. H. pylori eventually induces gast...

  14. WIF-1 might play additional role in carcinogenesis and cancer growth via EGFR signaling pathway

    OpenAIRE

    Tan Wei Chow; Ming Thong Ong; Shaharum Shamsuddin

    2013-01-01

    All Protein-protein interaction is a well-known phenomenon in cancer cell signaling pathway. To study the potential docking between WIF-1 and EGFR molecules, initial protein-protein docking was performed using CAPRI-listed online servers, namely ZDOCK, GRAMM-X, HEX and PatchDock. The predicted docking conformation issued from various servers suggested the similar potential protein-protein conformational interaction. The lowest docking energy of WIF-1/EGFR binding calculated using HEX server w...

  15. A structured approach for the engineering of biochemical network models, illustrated for signalling pathways

    OpenAIRE

    Breitling, Rainer; Gilbert, David; Heiner, Monika; Orton, Richard

    2008-01-01

    Quantitative models of biochemical networks (signal transduction cascades, metabolic pathways, gene regulatory circuits) are a central component of modern systems biology. Building and managing these complex models is a major challenge that can benefit from the application of formal methods adopted from theoretical computing science. Here we provide a general introduction to the field of formal modelling, which emphasizes the intuitive biochemical basis of the modelling process, but is also a...

  16. Global microRNA profiles and signaling pathways in the development of cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, H.J.; Ouyang, W.; Liu, J.H.; Sun, Y.G.; Hu, R.; Huang, L.H.; Xian, J.L. [Southern Medical University, Department of Nuclear Medicine, Zhujiang Hospital, Guangzhou, China, Department of Nuclear Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Jing, C.F.; Zhou, M.J. [Sun Yat-Sen University, South China Sea Marine Biotechnology, National Engineering Research Center, Guangzhou, China, National Engineering Research Center, South China Sea Marine Biotechnology, Sun Yat-Sen University, Guangzhou (China)

    2014-04-11

    Hypertrophy is a major predictor of progressive heart disease and has an adverse prognosis. MicroRNAs (miRNAs) that accumulate during the course of cardiac hypertrophy may participate in the process. However, the nature of any interaction between a hypertrophy-specific signaling pathway and aberrant expression of miRNAs remains unclear. In this study, Spague Dawley male rats were treated with transverse aortic constriction (TAC) surgery to mimic pathological hypertrophy. Hearts were isolated from TAC and sham operated rats (n=5 for each group at 5, 10, 15, and 20 days after surgery) for miRNA microarray assay. The miRNAs dysexpressed during hypertrophy were further analyzed using a combination of bioinformatics algorithms in order to predict possible targets. Increased expression of the target genes identified in diverse signaling pathways was also analyzed. Two sets of miRNAs were identified, showing different expression patterns during hypertrophy. Bioinformatics analysis suggested the miRNAs may regulate multiple hypertrophy-specific signaling pathways by targeting the member genes and the interaction of miRNA and mRNA might form a network that leads to cardiac hypertrophy. In addition, the multifold changes in several miRNAs suggested that upregulation of rno-miR-331*, rno-miR-3596b, rno-miR-3557-5p and downregulation of rno-miR-10a, miR-221, miR-190, miR-451 could be seen as biomarkers of prognosis in clinical therapy of heart failure. This study described, for the first time, a potential mechanism of cardiac hypertrophy involving multiple signaling pathways that control up- and downregulation of miRNAs. It represents a first step in the systematic discovery of miRNA function in cardiovascular hypertrophy.

  17. The PPARα - FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway

    OpenAIRE

    Vernia, Santiago; Cavanagh-Kyros, Julie; Garcia-Haro, Luisa; Sabio, Guadalupe; Barrett, Tamera; Jung, Dae Young; Kim, Jason K.; Xu, Jia; Shulha, Hennady P.; Garber, Manuel; Gao, Guangping; Davis, Roger J

    2014-01-01

    The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high fat diet, including the development of obesity and insulin resistance. These metabolic adaptations involve altered liver function. Here we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα). JNK therefore causes decreased expression of PPARα target genes that increase fatty acid oxidation...

  18. Eat to reproduce: a key role for the insulin signaling pathway in adult insects

    OpenAIRE

    LiesbethBadisco

    2013-01-01

    Insects, like all heterotrophic organisms, acquire from their food the nutrients that are essential for anabolic processes that lead to growth (larval stages) or reproduction (adult stage). In adult females, this nutritional input is processed and results in a very specific output, i.e. the production of fully developed eggs ready for fertilization and deposition. An important role in this input-output transition is attributed to the insulin signaling pathway (ISP). The ISP is considered to a...

  19. Interferon-γ regulates intestinal epithelial homeostasis through converging β-catenin signaling pathways

    OpenAIRE

    Nava, Porfirio; Koch, Stefan; Laukoetter, Mike G.; Lee, Winston Y.; Kolegraff, Keli; Capaldo, Christopher T.; Beeman, Neal; Addis, Caroline; Gerner-Smidt, Kirsten; Neumaier, Irmgard; Skerra, Arne; Li, Linheng; Parkos, Charles A.; Nusrat, Asma

    2010-01-01

    Inflammatory cytokines have been proposed to regulate epithelial homeostasis during intestinal inflammation. We report here that interferon-γ (IFN-γ) regulates the crucial homeostatic functions of cell proliferation and apoptosis through serine-threonine protein kinase AKT-β-catenin and Wingless-Int (Wnt)-β-catenin signaling pathways. Short-term exposure of intestinal epithelial cells to IFN-γ resulted in activation of β-catenin through AKT, followed by induction of the secreted Wnt inhibitor...

  20. Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

    OpenAIRE

    Zhang, Xinhua; Zang, Ning; Wei, Yu; Yin, Jin; Teng, Ruobing; Seftel, Allen; DiSanto, Michael E.

    2011-01-01

    Testosterone (T) plays a permissive role in the development of benign prostatic hyperplasia (BPH), and phosphodiesterase 5 inhibitors (PDE5is) have been found to be effective for BPH and lower urinary tract symptoms (LUTS) in clinical trials. This study investigated the effect of T on smooth muscle (SM) contractile and regulatory signaling pathways, including PDE5 expression and functional activity in prostate in male rats (sham-operated, surgically castrated, and castrated with T supplementa...

  1. Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression

    OpenAIRE

    Keasey, Matthew P.; Kang, Seong Su; Lovins, Chiharu; Hagg, Theo

    2013-01-01

    Background Ciliary neurotrophic factor (CNTF) expression is repressed in astrocytes by neuronal contact in the CNS and is rapidly induced by injury. Here, we defined an inhibitory integrin signaling pathway. Results The integrin substrates laminin, fibronectin and vitronectin, but not collagen, thrombospondin or fibrinogen, reduced CNTF expression in C6 astroglioma cells. Antibodies against αv and β5, but not α6 or β1, integrin induced CNTF. Together, the ligand and antibody specificity sugge...

  2. Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity

    OpenAIRE

    Schlessinger, Karni; McManus, Edward J.; Hall, Alan

    2007-01-01

    Scratch-induced disruption of cultured monolayers induces polarity in front row cells that can be visualized by spatially localized polymerization of actin at the front of the cell and reorientation of the centrosome/Golgi to face the leading edge. We previously reported that centrosomal reorientation and microtubule polarization depend on a Cdc42-regulated signal transduction pathway involving activation of the Par6/aPKC complex followed by inhibition of GSK-3β and accumulation of the adenom...

  3. Global microRNA profiles and signaling pathways in the development of cardiac hypertrophy

    International Nuclear Information System (INIS)

    Hypertrophy is a major predictor of progressive heart disease and has an adverse prognosis. MicroRNAs (miRNAs) that accumulate during the course of cardiac hypertrophy may participate in the process. However, the nature of any interaction between a hypertrophy-specific signaling pathway and aberrant expression of miRNAs remains unclear. In this study, Spague Dawley male rats were treated with transverse aortic constriction (TAC) surgery to mimic pathological hypertrophy. Hearts were isolated from TAC and sham operated rats (n=5 for each group at 5, 10, 15, and 20 days after surgery) for miRNA microarray assay. The miRNAs dysexpressed during hypertrophy were further analyzed using a combination of bioinformatics algorithms in order to predict possible targets. Increased expression of the target genes identified in diverse signaling pathways was also analyzed. Two sets of miRNAs were identified, showing different expression patterns during hypertrophy. Bioinformatics analysis suggested the miRNAs may regulate multiple hypertrophy-specific signaling pathways by targeting the member genes and the interaction of miRNA and mRNA might form a network that leads to cardiac hypertrophy. In addition, the multifold changes in several miRNAs suggested that upregulation of rno-miR-331*, rno-miR-3596b, rno-miR-3557-5p and downregulation of rno-miR-10a, miR-221, miR-190, miR-451 could be seen as biomarkers of prognosis in clinical therapy of heart failure. This study described, for the first time, a potential mechanism of cardiac hypertrophy involving multiple signaling pathways that control up- and downregulation of miRNAs. It represents a first step in the systematic discovery of miRNA function in cardiovascular hypertrophy

  4. Mathematical model of cAMP-dependent signaling pathway in constitutive and UV-induced melanogenesis

    Science.gov (United States)

    Stolnitz, Mikhail M.; Peshkova, Anna Y.

    2002-07-01

    Cascade of reactions of cAMP-dependent signaling pathway in melanocytes is investigated by mathematical modeling. Model takes into account (alpha) -melanocyte stimulating hormone binding to melanocortin-1 receptor, adenylate cyclase activation by G-protein, increase of the intracellular cAMP concentration, PKA activation by cAMP, CREB phosphorylation by PKA, microphthalmia gene expression, microphthalmia binding to tyrosinase gene promoter, increase of tyrosinase synthesis. Positive and negative feedback loops of this system are analyzed.

  5. Functionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle

    OpenAIRE

    Littlejohn, Mathew D; Henty, Kristen M.; Tiplady, Kathryn; Johnson, Thomas; Harland, Chad; Lopdell, Thomas; Sherlock, Richard G.; Li, Wanbo; Lukefahr, Steven D.; Shanks, Bruce C.; Garrick, Dorian J; Snell, Russell G.; Spelman, Richard J; Stephen R. Davis

    2014-01-01

    Lactation, hair development and homeothermy are characteristic evolutionary features that define mammals from other vertebrate species. Here we describe the discovery of two autosomal dominant mutations with antagonistic, pleiotropic effects on all three of these biological processes, mediated through the prolactin signalling pathway. Most conspicuously, mutations in prolactin (PRL) and its receptor (PRLR) have an impact on thermoregulation and hair morphology phenotypes, giving prominence to...

  6. Modulation of IL-6 signaling pathways by PUFAs in prostate cancer cells

    Czech Academy of Sciences Publication Activity Database

    Staršíchová, Andrea; Lincová, Eva; Pernicová, Zuzana; Kozubík, Alois; Souček, Karel

    Budapest, 2008. s. 193-194. [ISAC XXIV International Congress, Cytometry in the Age of Systems Biology. 17.05.2008-21.05.2008, Budapest] R&D Projects: GA ČR(CZ) GA204/07/0834; GA ČR(CZ) GA310/07/0961 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : interleukin-6 * signaling pathways * prostate Subject RIV: BO - Biophysics

  7. Myocardial ischemic post-conditioning attenuates ischemia reperfusion injury via PTEN/Akt signal pathway

    OpenAIRE

    LI, CHUN-MEI; Shen, Shu-Wen; Tao WANG; Zhang, Xing-Hua

    2015-01-01

    Objectives: To investigate whether myocardial ischemic post-conditioning attenuates ischemia reperfusion injury via PTEN/Akt signal pathway. Design: Forty-five male Sprague-Dawley rats were randomly divided into three groups: Sham, Ischemia reperfusion (I/R) and Ischemic post-conditioning (IPost) group. After the experiment finished, myocardial infarction area was examined. Serum creatine phosphokinase and lactate dehydrogenase activity were detected at baseline and the end of reperfusion. Th...

  8. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components

    OpenAIRE

    Kim, Nam-Gyun; Koh, Eunjin; Chen, Xiao; Gumbiner, Barry M.

    2011-01-01

    Contact inhibition of cell growth is essential for embryonic development and maintenance of tissue architecture in adult organisms, and the growth of tumors is characterized by a loss of contact inhibition of proliferation. The recently identified Hippo signaling pathway has been implicated in contact inhibition of proliferation as well as organ size control. The modulation of the phosphorylation and nuclear localization of Yes-associated protein (YAP) by the highly conserved kinase cascade o...

  9. βMolecular Pathways: Novel Approaches for Improved Therapeutic Targeting of Hedgehog Signaling in Cancer Stem Cells

    OpenAIRE

    Justilien, Verline; Fields, Alan P.

    2015-01-01

    The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation including the maintenance of the cancer stem cell (CSC) phenotype. Pre-clinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspe...

  10. The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Erhong; Hanna, Ann; Samant, Rajeev S.; Shevde, Lalita A., E-mail: lsamant@uab.edu [Department of Pathology, Comprehensive Cancer Center, University of Alabama at Birmingham, WTI320D, 1824 6th Avenue South, Birmingham, AL 35233 (United States)

    2015-07-21

    Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair). Aberrant activation of the Hedgehog (Hh) signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer.

  11. The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

    Directory of Open Access Journals (Sweden)

    Erhong Meng

    2015-07-01

    Full Text Available Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair. Aberrant activation of the Hedgehog (Hh signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer.

  12. Expression analysis of eight amphioxus genes involved in the Wnt/β-catenin signaling pathway

    Science.gov (United States)

    WANG, Jing; LI, Guang; QIAN, Guang-Hui; HUA, Jun-Hao; WANG, Yi-Quan

    2016-01-01

    The Wnt/β-catenin signaling pathway plays a crucial role in the embryonic development of metazoans. Although the pathway has been studied extensively in many model animals, its function in amphioxus, the most primitive chordate, remains largely uncharacterized. To obtain basic data for functional analysis, we identified and isolated seven genes (Lrp5/6, Dvl, APC, CkIα, CkIδ, Gsk3β, and Gro) of the Wnt/β-catenin signaling pathway from the amphioxus (Branchiostoma floridae) genome. Phylogenetic analysis revealed that amphioxus had fewer members of each gene family than that found in vertebrates. Whole-mount in situ hybridization showed that the genes were maternally expressed and broadly distributed throughout the whole embryo at the cleavage and blastula stages. Among them, Dvl was expressed asymmetrically towards the animal pole, while the others were evenly distributed in all blastomeres. At the mid-gastrula stage, the genes were specifically expressed in the primitive endomesoderm, but displayed different patterns. When the embryo developed into the neurula stage, the gene expressions were mainly detected in either paraxial somites or the tail bud. With the development of the embryo, the expression levels further decreased gradually and remained only in some pharyngeal regions or the tail bud at the larva stage. Our results suggest that the Wnt/β-catenin pathway might be involved in amphioxus somite formation and posterior growth, but not in endomesoderm specification. PMID:27265651

  13. The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

    International Nuclear Information System (INIS)

    Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair). Aberrant activation of the Hedgehog (Hh) signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer

  14. Plasma membrane calcium ATPase proteins as novel regulators of signal transduction pathways

    Institute of Scientific and Technical Information of China (English)

    Mary; Louisa; Holton; Michael; Emerson; Ludwig; Neyses; Angel; L; Armesilla

    2010-01-01

    Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs regulate these pathways by targeting specific proteins to cellular sub-domains where the levels of intracellular freecalcium are kept low by the calcium ejection properties of PMCAs. According to this model, PMCAs have been shown to interact functionally with the calcium-sensitive proteins neuronal nitric oxide synthase, calmodulindependent serine protein kinase, calcineurin and endothelial nitric oxidase synthase. Transgenic animals with altered expression of PMCAs are being used to evaluate the physiological significance of these interactions. To date, PMCA interactions with calcium-dependent partner proteins have been demonstrated to play a crucial role in the pathophysiology of the cardiovascular system via regulation of the nitric oxide and calcineurin/nuclear factor of activated T cells pathways. This new evidence suggests that PMCAs play a more sophisticated role than the mere ejection of calcium from the cells, by acting as modulators of signaling transduction pathways.

  15. Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Vladan P. Čokić

    2015-01-01

    Full Text Available The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34+ cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34+ cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.

  16. Dendritic cell derived IL-2 inhibits survival of terminally mature cells via an autocrine signaling pathway.

    Science.gov (United States)

    Balachander, Akhila; Nabti, Sabrina; Sobota, Radoslaw M; Foo, Shihui; Zolezzi, Francesca; Lee, Bernett T K; Poidinger, Michael; Ricciardi-Castagnoli, Paola

    2015-05-01

    DCs are crucial for sensing pathogens and triggering immune response. Upon activation by pathogen-associated molecular pattern (PAMP) ligands, GM-CSF myeloid DCs (GM-DCs) secrete several cytokines, including IL-2. DC IL-2 has been shown to be important for innate and adaptive immune responses; however, IL-2 importance in DC physiology has never been demonstrated. Here, we show that autocrine IL-2 signaling is functional in murine GM-DCs in an early time window after PAMPs stimulation. IL-2 signaling selectively activates the JAK/STAT5 pathway by assembling holo-receptor complexes at the cell surface. Using the sensitivity of targeted mass spectrometry, we show conclusively that GM-DCs express CD122, the IL-2 receptor β-chain, at steady state. In myeloid DCs, this cytokine pathway inhibits survival of PAMP-matured GM-DCs which is crucial for maintaining immune tolerance and preventing autoimmunity. Our findings suggest that immune regulation by this novel autocrine signaling pathway can potentially be used in DC immunotherapy. PMID:25652593

  17. Combinatory annotation of cell membrane receptors and signalling pathways of Bombyx mori prothoracic glands

    Science.gov (United States)

    Moulos, Panagiotis; Samiotaki, Martina; Panayotou, George; Dedos, Skarlatos G.

    2016-01-01

    The cells of prothoracic glands (PG) are the main site of synthesis and secretion of ecdysteroids, the biochemical products of cholesterol conversion to steroids that shape the morphogenic development of insects. Despite the availability of genome sequences from several insect species and the extensive knowledge of certain signalling pathways that underpin ecdysteroidogenesis, the spectrum of signalling molecules and ecdysteroidogenic cascades is still not fully comprehensive. To fill this gap and obtain the complete list of cell membrane receptors expressed in PG cells, we used combinatory bioinformatic, proteomic and transcriptomic analysis and quantitative PCR to annotate and determine the expression profiles of genes identified as putative cell membrane receptors of the model insect species, Bombyx mori, and subsequently enrich the repertoire of signalling pathways that are present in its PG cells. The genome annotation dataset we report here highlights modules and pathways that may be directly involved in ecdysteroidogenesis and aims to disseminate data and assist other researchers in the discovery of the role of such receptors and their ligands. PMID:27576083

  18. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    International Nuclear Information System (INIS)

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer

  19. Does a Common Pathway Transduce Symbiotic Signals in Plant-Microbe Interactions?

    Science.gov (United States)

    Genre, Andrea; Russo, Giulia

    2016-01-01

    Recent years have witnessed major advances in our knowledge of plant mutualistic symbioses such as the rhizobium-legume symbiosis (RLS) and arbuscular mycorrhizas (AM). Some of these findings caused the revision of longstanding hypotheses, but one of the most solid theories is that a conserved set of plant proteins rules the transduction of symbiotic signals from beneficial glomeromycetes and rhizobia in a so-called common symbiotic pathway (CSP). Nevertheless, the picture still misses several elements, and a few crucial points remain unclear. How does one common pathway discriminate between - at least - two symbionts? Can we exclude that microbes other than AM fungi and rhizobia also use this pathway to communicate with their host plants? We here discuss the possibility that our current view is biased by a long-lasting focus on legumes, whose ability to develop both AM and RLS is an exception among plants and a recent innovation in their evolution; investigations in non-legumes are starting to place legume symbiotic signaling in a broader perspective. Furthermore, recent studies suggest that CSP proteins act in a wider scenario of symbiotic and non-symbiotic signaling. Overall, evidence is accumulating in favor of distinct activities for CSP proteins in AM and RLS, depending on the molecular and cellular context where they act. PMID:26909085

  20. Large scale statistical inference of signaling pathways from RNAi and microarray data

    Directory of Open Access Journals (Sweden)

    Poustka Annemarie

    2007-10-01

    Full Text Available Abstract Background The advent of RNA interference techniques enables the selective silencing of biologically interesting genes in an efficient way. In combination with DNA microarray technology this enables researchers to gain insights into signaling pathways by observing downstream effects of individual knock-downs on gene expression. These secondary effects can be used to computationally reverse engineer features of the upstream signaling pathway. Results In this paper we address this challenging problem by extending previous work by Markowetz et al., who proposed a statistical framework to score networks hypotheses in a Bayesian manner. Our extensions go in three directions: First, we introduce a way to omit the data discretization step needed in the original framework via a calculation based on p-values instead. Second, we show how prior assumptions on the network structure can be incorporated into the scoring scheme using regularization techniques. Third and most important, we propose methods to scale up the original approach, which is limited to around 5 genes, to large scale networks. Conclusion Comparisons of these methods on artificial data are conducted. Our proposed module network is employed to infer the signaling network between 13 genes in the ER-α pathway in human MCF-7 breast cancer cells. Using a bootstrapping approach this reconstruction can be found with good statistical stability. The code for the module network inference method is available in the latest version of the R-package nem, which can be obtained from the Bioconductor homepage.

  1. Does a Common Pathway Transduce Symbiotic Signals in Plant–Microbe Interactions?

    Science.gov (United States)

    Genre, Andrea; Russo, Giulia

    2016-01-01

    Recent years have witnessed major advances in our knowledge of plant mutualistic symbioses such as the rhizobium-legume symbiosis (RLS) and arbuscular mycorrhizas (AM). Some of these findings caused the revision of longstanding hypotheses, but one of the most solid theories is that a conserved set of plant proteins rules the transduction of symbiotic signals from beneficial glomeromycetes and rhizobia in a so-called common symbiotic pathway (CSP). Nevertheless, the picture still misses several elements, and a few crucial points remain unclear. How does one common pathway discriminate between – at least – two symbionts? Can we exclude that microbes other than AM fungi and rhizobia also use this pathway to communicate with their host plants? We here discuss the possibility that our current view is biased by a long-lasting focus on legumes, whose ability to develop both AM and RLS is an exception among plants and a recent innovation in their evolution; investigations in non-legumes are starting to place legume symbiotic signaling in a broader perspective. Furthermore, recent studies suggest that CSP proteins act in a wider scenario of symbiotic and non-symbiotic signaling. Overall, evidence is accumulating in favor of distinct activities for CSP proteins in AM and RLS, depending on the molecular and cellular context where they act. PMID:26909085

  2. Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway.

    Science.gov (United States)

    Ma, Lijie; Dong, Pingping; Liu, Longzi; Gao, Qiang; Duan, Meng; Zhang, Si; Chen, She; Xue, Ruyi; Wang, Xiaoying

    2016-04-29

    Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstrated that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. PMID:27003260

  3. The signal transduction pathway in the proliferation of airway smooth muscle cells induced by urotensin Ⅱ

    Institute of Scientific and Technical Information of China (English)

    陈亚红; 赵鸣武; 姚婉贞; 庞永政; 唐朝枢

    2004-01-01

    Background Human urotensin Ⅱ (UⅡ) is the most potent mammalian vasoconstrictor identified so far. Our previous study showed that UⅡ is a potent mitogen of airway smooth muscle cells (ASMC) inducing ASMC proliferation in a dose-dependent manner. The signal transduction pathway of UⅡ mitogenic effect remains to be clarified. This study was conducted to investigate the signal transduction pathway in the proliferation of ASMC induced by UⅡ.Methods In primary cultures of rat ASMCs, activities of protein kinase C (PKC), mitogen-activated protein kinase (MAPK) and calcineurin (CaN) induced by UⅡ were measured. The effect of CaN on PKC and MAPK was studied by adding cyclosporin A (CsA), a specific inhibitor of CaN. Using H7 and PD98059, inhibitors of PKC and MAPK, respectively, to study the effect of PKC and MAPK on CaN. The cytosolic free calcium concentration induced by UⅡ was measured using Fura-2/AM. Results UⅡ 10-7 mol/L stimulated ASMC PKC and MAPK activities by 44% and 24% (P0.05). CsA 10-6 mol/L inhibited UⅡ-stimulated PKC activity by 14% (P0.05).Conclusions UⅡ increases cytosolic free calcium concentration and activates PKC, MAPK and CaN. The signal transduction pathway between PKC and CaN has cross-talk.

  4. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yasuko Kitagishi

    2013-10-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer.

  5. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Satoru, E-mail: smatsuda@cc.nara-wu.ac.jp; Kitagishi, Yasuko [Department of Food Science and Nutrition, Nara Women’s University, Kita-Uoya Nishimachi, Nara 630-8506 (Japan)

    2013-10-21

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer.

  6. Phosphatidylserine enhances IKBKAP transcription by activating the MAPK/ERK signaling pathway.

    Science.gov (United States)

    Donyo, Maya; Hollander, Dror; Abramovitch, Ziv; Naftelberg, Shiran; Ast, Gil

    2016-04-01

    Familial dysautonomia (FD) is a genetic disorder manifested due to abnormal development and progressive degeneration of the sensory and autonomic nervous system. FD is caused by a point mutation in the IKBKAP gene encoding the IKAP protein, resulting in decreased protein levels. A promising potential treatment for FD is phosphatidylserine (PS); however, the manner by which PS elevates IKAP levels has yet to be identified. Analysis of ChIP-seq results of the IKBKAP promoter region revealed binding of the transcription factors CREB and ELK1, which are regulated by the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) signaling pathway. We show that PS treatment enhanced ERK phosphorylation in cells derived from FD patients. ERK activation resulted in elevated IKBKAP transcription and IKAP protein levels, whereas pretreatment with the MAPK inhibitor U0126 blocked elevation of the IKAP protein level. Overexpression of either ELK1 or CREB activated the IKBKAP promoter, whereas downregulation of these transcription factors resulted in a decrease of the IKAP protein. Additionally, we show that PS improves cell migration, known to be enhanced by MAPK/ERK activation and abrogated in FD cells. In conclusion, our results demonstrate that PS activates the MAPK/ERK signaling pathway, resulting in activation of transcription factors that bind the promoter region of IKBKAP and thus enhancing its transcription. Therefore, compounds that activate the MAPK/ERK signaling pathway could constitute potential treatments for FD. PMID:26769675

  7. Targeting specific cell signaling transduction pathways by dietary and medicinal phytochemicals in cancer chemoprevention

    International Nuclear Information System (INIS)

    Natural phytochemicals derived from dietary sources or medicinal plants have gained significant recognition in the potential management of several human clinical conditions. Much research has also been geared towards the evaluation of plant extracts as effective prophylactic agents since they can act on specific and/or multiple molecular and cellular targets. Plants have been an abundant source of highly effective phytochemicals which offer great potential in the fight against cancer by inhibiting the process of carcinogenesis through the upregulation of cytoprotective genes that encode for carcinogen detoxifying enzymes and antioxidant enzymes. The mechanistic insight into chemoprevention further includes induction of cell cycle arrest and apoptosis or inhibition of signal transduction pathways mainly the mitogen-activated protein kinases (MAPK), protein kinases C (PKC), phosphoinositide 3-kinase (PI3K), glycogen synthase kinase (GSK) which lead to abnormal cyclooxygenase-2 (COX-2), activator protein-1 (AP-1), nuclear factor-kappaB (NF-κB) and c-myc expression. Effectiveness of chemopreventive agents reflects their ability to counteract certain upstream signals that leads to genotoxic damage, redox imbalances and other forms of cellular stress. Targeting malfunctioning molecules along the disrupted signal transduction pathway in cancer represent a rational strategy in chemoprevention. NF-κB and AP-1 provide mechanistic links between inflammation and cancer, and moreover regulate tumor angiogenesis and invasiveness, indicating that signaling pathways that mediate their activation provide attractive targets for new chemotherapeutic approaches. Thus cell signaling cascades and their interacting factors have become important targets of chemoprevention and phenolic phytochemicals and plant extracts seem to be promising in this endeavor.

  8. How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario

    Science.gov (United States)

    Arrázola, Macarena S.; Silva-Alvarez, Carmen; Inestrosa, Nibaldo C.

    2015-01-01

    Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is characterized by progressive memory loss and cognitive decline. One of the hallmarks of AD is the overproduction of amyloid-beta aggregates that range from the toxic soluble oligomer (Aβo) form to extracellular accumulations in the brain. Growing evidence indicates that mitochondrial dysfunction is a common feature of neurodegenerative diseases and is observed at an early stage in the pathogenesis of AD. Reports indicate that mitochondrial structure and function are affected by Aβo and can trigger neuronal cell death. Mitochondria are highly dynamic organelles, and the balance between their fusion and fission processes is essential for neuronal function. Interestingly, in AD, the process known as “mitochondrial dynamics” is also impaired by Aβo. On the other hand, the activation of the Wnt signaling pathway has an essential role in synaptic maintenance and neuronal functions, and its deregulation has also been implicated in AD. We have demonstrated that canonical Wnt signaling, through the Wnt3a ligand, prevents the permeabilization of mitochondrial membranes through the inhibition of the mitochondrial permeability transition pore (mPTP), induced by Aβo. In addition, we showed that non-canonical Wnt signaling, through the Wnt5a ligand, protects mitochondria from fission-fusion alterations in AD. These results suggest new approaches by which different Wnt signaling pathways protect neurons in AD, and support the idea that mitochondria have become potential therapeutic targets for the treatment of neurodegenerative disorders. Here we discuss the neuroprotective role of the canonical and non-canonical Wnt signaling pathways in AD and their differential modulation of mitochondrial processes, associated with mitochondrial dysfunction and neurodegeneration. PMID:25999816

  9. Conformational transition in signal transduction: metastable states and transition pathways in the activation of a signaling protein.

    Science.gov (United States)

    Banerjee, Rahul; Yan, Honggao; Cukier, Robert I

    2015-06-01

    Signal transduction is of vital importance to the growth and adaptation of living organisms. The key to understand mechanisms of biological signal transduction is elucidation of the conformational dynamics of its signaling proteins, as the activation of a signaling protein is fundamentally a process of conformational transition from an inactive to an active state. A predominant form of signal transduction for bacterial sensing of environmental changes in the wild or inside their hosts is a variety of two-component systems, in which the conformational transition of a response regulator (RR) from an inactive to an active state initiates responses to the environmental changes. Here, RR activation has been investigated using RR468 as a model system by extensive unbiased all-atom molecular dynamics (MD) simulations in explicit solvent, starting from snapshots along a targeted MD trajectory that covers the conformational transition. Markov state modeling, transition path theory, and geometric analyses of the wealth of the MD data have provided a comprehensive description of the RR activation. It involves a network of metastable states, with one metastable state essentially the same as the inactive state and another very similar to the active state that are connected via a small set of intermediates. Five major pathways account for >75% of the fluxes of the conformational transition from the inactive to the active-like state. The thermodynamic stability of the states and the activation barriers between states are found, to identify rate-limiting steps. The conformal transition is initiated predominantly by movements of the β3α3 loop, followed by movements of the β4α4-loop and neighboring α4 helix region, and capped by additional movements of the β3α3 loop. A number of transient hydrophobic and hydrogen bond interactions are revealed, and they may be important for the conformational transition. PMID:25945797

  10. Computational Modeling of PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer

    Science.gov (United States)

    Pappalardo, Francesco; Russo, Giulia; Candido, Saverio; Pennisi, Marzio; Cavalieri, Salvatore; Motta, Santo; McCubrey, James A.; Nicoletti, Ferdinando; Libra, Massimo

    2016-01-01

    Background Malignant melanoma is an aggressive tumor of the skin and seems to be resistant to current therapeutic approaches. Melanocytic transformation is thought to occur by sequential accumulation of genetic and molecular alterations able to activate the Ras/Raf/MEK/ERK (MAPK) and/or the PI3K/AKT (AKT) signalling pathways. Specifically, mutations of B-RAF activate MAPK pathway resulting in cell cycle progression and apoptosis prevention. According to these findings, MAPK and AKT pathways may represent promising therapeutic targets for an otherwise devastating disease. Result Here we show a computational model able to simulate the main biochemical and metabolic interactions in the PI3K/AKT and MAPK pathways potentially involved in melanoma development. Overall, this computational approach may accelerate the drug discovery process and encourages the identification of novel pathway activators with consequent development of novel antioncogenic compounds to overcome tumor cell resistance to conventional therapeutic agents. The source code of the various versions of the model are available as S1 Archive. PMID:27015094

  11. Identification of 2-aminopyrimidine derivatives as inhibitors of the canonical Wnt signaling pathway.

    Science.gov (United States)

    Del Bello, Fabio; Farande, Aniket; Giannella, Mario; Piergentili, Alessandro; Quaglia, Wilma; Benicchi, Tiziana; Cappelli, Federico; Nencini, Arianna; Salerno, Massimiliano; Thomas, Russell J; Travagli, Massimilano; Varrone, Maurizio

    2015-09-01

    The canonical Wnt signaling pathway plays a fundamental role in embryonic as well as in adult development. Consequently, dysregulation of the pathway has been linked to a wide spectrum of pathological conditions. In a program aimed at the identification of small molecule inhibitors of the canonical Wnt pathway we identified a series of 2-aminopyrimidine derivatives which specifically inhibited the pathway with minimal or no sign of cellular toxicity. The hit molecules 1 and 2 showed promising inhibitory activity with IC50 values of approximately 10 μM, but low solubility and metabolic stability. During the early stage of the hit series exploration, the pyrimidine core was variously decorated to obtain active compounds with a better physico-chemical profile. In particular, compound 13 showed Wnt inhibition activity comparable to hit molecules 1 and 2, with improved physico-chemical properties. Therefore, this series of compounds may be considered a promising starting point for the design of novel small molecule inhibitors of the canonical Wnt pathway. PMID:26233797

  12. Wingless and its signalling pathway have common and separable functions during tracheal development.

    Science.gov (United States)

    Llimargas, M

    2000-10-01

    The Drosophila tracheal tree consists of a tubular network of epithelial branches that constitutes the respiratory system. Groups of tracheal cells migrate towards stereotyped directions while they acquire specific tracheal fates. This work shows that the wingless/WNT signalling pathway is needed within the tracheal cells for the formation of the dorsal trunk and for fusion of the branches. These functions are achieved through the regulation of target genes, such as spalt in the dorsal trunk and escargot in the fusion cells. The pathway also aids tracheal invagination and helps guide the ganglionic branch. Moreover the wingless/WNT pathway displays antagonistic interactions with the DPP (decapentaplegic) pathway, which regulates branching along the dorsoventral axis. Remarkably, the wingless gene itself, acting through its canonical pathway, seems not to be absolutely required for all these tracheal functions. However, the artificial overexpression of wingless in tracheal cells mimics the overexpression of a constitutively activated armadillo protein. The results suggest that another gene product, possibly a WNT, could help to trigger the wingless cascade in the developing tracheae. PMID:11003840

  13. Eight paths of ERK1/2 signalling pathway regulating hepatocyte proliferation in rat liver regeneration

    Indian Academy of Sciences (India)

    J. W. Li; G. P. Wang; J. Y. Fan; C. F. Chang; C. S. Xu

    2011-12-01

    Although it is known that hormones, growth factors and integrin promote hepatocyte proliferation in liver regeneration (LR) through ERK1/2 signalling pathway, reports about regulating processes of its intracellular paths in hepatocytes of LR are limited. This study aims at exploring which paths of ERK1/2 signalling pathway participate in the regulation of rat LR, especially in hepatocyte proliferation, and how they do so. In all, 14 paths and 165 genes are known to be involved in ERK1/2 signalling pathway. Of them, 161 genes are included in Rat Genome 230 2.0 Array. This array was used to detect expression changes of genes related to ERK1/2 signalling pathway in isolated hepatocytes of rat LR, showing that 60 genes were related to hepatocytes of LR. In addition, bioinformatics and systems biology methods were used to analyse the roles of 14 above paths in regenerating hepatocytes. We found that three paths, RTK → SHC → GRB2/SOS → RAS → RAF, Integrin → FAK → RAC → PAK → RAF and G → PI3K → RAC → PAK → RAF, promoted the G1 phase progression of hepatocytes by activating ERK1/2. A further four paths, Gq → PLC → PKC → SRC/PYK2 → GRB2/SOS → RAS → RAF, RTK → PLC → PKC → SRC/PYK2 → GRB2/SOS → RAS → RAF, Integrin → FAK/SRC → GRB2/SOS → RAS → RAF and Integrin → FAK → RAC → PAK → RAF, advanced the cell progression of S phase and G2/M checkpoint by activating ERK1/2, and so did PP1/2 → Mek1/2 by decreasing the negative influence on ERK1/2. At the late phase of LR, Gs → AC → EPAC → Rap1 → Raf blocked hepatocyte proliferation by decreasing the activity of ERK1/2 and so did PP1/2 → Mek1/2. In summary, 60 genes and 8 paths of ERK1/2 signalling pathway regulated hepatocyte proliferation in rat LR.

  14. Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway

    International Nuclear Information System (INIS)

    Highlights: • Curcumol suppresses osteoclasts differentiation in vitro. • Curcumol impairs JNK/AP-1 signaling pathway. • Curcumol may be used for treating osteoclast related diseases. - Abstract: Osteoclasts, derived from hemopoietic progenitors of the monocyte/macrophage lineage, have a unique role in bone resorption, and are considered a potential therapeutic target in the treatment of such pathologic bone diseases as osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we demonstrate that curcumol, one of the major components of the essential oil of Rhizoma Curcumae, exhibits an inhibitory effect on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation with both bone marrow-derived macrophages and RAW264.7 cells in a dose-dependent manner. In addition, RANKL-induced mRNA expression of osteoclast-specific genes, such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K, is prominently reduced in the presence of curcumol. Furthermore, the molecular mechanism of action was investigated, and curcumol inhibited osteoclastogenesis by specifically impairing RANKL-induced c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling, which was further identified in rescue studies by means of anisomycin, a JNK signaling-specific activator. Taken together, these findings suggest that curcumol suppresses RANKL-induced osteoclast differentiation through the JNK/AP-1 signaling pathway, and may be useful as a therapeutic treatment for bone resorption-associated diseases

  15. Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Mingxiang, E-mail: yu.mingxiang@zs-hospital.sh.cn [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Chen, Xianying [Department of Endocrinology and Metabolism, Hainan Provincial Nong Ken Hospital, Hainan (China); Lv, Chaoyang [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Yi, Xilu [Department of Endocrinology and Metabolism, Shanghai Songjiang District Central Hospital, Shanghai (China); Zhang, Yao; Xue, Mengjuan; He, Shunmei [Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai (China); Zhu, Guoying [Institute of Radiation Medicine, Fudan University, Shanghai (China); Wang, Hongfu, E-mail: hfwang@shmu.edu.cn [Institute of Radiation Medicine, Fudan University, Shanghai (China)

    2014-05-02

    Highlights: • Curcumol suppresses osteoclasts differentiation in vitro. • Curcumol impairs JNK/AP-1 signaling pathway. • Curcumol may be used for treating osteoclast related diseases. - Abstract: Osteoclasts, derived from hemopoietic progenitors of the monocyte/macrophage lineage, have a unique role in bone resorption, and are considered a potential therapeutic target in the treatment of such pathologic bone diseases as osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we demonstrate that curcumol, one of the major components of the essential oil of Rhizoma Curcumae, exhibits an inhibitory effect on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation with both bone marrow-derived macrophages and RAW264.7 cells in a dose-dependent manner. In addition, RANKL-induced mRNA expression of osteoclast-specific genes, such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K, is prominently reduced in the presence of curcumol. Furthermore, the molecular mechanism of action was investigated, and curcumol inhibited osteoclastogenesis by specifically impairing RANKL-induced c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling, which was further identified in rescue studies by means of anisomycin, a JNK signaling-specific activator. Taken together, these findings suggest that curcumol suppresses RANKL-induced osteoclast differentiation through the JNK/AP-1 signaling pathway, and may be useful as a therapeutic treatment for bone resorption-associated diseases.

  16. Saw Palmetto Extract Inhibits Metastasis and Antiangiogenesis through STAT3 Signal Pathway in Glioma Cell

    Directory of Open Access Journals (Sweden)

    Hong Ding

    2015-01-01

    Full Text Available Signal transducer and activator of transcription factor 3 (STAT3 plays an important role in the proliferation and angiogenesis in human glioma. Previous research indicated that saw palmetto extract markedly inhibited the proliferation of human glioma cells through STAT3 signal pathway. But its effect on tumor metastasis and antiangiogenesis is not clear. This study is to further clear the impact of saw palmetto extract on glioma cell metastasis, antiangiogenesis, and its mechanism. TUNEL assay indicated that the apoptotic cells in the saw palmetto treated group are higher than that in the control group (p<0.05. The apoptosis related protein is detected and the results revealed that saw palmetto extract inhibits the proliferation of human glioma. Meanwhile pSTAT3 is lower in the experimental group and CD34 is also inhibited in the saw palmetto treated group. This means that saw palmetto extract could inhibit the angiogenesis in glioma. We found that saw palmetto extract was an important phytotherapeutic drug against the human glioma through STAT3 signal pathway. Saw palmetto extract may be useful as an adjunctive therapeutic agent for treatment of individuals with glioma and other types of cancer in which STAT3 signaling is activated.

  17. A Signaling Pathway Involving TGF-beta2 and Snail in Hair Follicle Morphogenesis

    Directory of Open Access Journals (Sweden)

    Jamora Colin

    2004-01-01

    Full Text Available In a common theme of organogenesis, certain cells within a multipotent epithelial sheet exchange signals with their neighbors and develop into a bud structure. Using hair bud morphogenesis as a paradigm, we employed mutant mouse models and cultured keratinocytes to dissect the contributions of multiple extracellular cues in orchestrating adhesion dynamics and proliferation to shape the cluster of cells involved. We found that transforming growth factor beta2 signaling is necessary to transiently induce the transcription factor Snail and activate the Ras-mitogen-activated protein kinase (MAPK pathway in the bud. In the epidermis, Snail misexpression leads to hyperproliferation and a reduction in intercellular adhesion. When E-cadherin is transcriptionally down-regulated, associated adhesion proteins with dual functions in signaling are released from cell-cell contacts, a process which we demonstrate leads to Ras-MAPK activation. These studies provide insights into how multipotent cells within a sheet are stimulated to undergo transcriptional changes that result in proliferation, junctional remodeling, and bud formation. This novel signaling pathway further weaves together the web of different morphogens and downstream transcriptional events that guide hair bud formation within the developing skin.

  18. Signal transduction pathways and transcription factors triggered by arsenic trioxide in leukemia cells

    International Nuclear Information System (INIS)

    Arsenic trioxide (As2O3) is widely used to treat acute promyelocytic leukemia (APL). Several lines of evidence have indicated that As2O3 affects signal transduction and transactivation of transcription factors, resulting in the stimulation of apoptosis in leukemia cells, because some transcription factors are reported to associate with the redox condition of the cells, and arsenicals cause oxidative stress. Thus, the disturbance and activation of the cellular signaling pathway and transcription factors due to reactive oxygen species (ROS) generation during arsenic exposure may explain the ability of As2O3 to induce a complete remission in relapsed APL patients. In this report, we review recent findings on ROS generation and alterations in signal transduction and in transactivation of transcription factors during As2O3 exposure in leukemia cells.

  19. Regulation of the Ras-MAPK and PI3K-mTOR Signalling Pathways by Alternative Splicing in Cancer

    Directory of Open Access Journals (Sweden)

    Zahava Siegfried

    2013-01-01

    Full Text Available Alternative splicing is a fundamental step in regulation of gene expression of many tumor suppressors and oncogenes in cancer. Signalling through the Ras-MAPK and PI3K-mTOR pathways is misregulated and hyperactivated in most types of cancer. However, the regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing is less well established. Recent studies have shown the contribution of alternative splicing regulation of these signalling pathways which can lead to cellular transformation, cancer development, and tumor maintenance. This review will discuss findings in the literature which describe new modes of regulation of components of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing. We will also describe the mechanisms by which signals from extracellular stimuli can be communicated to the splicing machinery and to specific RNA-binding proteins that ultimately control exon definition events.

  20. Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells.

    Science.gov (United States)

    Boutin, Alisa; Neumann, Susanne; Gershengorn, Marvin C

    2016-05-01

    It has been shown that the TSH receptor (TSHR) couples to a number of different signaling pathways, although the Gs-cAMP pathway has been considered primary. Here, we measured the effects of TSH on bone marker mRNA and protein expression in preosteoblast-like U2OS cells stably expressing TSHRs. We determined which signaling cascades are involved in the regulation of IL-11, osteopontin (OPN), and alkaline phosphatase (ALPL). We demonstrated that TSH-induced up-regulation of IL-11 is primarily mediated via the Gs pathway as IL-11 was up-regulated by forskolin (FSK), an adenylyl cyclase activator, and inhibited by protein kinase A inhibitor H-89 and by silencing of Gαs by small interfering RNA. OPN levels were not affected by FSK, but its up-regulation was inhibited by TSHR/Gi-uncoupling by pertussis toxin. Pertussis toxin decreased p38 MAPK kinase phosphorylation, and a p38 inhibitor and small interfering RNA knockdown of p38α inhibited OPN induction by TSH. Up-regulation of ALPL expression required high doses of TSH (EC50 = 395nM), whereas low doses (EC50 = 19nM) were inhibitory. FSK-stimulated cAMP production decreased basal ALPL expression, whereas protein kinase A inhibition by H-89 and silencing of Gαs increased basal levels of ALPL. Knockdown of Gαq/11 and a protein kinase C inhibitor decreased TSH-stimulated up-regulation of ALPL, whereas a protein kinase C activator increased ALPL levels. A MAPK inhibitor and silencing of ERK1/2 inhibited TSH-stimulated ALPL expression. We conclude that TSH regulates expression of different bone markers via distinct signaling pathways. PMID:26950201

  1. Hedgehog信号通路与肿瘤%Relationship between Hedgehog signaling pathway and related tumors

    Institute of Scientific and Technical Information of China (English)

    王琪琳; 苏玲; 刘相国

    2011-01-01

    Hedgehog 信号通路在胚胎发育中细胞的生长分化、组织器官形成以及成体干细胞的维持和自稳态的保持等方面具有重要作用.同时,Hedgehog信号通路与wnt信号通路、Notch信号通路等相互作用,密切联系,在肿瘤的发生、发展过程中也起到关键作用.论文综述了Hedgehog信号通路的作用机理,与其他信号通路、蛋白质因子的相互联系,以及在肿瘤研究中所关注的靶位点和小分子化合物抑制剂,对于癌症的预防和治疗具有一定的参考价值.%Hedgehog signaling plays an essential role in embryonic differentiation, pattern formation and adult cell homeostasis. Simultaneously hedgehog signaling has closd correlation with Wnt signaling and Notch signaling, and plays a critical role in tumor initiation and progression. This review focuses on the regulatory mechanism and physiological functions of Hedgehog signaling, and the relationship with other signaling pathways and protein factors. The target sites and small molecular inhibitors in tumor have also been summarized, which might be beneficial to cancer therapeutic intervention.

  2. Proteomics, pathway array and signaling network-based medicine in cancer

    Directory of Open Access Journals (Sweden)

    Xu Hong

    2009-10-01

    Full Text Available Abstract Cancer is a multifaceted disease that results from dysregulated normal cellular signaling networks caused by genetic, genomic and epigenetic alterations at cell or tissue levels. Uncovering the underlying protein signaling network changes, including cell cycle gene networks in cancer, aids in understanding the molecular mechanism of carcinogenesis and identifies the characteristic signaling network signatures unique for different cancers and specific cancer subtypes. The identified signatures can be used for cancer diagnosis, prognosis, and personalized treatment. During the past several decades, the available technology to study signaling networks has significantly evolved to include such platforms as genomic microarray (expression array, SNP array, CGH array, etc. and proteomic analysis, which globally assesses genetic, epigenetic, and proteomic alterations in cancer. In this review, we compared Pathway Array analysis with other proteomic approaches in analyzing protein network involved in cancer and its utility serving as cancer biomarkers in diagnosis, prognosis and therapeutic target identification. With the advent of bioinformatics, constructing high complexity signaling networks is possible. As the use of signaling network-based cancer diagnosis, prognosis and treatment is anticipated in the near future, medical and scientific communities should be prepared to apply these techniques to further enhance personalized medicine.

  3. Rare genomic variants link bipolar disorder to CREB regulated intracellular signaling pathways

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    Berit eKerner

    2013-11-01

    Full Text Available Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood stabilizing drugs, such as tricyclic antidepressants, lithium and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder.

  4. Efficient retina formation requires suppression of both Activin and BMP signaling pathways in pluripotent cells

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    Kimberly A. Wong

    2015-03-01

    Full Text Available Retina formation requires the correct spatiotemporal patterning of key regulatory factors. While it is known that repression of several signaling pathways lead to specification of retinal fates, addition of only Noggin, a known BMP antagonist, can convert pluripotent Xenopus laevis animal cap cells to functional retinal cells. The aim of this study is to determine the intracellular molecular events that occur during this conversion. Surprisingly, blocking BMP signaling alone failed to mimic Noggin treatment. Overexpressing Noggin in pluripotent cells resulted in a concentration-dependent suppression of both Smad1 and Smad2 phosphorylation, which act downstream of BMP and Activin signaling, respectively. This caused a decrease in downstream targets: endothelial marker, xk81, and mesodermal marker, xbra. We treated pluripotent cells with dominant-negative receptors or the chemical inhibitors, dorsomorphin and SB431542, which each target either the BMP or Activin signaling pathway. We determined the effect of these treatments on retina formation using the Animal Cap Transplant (ACT assay; in which treated pluripotent cells were transplanted into the eye field of host embryos. We found that inhibition of Activin signaling, in the presence of BMP signaling inhibition, promotes efficient retinal specification in Xenopus tissue, mimicking the affect of adding Noggin alone. In whole embryos, we found that the eye field marker, rax, expanded when adding both dominant-negative Smad1 and Smad2, as did treating the cells with both dorsomorphin and SB431542. Future studies could translate these findings to a mammalian culture assay, in order to more efficiently produce retinal cells in culture.

  5. Transcriptional gene expression profiles of HGF/SF-met signaling pathway in colorectal carcinoma

    Institute of Scientific and Technical Information of China (English)

    Xue-Nong Li; Yan-Qing Ding; Guo-Bing Liu

    2003-01-01

    AIM: To explore the transcriptional gene expression profiles of HGF/SF-met signaling pathway in colorectal carcinoma to understand mechanisms of the signaling pathway at so gene level.METHODS: Total RNA was isolated from human colorectal carcinoma cell line LoVo treated with HGF/SF (80 ng/L)for 48 h. Fluorescent probes were prepared from RNA labeled with cy3-dUTP for the control groups and with cy5-dUTP for the HGF/SF-treated groups through reversetranscription. The probes were mixed and hybridized on the microarray at 60 ℃ for 15-20 h, then the microarray was scanned by laser scanner (GenePix 4000B). The intensity of each spot and ratios of Cy5/Cy3 were analyzed and finally the differentially expressed genes were selected by GenePix Pro 3.0 software. 6 differential expression genes (3 up-regulated genes and 3 down-regulated genes) were selected randomly and analyzed by β-actin semiquantitative RT-PCR.RESULTS: The fluorescent intensities of built-in negative control spots were less than 200, and the fluorescent intensities of positive control spots were more than 5000.Of the 4004 human genes analyzed by microarray, 129 genes (holding 3.22 % of the investigated genes) revealed differential expression in HGF/SF-treated groups compared with the control groups, of which 61 genes were up-regulated (holding 1.52 % of the investigated genes) and 68 genes were down-regulated (holding 1.70 % of the investigated genes), which supplied abundant information about target genes of HGF/SF-met signaling.CONCLUSION: HGF/SF-met signaling may up-regulate oncogenes, signal transduction genes, apoptosis-related genes, metastasis related genes, and down-regulate a number of genes. The complexity of HGF/SF-met signaling to control the gene expression is revealed as a whole by the gene chip technology.

  6. Multifunctional DDX3: dual roles in various cancer development and its related signaling pathways

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    Zhao, Luqing; Mao, Yitao; Zhou, Jianhua; Zhao, Yuelong; Cao, Ya; Chen, Xiang

    2016-01-01

    DEAD-box RNA helicase 3 (DDX3) is a highly conserved family member of DEAD-box protein, which is a cluster of ATP-dependent and the largest family of RNA helicase. DEAD-box family is characterized by the regulation of ATPase and helicase activities, the modulation of RNA metabolism, and the actors of RNA binding proteins or molecular chaperones to interact with other proteins or RNA. For DDX3, it exerts its multifaceted roles in viral manipulation, stress response, hypoxia, radiation response and apoptosis, and is closely related to cancer development and progression. DDX3 has dual roles in different cancer types and can act as either an oncogene or tumor suppressor gene during cancer progression. In the present review, we mainly provide an overview of current knowledge on dual roles of DDX3 in various types of cancer, including breast cancer, lung cancer, colorectal cancer, hepatocellular carcinoma, oral squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme and gallbladder carcinoma, and illustrate the regulatory mechanisms for leading these two controversial biological effects. Furthermore, we summarize the essential signaling pathways that DDX3 participated, especially the Wnt/β-catenin signaling and EMT related signaling (TGF-β, Notch, Hedgehog pathways), which are crucial to DDX3 mediated cancer metastasis process. Thoroughly exploring the dual roles of DDX3 in cancer development and the essential signaling pathways it involved, it will help us open new perspectives to develop novel promising targets to elevate therapeutic effects and facilitate the “Personalized medicine” or “Precision medicine” to come into clinic.

  7. Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival.

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    Yang, Ju Dong; Sun, Zhifu; Hu, Chunling; Lai, Jinping; Dove, Rebecca; Nakamura, Ikuo; Lee, Ju-Seog; Thorgeirsson, Snorri S; Kang, Koo Jeong; Chu, In-Sun; Roberts, Lewis R

    2011-02-01

    The heparin-degrading endosulfatases sulfatase 1 (SULF1) and sulfatase 2 (SULF2) have opposing effects in hepatocarcinogenesis despite structural similarity. Using mRNA expression arrays, we analyzed the correlations of SULF expression with signaling networks in human hepatocellular carcinomas (HCCs) and the associations of SULF expression with tumor phenotype and patient survival. Data from two mRNA microarray analyses of 139 and 36 HCCs and adjacent tissues were used as training and validation sets. Partek and Metacore software were used to identify SULF correlated genes and their associated signaling pathways. Associations between SULF expression, the hepatoblast subtype of HCC, and survival were examined. Both SULF1 and 2 had strong positive correlations with periostin, IQGAP1, TGFB1, and vimentin and inverse correlations with HNF4A and IQGAP2. Genes correlated with both SULFs were highly associated with the cell adhesion, cytoskeletal remodeling, blood coagulation, TGFB, and Wnt/β-catenin and epithelial mesenchymal transition signaling pathways. Genes uniquely correlated with SULF2 were more associated with neoplastic processes than genes uniquely correlated with SULF1. High SULF expression was associated with the hepatoblast subtype of HCC. There was a bimodal effect of SULF1 expression on prognosis, with patients in the lowest or highest tertile having a worse prognosis than those in the middle tertile. SULFs have complex effects on HCC signaling and patient survival. There are functionally similar associations with cell adhesion, ECM remodeling, TGFB, and WNT pathways, but also unique associations of SULF1 and SULF2. The roles and targeting of the SULFs in cancer require further investigation. PMID:21104785

  8. The signal transduction pathways and molecules for ES cells self-renewal

    Institute of Scientific and Technical Information of China (English)

    LIU Na; LU Min

    2005-01-01

    Embryonic stem cells (ES cells) are derived from the inner cell mass (ICM) of blastocysts. ES cells can divide and produce identical copies of them over and over again (self-renewal) in vitro for a long time, and retain the capability of differentiating into all cell types when induced by appropriate signals. Their capability of multilineage differentiation might be exploited for cell-based therapies. Therefore, ES cells have a broad prospect in many clinical applications. To achieve success in the clinical applications, we have to understand how ES cells propagate and differentiate into specific cell types. The cytokine LIF can sustain the self-renewal of certain mouse ES cells (mES cells) through activation of the signal transduction pathway LIF/gp130/ STAT3. In this pathway the transcription factor STAT3 is a crucial factor. Furthermore, Oct-3/4 plays a very important role in maintaining the ES cell pluripotency. Oct-3/4 regulates embryo development through its co-factor Sox2 and Rox-1. Recently nanog, a new homeodomain gene, was found and it has been shown to be crucial for the renewal and pluripotency of ES cells. Three other signals BMP, Wnt and ERK also can influence differentiation and propagation of ES cells. This review article summarizes recent progress in this area, mainly focusing on the LIF signaling pathway and the transcription factors Oct-3/4 and Nanog. Although it is still unclear how these components cooperate, a model is presented here to provide a design for solving this problem.

  9. Trichoderma Biocontrol: Signal Transduction Pathways Involved in Host Sensing and Mycoparasitism

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    Susanne Zeilinger

    2007-01-01

    Full Text Available Fungi of the genus Trichoderma are used as biocontrol agents against several plant pathogenic fungi like Rhizoctonia spp., Pythium spp., Botrytis cinerea and Fusarium spp. which cause both soil-borne and leaf- or flower-borne diseases of agricultural plants. Plant disease control by Trichoderma is based on complex interactions between Trichoderma, the plant pathogen and the plant. Until now, two main components of biocontrol have been identified: direct activity of Trichoderma against the plant pathogen by mycoparasitism and induced systemic resistance in plants. As the mycoparasitic interaction is host-specific and not merely a contact response, it is likely that signals from the host fungus are recognised by Trichoderma and provoke transcription of mycoparasitism-related genes.In the last few years examination of signalling pathways underlying Trichoderma biocontrol started and it was shown that heterotrimeric G-proteins and mitogen-activated protein (MAP kinases affected biocontrol-relevant processes such as the production of hydrolytic enzymes and antifungal metabolites and the formation of infection structures. MAPK signalling was also found to be involved in induction of plant systemic resistance in Trichoderma virens and in the hyperosmotic stress response in Trichoderma harzianum. Analyses of the function of components of the cAMP pathway during Trichoderma biocontrol revealed that mycoparasitism-associated coiling and chitinase production as well as secondary metabolism are affected by the internal cAMP level; in addition, a cross talk between regulation of light responses and the cAMP signalling pathway was found in Trichoderma atroviride.

  10. Cooperation of Notch and Ras/MAPK signaling pathways in human breast carcinogenesis

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    Dey Devaveena

    2009-12-01

    Full Text Available Abstract Background Recent studies have implicated aberrant Notch signaling in breast cancers. Yet, relatively little is known about the pattern of expression of various components of the Notch pathway, or its mechanism of action. To better understand the role of the Notch pathway in breast cancer, we have undertaken a detailed expression analysis of various Notch receptors, their ligands, and downstream targets at different stages of breast cancer progression. Results We report here that there is a general increase in the expression levels of Notch 1, 2, 4, Jagged1, Jagged2, and Delta-like 4 proteins in breast cancers, with simultaneous upregulation of multiple Notch receptors and ligands in a given cancer tissue. While Notch3 and Delta-like1 were undetectable in normal tissues, moderate to high expression was detected in several cancers. We detected the presence of active, cleaved Notch1, along with downstream targets of the Notch pathway, Hes1/Hes5, in ~75% of breast cancers, clearly indicating that in a large proportion of breast cancers Notch signaling is aberrantly activated. Furthermore, we detected cleaved Notch1 and Hes1/5 in early precursors of breast cancers - hyperplasia and ductal carcinoma in situ - suggesting that aberrant Notch activation may be an early event in breast cancer progression. Mechanistically, while constitutively active Notch1 alone failed to transform immortalized breast cells, it synergized with the Ras/MAPK pathway to mediate transformation. This cooperation is reflected in vivo, as a subset of cleaved Notch positive tumors additionally expressed phopsho-Erk1/2 in the nuclei. Such cases exhibited high node positivity, suggesting that Notch-Ras cooperation may lead to poor prognosis. Conclusions High level expression of Notch receptors and ligands, and its increased activation in several breast cancers and early precursors, places Notch signaling as a key player in breast cancer pathogenesis. Its cooperation with

  11. Characterization of gene expression and activated signaling pathways in solid-pseudopapillary neoplasm of pancreas.

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    Park, Minhee; Kim, Minhyung; Hwang, Daehee; Park, Misun; Kim, Won Kyu; Kim, Sang Kyum; Shin, Jihye; Park, Eun Sung; Kang, Chang Moo; Paik, Young-Ki; Kim, Hoguen

    2014-04-01

    Solid-pseudopapillary neoplasm is an uncommon pancreatic tumor with distinct clinicopathologic features. Solid-pseudopapillary neoplasms are characterized by mutations in exon 3 of CTNNB1. However, little is known about the gene and microRNA expression profiles of solid-pseudopapillary neoplasms. Thus, we sought to characterize solid-pseudopapillary neoplasm-specific gene expression and identify the signaling pathways activated in these tumors. Comparisons of gene expression in solid-pseudopapillary neoplasm to pancreatic ductal carcinomas, neuroendocrine tumors, and non-neoplastic pancreatic tissues identified solid-pseudopapillary neoplasm-specific mRNA and microRNA profiles. By analyzing 1686 (1119 upregulated and 567 downregulated) genes differentially expressed in solid-pseudopapillary neoplasm, we found that the Wnt/β-catenin, Hedgehog, and androgen receptor signaling pathways, as well as genes involved in epithelial mesenchymal transition, are activated in solid-pseudopapillary neoplasms. We validated these results experimentally by assessing the expression of β-catenin, WIF-1, GLI2, androgen receptor, and epithelial-mesenchymal transition-related markers with western blotting and immunohistochemistry. Our analysis also revealed 17 microRNAs, especially the miR-200 family and miR-192/215, closely associated with the upregulated genes associated with the three pathways activated in solid-pseudopapillary neoplasm and epithelial mesenchymal transition. Our results provide insight into the molecular mechanisms underlying solid-pseudopapillary neoplasm tumorigenesis and its characteristic less epithelial cell differentiation than the other common pancreatic tumors. PMID:24072181

  12. Environmental Enrichment Attenuated Sevoflurane-Induced Neurotoxicity through the PPAR-γ Signaling Pathway

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    Yupeng Zhao

    2015-01-01

    Full Text Available Sevoflurane is the most widely used inhaled anesthetic. Environmental enrichment (EE can reverse sevoflurane-induced learning and memory impairment in young mice. However, the mechanism by which EE elicits this effect is unclear. The peroxisome proliferator-activated receptor (PPAR regulatory pathway plays a critical role in the regulation of inflammation in central nervous system diseases. In this study, we investigated whether EE attenuates sevoflurane-induced learning and memory disability via the PPAR signaling pathway. Six-day-old mice were treated with 3% sevoflurane for 2 hours daily from postnatal day 6 (P6 to P8. Then, the mice were treated with EE. The effects of sevoflurane on learning and memory function, PPAR-γ expression in the brain, and the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and 5-bromodeoxyuridine-positive cells in the hippocampus were determined. Sevoflurane induced neuronal apoptosis and neurogenesis inhibition, which may impair learning and memory in young mice. Furthermore, sevoflurane downregulated PPAR-γ expression. Both EE and the PPAR-γ agonist, rosiglitazone, attenuated sevoflurane-induced neuronal apoptosis, neurogenesis inhibition, and learning and memory impairment. Our findings suggest that EE ameliorated sevoflurane-induced neurotoxicity and learning and memory impairment through the PPAR-γ signaling pathway. PPAR-γ may be a potential therapeutic target for preventing or treating sevoflurane-induced neurotoxicity.

  13. Sitagliptin attenuates cardiomyopathy by modulating the JAK/STAT signaling pathway in experimental diabetic rats

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    Al-Rasheed, Nouf M; Al-Rasheed, Nawal M; Hasan, Iman H; Al-Amin, Maha A; Al-Ajmi, Hanaa N; Mahmoud, Ayman M

    2016-01-01

    Sitagliptin, a dipeptidyl peptidase-4 inhibitor, has been reported to promote cardioprotection in diabetic hearts by limiting hyperglycemia and hyperlipidemia. However, little is known about the involvement of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway modulation in the cardioprotective effects of sitagliptin. The current study aimed to investigate the protective effects of sitagliptin against diabetic cardiomyopathy (DCM), focusing on the modulation of the JAK/STAT pathway. Diabetes was induced by streptozotocin injection, and rats received sitagliptin orally and daily for 90 days. Diabetic rats exhibited hyperglycemia, hyperlipidemia, and a significant increase in heart-to-body weight (HW/BW) ratio. Serum troponin I and creatine kinase MB, cardiac interleukin-6 (IL-6), lipid peroxidation, and nitric oxide levels showed significant increase in diabetic rats. In contrast, both enzymatic and nonenzymatic antioxidant defenses were significantly declined in the heart of diabetic rats. Histopathological study revealed degenerations, increased collagen deposition in the heart of diabetic rats. Sitagliptin alleviated hyperglycemia, hyperlipidemia, HW/BW ratio, histological architecture, oxidative stress, and inflammation, and rejuvenated the antioxidant defenses. In addition, cardiac levels of pJAK2 and pSTAT3 were increased in diabetic rats, an effect which was remarkably decreased after sitagliptin treatment. In conclusion, these results confer an evidence that sitagliptin has great therapeutic potential on DCM through down-regulation of the JAK/STAT signaling pathway.

  14. Signaling pathway-focused gene expression profiling in pressure overloaded hearts

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    Marco Musumeci

    2011-01-01

    Full Text Available The β-blocker propranolol displays antihypertrophic and antifibrotic properties in the heart subjected to pressure overload. Yet the underlying mechanisms responsible for these important effects remain to be completely understood. The purpose of this study was to determine signaling pathway-focused gene expression profile associated with the antihypertrophic action of propranolol in pressure overloaded hearts. To address this question, a focused real-time PCR array was used to screen left ventricular RNA expression of 84 gene transcripts representative of 18 different signaling pathways in C57BL/6 mice subjected to transverse aortic constriction (TAC or sham surgery. On the surgery day, mice received either propranolol (80 mg/kg/day or vehicle for 14 days. TAC caused a 49% increase in the left ventricular weight-to-body weight (LVW/BW ratio without changing gene expression. Propranolol blunted LVW/BW ratio increase by approximately 50% while causing about a 3-fold increase in the expression of two genes, namely Brca1 and Cdkn2a, belonging to the TGF-beta and estrogen pathways, respectively. In conclusion, after 2 weeks of pressure overload, TAC hearts show a gene expression profile superimposable to that of sham hearts. Conversely, propranolol treatment is associated with an increased expression of genes which negatively regulate cell cycle progression. It remains to be established whether a mechanistic link between gene expression changes and the antihypertrophic action of propranolol occurs.

  15. Reinstate the Damaged VEGF Signaling Pathway with VEGF-activating Transcription Factor

    Institute of Scientific and Technical Information of China (English)

    Yao-guo Yang; Heng Guan; Chang-wei Liu; Yong-jun Li

    2009-01-01

    Objective To investigate the role of vascular endothelial growth factor-activating transcriptional factor(VEGF-ATF)on the VEGF signaling pathway in diabetes mellitus.Methods Totally,20 C57BL/6 mice fed with high fat diet was induced into diabetes mellitus.Ten diabetes mellitus mice received a lower limb muscle injection with VEGF-ATF plasmid,and another ten were as control.VEGF-ATF is an engineered transcription factor designed to increase VEGF expression.Three days later,mice were sacrificed and the injected gastrocnemius was used for analysis.VEGF mRNA and protein expressions were examined by real-time PCR and ELISA respectively.VEGF receptor 2 mRNA expression was tested with RT-PCR.Phosphorylated Akt,Akt,endothelial nitric oxide synthase(eNOS),and phosphorylated eNOS were assessed by western blot.Results At 3 days post-injection,in mice with diabetes mellitus,VEGF gene transfer increased VEGF mRNA copies and VEGF protein expression in injected muscles compared with control;and reinstated the impaired VEGF signaling pathway with increasing the ratios of phosphorylated Akt/Akt and phosphorylated eNOS/eNOS.However,it did not affect the expression of VEGF receptor 2 mRNA.Conclusion Gene transfer with VEGF-ATF is able to reinstate the impaired VEGF downstream pathway,and potentially promote therapeutic angiogenesis in mice with diabetes mcllitus.

  16. Intracellular Signaling Pathways Involved in Childhood Acute Lymphoblastic Leukemia; Molecular Targets.

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    Layton Tovar, Cristian Fabián; Mendieta Zerón, Hugo

    2016-06-01

    Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by an uncontrolled proliferation of immature lymphoid cells. ALL is the most common hematologic malignancy in early childhood, and it reaches peak incidence between the ages of 2 and 3 years. The prognosis of ALL is associated with aberrant gene expression, in addition to the presence of numerical or structural chromosomal alterations, age, race, and immunophenotype. The Relapse rate with regard to pharmacological treatment rises in childhood; thus, the expression of biomarkers associated with the activation of cell signaling pathways is crucial to establish the disease prognosis. Intracellular pathways involved in ALL are diverse, including Janus kinase/Signal transducers and transcription activators (JAK-STAT), Phosphoinositide-3-kinase-protein kinase B (PI3K-AKT), Ras mitogen-activated protein kinase (Ras-MAPK), Glycogen synthase kinase-3β (GSK-3β), Nuclear factor-kappa beta (NF-κB), and Hypoxia-inducible transcription factor 1α (HIF-1α), among others. In this review, we present several therapeutic targets, intracellular pathways, and molecular markers that are being studied extensively at present. PMID:27065575

  17. The Potential of Vitamin D-Regulated Intracellular Signaling Pathways as Targets for Myeloid Leukemia Therapy

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    Elzbieta Gocek

    2015-03-01

    Full Text Available The current standard regimens for the treatment of acute myeloid leukemia (AML are curative in less than half of patients; therefore, there is a great need for innovative new approaches to this problem. One approach is to target new treatments to the pathways that are instrumental to cell growth and survival with drugs that are less harmful to normal cells than to neoplastic cells. In this review, we focus on the MAPK family of signaling pathways and those that are known to, or potentially can, interact with MAPKs, such as PI3K/AKT/FOXO and JAK/STAT. We exemplify the recent studies in this field with specific relevance to vitamin D and its derivatives, since they have featured prominently in recent scientific literature as having anti-cancer properties. Since microRNAs also are known to be regulated by activated vitamin D, this is also briefly discussed here, as are the implications of the emerging acquisition of transcriptosome data and potentiation of the biological effects of vitamin D by other compounds. While there are ongoing clinical trials of various compounds that affect signaling pathways, more studies are needed to establish the clinical utility of vitamin D in the treatment of cancer.

  18. Stem cell signaling as a target for novel drug discovery: recent progress in the WNT and Hedgehog pathways

    Institute of Scientific and Technical Information of China (English)

    Songzhu Michael AN; Qiang Peter DING; Ling-song LI

    2013-01-01

    One of the most exciting fields in biomedical research over the past few years is stem cell biology,and therapeutic application of stem cells to replace the diseased or damaged tissues is also an active area in development.Although stem cell therapy has a number of technical challenges and regulatory hurdles to overcome,the use of stem cells as tools in drug discovery supported by mature technologies and established regulatory paths is expected to generate more immediate returns.In particular,the targeting of stem cell signaling pathways is opening up a new avenue for drug discovery.Aberrations in these pathways result in various diseases,including cancer,fibrosis and degenerative diseases.A number of drug targets in stem cell signaling pathways have been identified.Among them,WNT and Hedgehog are two most important signaling pathways,which are the focus of this review.A hedgehog pathway inhibitor,vismodegib (Erivedge),has recently been approved by the US FDA for the treatment of skin cancer,while several drug candidates for the WNT pathway are entering clinical trials.We have discovered that the stem cell signaling pathways respond to traditional Chinese medicines.Substances isolated from herbal medicine may act specifically on components of stem cell signaling pathways with high affinities.As many of these events can be explained through molecular interactions,these phenomena suggest that discovery of stem cell-targeting drugs from natural products may prove to be highly successful.

  19. Expression profile of critical genes involved in FGF signaling pathway in the developing human primary dentition.

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    Huang, Feng; Hu, Xiaoxiao; Fang, Chunni; Liu, Hong; Lin, Chensheng; Zhang, Yanding; Hu, Xuefeng

    2015-11-01

    Mammalian tooth development is regulated by paracrine signal molecules of several conserved family interactions between epithelium and mesenchyme. The expression patterns and regulative roles of FGF signaling have been extensively studied in the mouse odontogenesis; however, that is not well known in human tooth development. In order to unveil the molecular mechanisms that regulate human tooth morphogenesis, we examined the expression patterns of the critical molecules involved in FGF signaling pathway in the developing human tooth germ by in situ hybridization, immunohistochemistry, and real-time RT-PCR, including FGF ligands, receptors, and intracellular transducer. We found overlapping but distinct expression pattern of FGF ligands and receptors in the different stages and components. Expression of FGF4, FGF7, FGF8, and FGF9 persists widespread in human tooth mesenchyme, which is quite different to that of in mouse. FGFR1 may be the major receptor in regulate mechanisms of FGF signals in human tooth development. Real-time RT-PCR indeed confirmed the results of in situ hybridization. Results of K-Ras, p-ERK1/2, p-p38, p-JNK, and p-PDK1 expression reveal spatial and temporal patterns of FGF signaling during morphogenesis and organogenesis of human tooth germ. Activity of the FGF signaling transducer protein in human tooth germ was much higher than that of in mouse. Our results provided important FGF singling information in the developing process, pinpoint to the domains where the downstream target genes of FGF signaling can be sought, and enlightened our knowledge about the nature of FGF signaling in human tooth germ. PMID:26266341

  20. Non-small-cell lung carcinoma: role of the Notch signaling pathway

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    Barse L

    2015-06-01

    conditions, such as hypoxia. Keywords: Notch-1, Notch-3, developmental signaling pathways, Notch inhibitors, NSCLC progenitor cells, CBF-1, MamL

  1. Differential gene expressions of the MAPK signaling pathway in enterovirus 71-infected rhabdomyosarcoma cells

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    Weifeng Shi

    2013-08-01

    Full Text Available BACKGROUND: Mitogen-activated protein kinase (MAPK signaling pathway plays an important role in response to viral infection. The aim of this study was to explore the function and mechanism of MAPK signaling pathway in enterovirus 71 (EV71 infection of human rhabdomyosarcoma (RD cells. METHODS: Apoptosis of RD cells was observed using annexin V-FITC/PI binding assay under a fluorescence microscope. Cellular RNA was extracted and transcribed to cDNA. The expressions of 56 genes of MAPK signaling pathway in EV71-infected RD cells at 8 h and 20 h after infection were analyzed by PCR array. The levels of IL-2, IL-4, IL-10, and TNF-α in the supernatant of RD cells infected with EV71 at different time points were measured by ELISA. RESULTS: The viability of RD cells decreased obviously within 48 h after EV71 infection. Compared with the control group, EV71 infection resulted in the significantly enhanced releases of IL-2, IL-4, IL-10 and TNF-α from infected RD cells (p < 0.05. At 8 h after infection, the expressions of c-Jun, c-Fos, IFN-i, MEKK1, MLK3 and NIK genes in EV71-infected RD cells were up-regulated by 2.08-6.12-fold, whereas other 19 genes (e.g. AKT1, AKT2, E2F1, IKK and NF-κB1 exhibited down-regulation. However, at 20 h after infection, those MAPK signaling molecules including MEKK1, ASK1, MLK2, MLK3, NIK, MEK1, MEK2, MEK4, MEK7, ERK1, JNK1 and JNK2 were up-regulated. In addition, the expressions of AKT2, ELK1, c-Jun, c-Fos, NF-κB p65, PI3K and STAT1 were also increased. CONCLUSION: EV71 infection induces the differential gene expressions of MAPK signaling pathway such as ERK, JNK and PI3K/AKT in RD cells, which may be associated with the secretions of inflammatory cytokines and host cell apoptosis.

  2. Endogenous Sulfur Dioxide Inhibits Vascular Calcification in Association with the TGF-β/Smad Signaling Pathway.

    Science.gov (United States)

    Li, Zhenzhen; Huang, Yaqian; Du, Junbao; Liu, Angie Dong; Tang, Chaoshu; Qi, Yongfen; Jin, Hongfang

    2016-01-01

    The study was designed to investigate whether endogenous sulfur dioxide (SO₂) plays a role in vascular calcification (VC) in rats and its possible mechanisms. In vivo medial vascular calcification was induced in rats by vitamin D3 and nicotine for four weeks. In vitro calcification of cultured A7r5 vascular smooth muscle cells (VSMCs) was induced by calcifying media containing 5 mmol/L CaCl₂. Aortic smooth muscle (SM) α-actin, runt-related transcription factor 2 (Runx2), transforming growth factor-β (TGF-β) and Smad expression was measured. VC rats showed dispersed calcified nodules among the elastic fibers in calcified aorta with increased aortic calcium content and alkaline phosphatase (ALP) activity. SM α-actin was markedly decreased, but the osteochondrogenic marker Runx2 concomitantly increased and TGF-β/Smad signaling was activated, in association with the downregulated SO₂/aspartate aminotransferase (AAT) pathway. However, SO₂ supplementation successfully ameliorated vascular calcification, and increased SM α-actin expression, but inhibited Runx2 and TGF-β/Smad expression. In calcified A7r5 VSMCs, the endogenous SO₂/AAT pathway was significantly downregulated. SO₂ treatment reduced the calcium deposits, calcium content, ALP activity and Runx2 expression and downregulated the TGF-β/Smad pathway in A7r5 cells but increased SM α-actin expression. In brief, SO₂ significantly ameliorated vascular calcification in association with downregulation of the TGF-β/Smad pathway. PMID:26907267

  3. Analysis of EGFR signaling pathway in nasopharyngeal carcinoma cells by quantitative phosphoproteomics

    Directory of Open Access Journals (Sweden)

    He Qiu-Yan

    2011-06-01

    Full Text Available Abstract Background The epidermal growth factor receptor (EGFR is usually overexpressed in nasopharyngeal carcinoma (NPC and is associated with pathogenesis of NPC. However, the downstream signaling proteins of EGFR in NPC have not yet been completely understood at the system level. The aim of this study was identify novel downstream proteins of EGFR signaling pathway in NPC cells. Results We analyzed EGFR-regulated phosphoproteome in NPC CNE2 cells using 2D-DIGE and mass spectrometry analysis after phosphoprotein enrichment. As a result, 33 nonredundant phosphoproteins including five known EGFR-regulated proteins and twenty-eight novel EGFR-regulated proteins in CNE2 were identified, three differential phosphoproteins were selectively validated, and two differential phosphoproteins (GSTP1 and GRB2 were showed interacted with phospho-EGFR. Bioinformatics analysis showed that 32 of 33 identified proteins contain phosphorylation modification sites, and 17 identified proteins are signaling proteins. GSTP1, one of the EGFR-regulated proteins, associated with chemoresistance was analyzed. The results showed that GSTP1 could contribute to paclitaxel resistance in EGF-stimulated CNE2 cells. Furthermore, an EGFR signaling network based on the identified EGFR-regulated phosphoproteins were constructed using Pathway Studio 5.0 software, which includes canonical and novel EGFR-regulated proteins and implicates the possible biological roles for those proteins. Conclusion The data not only can extend our knowledge of canonical EGFR signaling, but also will be useful to understand the molecular mechanisms of EGFR in NPC pathogenesis and search therapeutic targets for NPC.

  4. Analysis of Human TAAR8 and Murine Taar8b Mediated Signaling Pathways and Expression Profile

    Directory of Open Access Journals (Sweden)

    Jessica Mühlhaus

    2014-11-01

    Full Text Available The thyroid hormone derivative 3-iodothyronamine (3-T1AM exerts metabolic effects in vivo that contradict known effects of thyroid hormones. 3-T1AM acts as a trace amine-associated receptor 1 (TAAR1 agonist and activates Gs signaling in vitro. Interestingly, 3-T1AM-meditated in vivo effects persist in Taar1 knockout-mice indicating that further targets of 3-T1AM might exist. Here, we investigated another member of the TAAR family, the only scarcely studied mouse and human trace-amine-associated receptor 8 (Taar8b, TAAR8. By RT-qPCR and locked-nucleic-acid (LNA in situ hybridization, Taar8b expression in different mouse tissues was analyzed. Functionally, we characterized TAAR8 and Taar8b with regard to cell surface expression and signaling via different G-protein-mediated pathways. Cell surface expression was verified by ELISA, and cAMP accumulation was quantified by AlphaScreen for detection of Gs and/or Gi/o signaling. Activation of G-proteins Gq/11 and G12/13 was analyzed by reporter gene assays. Expression analyses revealed at most marginal Taar8b expression and no gender differences for almost all analyzed tissues. In heart, LNA-in situ hybridization demonstrated the absence of Taar8b expression. We could not identify 3-T1AM as a ligand for TAAR8 and Taar8b, but both receptors were characterized by a basal Gi/o signaling activity, a so far unknown signaling pathway for TAARs.

  5. Analysis of Human TAAR8 and Murine Taar8b Mediated Signaling Pathways and Expression Profile

    Science.gov (United States)

    Mühlhaus, Jessica; Dinter, Juliane; Nürnberg, Daniela; Rehders, Maren; Depke, Maren; Golchert, Janine; Homuth, Georg; Yi, Chun-Xia; Morin, Silke; Köhrle, Josef; Brix, Klaudia; Tschöp, Matthias; Kleinau, Gunnar; Biebermann, Heike

    2014-01-01

    The thyroid hormone derivative 3-iodothyronamine (3-T1AM) exerts metabolic effects in vivo that contradict known effects of thyroid hormones. 3-T1AM acts as a trace amine-associated receptor 1 (TAAR1) agonist and activates Gs signaling in vitro. Interestingly, 3-T1AM-meditated in vivo effects persist in Taar1 knockout-mice indicating that further targets of 3-T1AM might exist. Here, we investigated another member of the TAAR family, the only scarcely studied mouse and human trace-amine-associated receptor 8 (Taar8b, TAAR8). By RT-qPCR and locked-nucleic-acid (LNA) in situ hybridization, Taar8b expression in different mouse tissues was analyzed. Functionally, we characterized TAAR8 and Taar8b with regard to cell surface expression and signaling via different G-protein-mediated pathways. Cell surface expression was verified by ELISA, and cAMP accumulation was quantified by AlphaScreen for detection of Gs and/or Gi/o signaling. Activation of G-proteins Gq/11 and G12/13 was analyzed by reporter gene assays. Expression analyses revealed at most marginal Taar8b expression and no gender differences for almost all analyzed tissues. In heart, LNA-in situ hybridization demonstrated the absence of Taar8b expression. We could not identify 3-T1AM as a ligand for TAAR8 and Taar8b, but both receptors were characterized by a basal Gi/o signaling activity, a so far unknown signaling pathway for TAARs. PMID:25391046

  6. Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery

    Directory of Open Access Journals (Sweden)

    Steinau Hans-Ulrich

    2011-01-01

    Full Text Available Abstract Background Adenoviral vectors have provided effective methods for in vivo gene delivery in therapeutic applications. However, these vectors can induce immune responses that may severely affect the ability of vector re-application. There is limited information about the mechanisms and signal transduction pathways involved in adenoviral recognition. For optimization of cutaneous gene therapy it is necessary to investigate molecular mechanisms of virus recognition in epidermal cells. The aim of this study was to investigate the signal transduction of the innate immunity after adenoviral DNA internalization in keratinocytes. Methods In vitro, keratinocytes were transfected with DNA, in the presence and absence of inhibitors for signalling molecules. In vivo, immunocompetent and athymic mice (n = 3 per group were twice transduced with an Ad-vector. Results The results show an acute induction of type-I-interferon after in vitro transfection. Inhibition of PI3K, p38 MAPK, JNK and NFkappaB resulted in a decreased expression of type-I-interferon. In contrast to immunocompetent mice, athymic mice demonstrated a constant transgene expression and reduced inflammatory response in vivo. Conclusion The results suggest an induction of the innate immunity triggered by cytoplasm localised DNA which is mediated by PI3K-, p38 MAPK-, JNK-, NFkappaB-, JAK/STAT- and ERK1/2-dependent pathways. A stable transgene expression and a reduced inflammatory response in immunodeficient mice have been observed. These results provide potential for an effective adenoviral gene delivery into immunosupressed skin.

  7. Signaling pathways involved in megakaryocyte-mediated proliferation of osteoblast lineage cells.

    Science.gov (United States)

    Cheng, Ying-Hua; Streicher, Drew A; Waning, David L; Chitteti, Brahmananda R; Gerard-O'Riley, Rita; Horowitz, Mark C; Bidwell, Joseph P; Pavalko, Fredrick M; Srour, Edward F; Mayo, Lindsey D; Kacena, Melissa A

    2015-03-01

    Recent studies suggest that megakaryocytes (MKs) may play a significant role in skeletal homeostasis, as evident by the occurrence of osteosclerosis in multiple MK related diseases (Lennert et al., 1975; Thiele et al., 1999; Chagraoui et al., 2006). We previously reported a novel interaction whereby MKs enhanced proliferation of osteoblast lineage/osteoprogenitor cells (OBs) by a mechanism requiring direct cell-cell contact. However, the signal transduction pathways and the downstream effector molecules involved in this process have not been characterized. Here we show that MKs contact with OBs, via beta1 integrin, activate the p38/MAPKAPK2/p90RSK kinase cascade in the bone cells, which causes Mdm2 to neutralizes p53/Rb-mediated check point and allows progression through the G1/S. Interestingly, activation of MAPK (ERK1/2) and AKT, collateral pathways that regulate the cell cycle, remained unchanged with MK stimulation of OBs. The MK-to-OB signaling ultimately results in significant increases in the expression of c-fos and cyclin A, necessary for sustaining the OB proliferation. Overall, our findings show that OBs respond to the presence of MKs, in part, via an integrin-mediated signaling mechanism, activating a novel response axis that de-represses cell cycle activity. Understanding the mechanisms by which MKs enhance OB proliferation will facilitate the development of novel anabolic therapies to treat bone loss associated with osteoporosis and other bone-related diseases. PMID:25160801

  8. Fragment C of Tetanus Toxin: New Insights into Its Neuronal Signaling Pathway

    Directory of Open Access Journals (Sweden)

    José Aguilera

    2012-06-01

    Full Text Available When Clostridium tetani was discovered and identified as a Gram-positive anaerobic bacterium of the genus Clostridium, the possibility of turning its toxin into a valuable biological carrier to ameliorate neurodegenerative processes was inconceivable. However, the non-toxic carboxy-terminal fragment of the tetanus toxin heavy chain (fragment C can be retrogradely transported to the central nervous system; therefore, fragment C has been used as a valuable biological carrier of neurotrophic factors to ameliorate neurodegenerative processes. More recently, the neuroprotective properties of fragment C have also been described in vitro and in vivo, involving the activation of Akt kinase and extracellular signal-regulated kinase (ERK signaling cascades through neurotrophin tyrosine kinase (Trk receptors. Although the precise mechanism of the molecular internalization of fragment C in neuronal cells remains unknown, fragment C could be internalized and translocated into the neuronal cytosol through a clathrin-mediated pathway dependent on proteins, such as dynamin and AP-2. In this review, the origins, molecular properties and possible signaling pathways of fragment C are reviewed to understand the biochemical characteristics of its intracellular and synaptic transport.

  9. Interferon-γ regulates intestinal epithelial homeostasis through converging β-catenin signaling pathways

    Science.gov (United States)

    Nava, Porfirio; Koch, Stefan; Laukoetter, Mike G; Lee, Winston Y; Kolegraff, Keli; Capaldo, Christopher T; Beeman, Neal; Addis, Caroline; Gerner-Smidt, Kirsten; Neumaier, Irmgard; Skerra, Arne; Li, Linheng; Parkos, Charles A; Nusrat, Asma

    2010-01-01

    SUMMARY Inflammatory cytokines have been proposed to regulate epithelial homeostasis during intestinal inflammation. We report here that interferon-γ (IFN-γ) regulates the crucial homeostatic functions of cell proliferation and apoptosis through serine-threonine protein kinase AKT-β-catenin and Wingless-Int (Wnt)-β-catenin signaling pathways. Short-term exposure of intestinal epithelial cells to IFN-γ resulted in activation of β-catenin through AKT, followed by induction of the secreted Wnt inhibitor Dkk1. Consequently, we observed an increase in Dkk1-mediated apoptosis upon extended IFN-γ treatment, and reduced proliferation through depletion of the Wnt co-receptor LRP6. These effects were enhanced by tumor necrosis factor-α (TNF)-α, suggesting synergism between the two cytokines. Consistent with these results, colitis in vivo was associated with decreased β-catenin-T-cell factor (TCF) signaling, loss of plasma membrane-associated LRP6, and reduced epithelial cell proliferation. Proliferation was partially restored in IFN-γ - deficient mice. Thus, we propose that IFN-γ regulates intestinal epithelial homeostasis by sequential regulation of converging β-catenin signaling pathways. PMID:20303298

  10. SLOB, a SLOWPOKE channel binding protein, regulates insulin pathway signaling and metabolism in Drosophila.

    Directory of Open Access Journals (Sweden)

    Amanda L Sheldon

    Full Text Available There is ample evidence that ion channel modulation by accessory proteins within a macromolecular complex can regulate channel activity and thereby impact neuronal excitability. However, the downstream consequences of ion channel modulation remain largely undetermined. The Drosophila melanogaster large conductance calcium-activated potassium channel SLOWPOKE (SLO undergoes modulation via its binding partner SLO-binding protein (SLOB. Regulation of SLO by SLOB influences the voltage dependence of SLO activation and modulates synaptic transmission. SLO and SLOB are expressed especially prominently in median neurosecretory cells (mNSCs in the pars intercerebralis (PI region of the brain; these cells also express and secrete Drosophila insulin like peptides (dILPs. Previously, we found that flies lacking SLOB exhibit increased resistance to starvation, and we reasoned that SLOB may regulate aspects of insulin signaling and metabolism. Here we investigate the role of SLOB in metabolism and find that slob null flies exhibit changes in energy storage and insulin pathway signaling. In addition, slob null flies have decreased levels of dilp3 and increased levels of takeout, a gene known to be involved in feeding and metabolism. Targeted expression of SLOB to mNSCs rescues these alterations in gene expression, as well as the metabolic phenotypes. Analysis of fly lines mutant for both slob and slo indicate that the effect of SLOB on metabolism and gene expression is via SLO. We propose that modulation of SLO by SLOB regulates neurotransmission in mNSCs, influencing downstream insulin pathway signaling and metabolism.

  11. Different roles for anti-sigma factors in siderophore signalling pathways of Pseudomonas aeruginosa.

    Science.gov (United States)

    Mettrick, Karla A; Lamont, Iain L

    2009-12-01

    Group IV (extracytoplasmic function) sigma factors direct the expression of a large number of regulons in bacteria. The activities of many Group IV sigma factors are inhibited by members of a family of anti-sigma factor proteins, with appropriate environmental signals causing the sigma factor to be released for interaction with core RNA polymerase and consequent transcription of target genes. One subgroup of Group IV sigmas directs expression of genes for uptake of siderophores (iron-chelating compounds) by Gram-negative bacteria. The activities of these sigma factors are controlled by anti-sigma factors that span the cytoplasmic membrane. Binding of siderophore by a receptor protein in the outer membrane results in signal transduction from the periplasmic portion to the cytoplasmic portion of the appropriate anti-sigma factor, with consequent activity of the cognate sigma factor and upregulation of the gene encoding the receptor protein. We have investigated receptor/anti-sigma/sigma factor signalling pathways for uptake of the siderophores ferrichrome and desferrioxamine by Pseudomonas aeruginosa. In these pathways the 'anti-sigma' proteins are normally required for sigma factor activity and the cytoplasmic parts of the 'anti-sigmas' have 'pro-sigma' activity. We suggest that the family of anti-sigma factor proteins may be better considered as 'sigma regulators'. PMID:19889096

  12. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis.

    Science.gov (United States)

    Mørk, N; Kofod-Olsen, E; Sørensen, K B; Bach, E; Ørntoft, T F; Østergaard, L; Paludan, S R; Christiansen, M; Mogensen, T H

    2015-12-01

    Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon production downstream of Toll-like receptor (TLR)3. In the present study, we used whole-exome sequencing to investigate the genetic profile of 16 adult patients with a history of HSE. We identified novel mutations in IRF3, TYK2 and MAVS, molecules involved in generating innate antiviral immune responses, which have not previously been associated with HSE. Moreover, data revealed mutations in TLR3, TRIF, TBK1 and STAT1 known to be associated with HSE in children but not previously described in adults. All discovered mutations were heterozygous missense mutations, the majority of which were associated with significantly decreased antiviral responses to HSV-1 infection and/or the TLR3 agonist poly(I:C) in patient peripheral blood mononuclear cells compared with controls. Altogether, this study demonstrates novel mutations in the TLR3 signaling pathway in molecules previously identified in children, suggesting that impaired innate immunity to HSV-1 may also increase susceptibility to HSE in adults. Importantly, the identification of mutations in innate signaling molecules not directly involved in TLR3 signaling suggests the existence of innate immunodeficiencies predisposing to HSE beyond the TLR3 pathway. PMID:26513235

  13. Postprandial activation of metabolic and inflammatory signalling pathways in human peripheral mononuclear cells.

    Science.gov (United States)

    Ehlers, Kerstin; Brand, Tina; Bangert, Adina; Hauner, Hans; Laumen, Helmut

    2014-06-28

    High-fat, high-carbohydrate (HFHC) meals induce an inflammatory response in mononuclear cells (MNC). Here, we studied the interaction between metabolic and inflammatory signalling pathways by the measurement of postprandial effects of three different test meals on intracellular Akt, S6 kinase (S6K)/mammalian target of rapamycin and NF-κB signalling in human MNC. We recruited six healthy, lean individuals. Each individual ingested three different meals in the morning separated by at least 3 d: a HFHC meal; an oral lipid-tolerance test meal; a healthy breakfast. Blood samples were obtained before and 1, 2, 4, 6 and 8 h after ingestion. Plasma insulin and IL-6 levels were measured. Intracellular metabolic and inflammatory signalling pathways were assessed by measuring the phosphorylation of Akt kinase and S6K, the degradation of inhibitory κB-α (IκB-α) protein and the DNA binding activity of NF-κB in MNC. mRNA expression levels of the Akt and NF-κB target genes Mn superoxide dismutase (MnSOD), CC-chemokine-receptor 5 (CCR5), intercellular adhesion molecule 1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) were measured by quantitative RT-PCR. We found a positive correlation of Akt phosphorylation with NF-κB activation (NF-κB binding activity: r 0·4500, P= 0·0003; IκB-α protein levels: r -0·5435, PMNC. PMID:24576401

  14. Silver Nanoparticles Induce HePG-2 Cells Apoptosis Through ROS-Mediated Signaling Pathways.

    Science.gov (United States)

    Zhu, Bing; Li, Yinghua; Lin, Zhengfang; Zhao, Mingqi; Xu, Tiantian; Wang, Changbing; Deng, Ning

    2016-12-01

    Recently, silver nanoparticles (AgNPs) have been shown to provide a novel approach to overcome tumors, especially those of hepatocarcinoma. However, the anticancer mechanism of silver nanoparticles is unclear. Thus, the purpose of this study was to estimate the effect of AgNPs on proliferation and activation of ROS-mediated signaling pathway on human hepatocellular carcinoma HePG-2 cells. A simple chemical method for preparing AgNPs with superior anticancer activity has been showed in this study. AgNPs were detected by transmission electronic microscopy (TEM) and energy dispersive X-ray (EDX). The size distribution and zeta potential of silver nanoparticles were detected by Zetasizer Nano. The average size of AgNPs (2 nm) observably increased the cellular uptake by endocytosis. AgNPs markedly inhibited the proliferation of HePG-2 cells through induction of apoptosis with caspase-3 activation and PARP cleavage. AgNPs with dose-dependent manner significantly increased the apoptotic cell population (sub-G1). Furthermore, AgNP-induced apoptosis was found dependent on the overproduction of reactive oxygen species (ROS) and affecting of MAPKs and AKT signaling and DNA damage-mediated p53 phosphorylation to advance HePG-2 cells apoptosis. Therefore, our results show that the mechanism of ROS-mediated signaling pathways may provide useful information in AgNP-induced HePG-2 cell apoptosis. PMID:27075340

  15. Silver Nanoparticles Induce HePG-2 Cells Apoptosis Through ROS-Mediated Signaling Pathways

    Science.gov (United States)

    Zhu, Bing; Li, Yinghua; Lin, Zhengfang; Zhao, Mingqi; Xu, Tiantian; Wang, Changbing; Deng, Ning

    2016-04-01

    Recently, silver nanoparticles (AgNPs) have been shown to provide a novel approach to overcome tumors, especially those of hepatocarcinoma. However, the anticancer mechanism of silver nanoparticles is unclear. Thus, the purpose of this study was to estimate the effect of AgNPs on proliferation and activation of ROS-mediated signaling pathway on human hepatocellular carcinoma HePG-2 cells. A simple chemical method for preparing AgNPs with superior anticancer activity has been showed in this study. AgNPs were detected by transmission electronic microscopy (TEM) and energy dispersive X-ray (EDX). The size distribution and zeta potential of silver nanoparticles were detected by Zetasizer Nano. The average size of AgNPs (2 nm) observably increased the cellular uptake by endocytosis. AgNPs markedly inhibited the proliferation of HePG-2 cells through induction of apoptosis with caspase-3 activation and PARP cleavage. AgNPs with dose-dependent manner significantly increased the apoptotic cell population (sub-G1). Furthermore, AgNP-induced apoptosis was found dependent on the overproduction of reactive oxygen species (ROS) and affecting of MAPKs and AKT signaling and DNA damage-mediated p53 phosphorylation to advance HePG-2 cells apoptosis. Therefore, our results show that the mechanism of ROS-mediated signaling pathways may provide useful information in AgNP-induced HePG-2 cell apoptosis.

  16. A sophisticated network of signaling pathways regulates stomatal defenses to bacterial pathogens.

    Science.gov (United States)

    Arnaud, Dominique; Hwang, Ildoo

    2015-04-01

    Guard cells are specialized cells forming stomatal pores at the leaf surface for gas exchanges between the plant and the atmosphere. Stomata have been shown to play an important role in plant defense as a part of the innate immune response. Plants actively close their stomata upon contact with microbes, thereby preventing pathogen entry into the leaves and the subsequent colonization of host tissues. In this review, we present current knowledge of molecular mechanisms and signaling pathways implicated in stomatal defenses, with particular emphasis on plant-bacteria interactions. Stomatal defense responses begin from the perception of pathogen-associated molecular patterns (PAMPs) and activate a signaling cascade involving the production of secondary messengers such as reactive oxygen species, nitric oxide, and calcium for the regulation of plasma membrane ion channels. The analyses on downstream molecular mechanisms implicated in PAMP-triggered stomatal closure have revealed extensive interplays among the components regulating hormonal signaling pathways. We also discuss the strategies deployed by pathogenic bacteria to counteract stomatal immunity through the example of the phytotoxin coronatine. PMID:25661059

  17. An in silico approach towards the identification of novel inhibitors of the TLR-4 signaling pathway.

    Science.gov (United States)

    Mahita, Jarjapu; Harini, K; Rao Pichika, Mallikarjuna; Sowdhamini, Ramanathan

    2016-06-01

    Precise functioning and fine-tuning of Toll-like receptor 4 (TLR4) signaling is a critical requirement for the smooth functioning of the innate immune system, since aberrant TLR4 activation causes excessive production of pro-inflammatory cytokines and interferons. This can result in life threatening conditions such as septic shock and other inflammatory disorders. The TRIF-related adaptor molecule (TRAM) adaptor protein is unique to the TLR4 signaling pathway and abrogation of TRAM-mediated TLR4 signaling is a promising strategy for developing therapeutics aimed at disrupting TRAM interactions with other components of the TLR4 signaling complex. The VIPER motif from the vaccinia virus-producing protein, A46 has been reported to disrupt TRAM-TLR4 interactions. We have exploited this information, in combination with homology modeling and docking approaches, to identify a potential binding site on TRAM lined by the BB loop and αC helix. Virtual screening of commercially available small molecules targeting the binding site enabled to short-list 12 small molecules to abrogate TRAM-mediated TLR4 signaling. Molecular dynamics and molecular mechanics calculations have been performed for the analysis of these receptor-ligand interactions. PMID:26264972

  18. Expression and clinical significance of the genes of Hedgehog signaling pathway in sporadic keratocystic odontogenic tumor of the jaw bones

    Institute of Scientific and Technical Information of China (English)

    Kong Li; Yuan Rong-tao; Jia Mu-yun; Wang Ke; Wang Bingchao; Yang Yinhui

    2015-01-01

    PURPOSE It was to study the role of genes of Hedgehog signaling pathway in sporadic keratocystic odontogenic tumor (KCOT)of the jaw bones.METHODS Fresh specimens of sporadic KCOT and the same patient 's normal oral mucosa were obtained.Then RNA was extracted.Gene chip was used to detect the genes of Hedgehog signaling pathway.RESULTS Com-pared to normal oral mucosa,there were five genes of Hedgehog signaling pathway in KCOT changed,including PRKX ,WNT5a,PTCH1 up -regulated.CONCLUSION There were abnormal ex-pressions of genes of Hedgehog pathway in sporadicKCOT.Genes of Hedgehog pathway played roles in sporadic KCOT.

  19. Mediators, Receptors, and Signalling Pathways in the Anti-Inflammatory and Antihyperalgesic Effects of Acupuncture

    Directory of Open Access Journals (Sweden)

    John L. McDonald

    2015-01-01

    Full Text Available Acupuncture has been used for millennia to treat allergic diseases including both intermittent rhinitis and persistent rhinitis. Besides the research on the efficacy and safety of acupuncture treatment for allergic rhinitis, research has also investigated how acupuncture might modulate immune function to exert anti-inflammatory effects. A proposed model has previously hypothesized that acupuncture might downregulate proinflammatory neuropeptides, proinflammatory cytokines, and neurotrophins, modulating transient receptor potential vallinoid (TRPV1, a G-protein coupled receptor which plays a central role in allergic rhinitis. Recent research has been largely supportive of this model. New advances in research include the discovery of a novel cholinergic anti-inflammatory pathway activated by acupuncture. A chemokine-mediated proliferation of opioid-containing macrophages in inflamed tissues, in response to acupuncture, has also been demonstrated for the first time. Further research on the complex cross talk between receptors during inflammation is also helping to elucidate the mediators and signalling pathways activated by acupuncture.

  20. GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway.

    Science.gov (United States)

    Ishida, Hidekazu; Saba, Rie; Kokkinopoulos, Ioannis; Hashimoto, Masakazu; Yamaguchi, Osamu; Nowotschin, Sonja; Shiraishi, Manabu; Ruchaya, Prashant; Miller, Duncan; Harmer, Stephen; Poliandri, Ariel; Kogaki, Shigetoyo; Sakata, Yasushi; Dunkel, Leo; Tinker, Andrew; Hadjantonakis, Anna-Katerina; Sawa, Yoshiki; Sasaki, Hiroshi; Ozono, Keiichi; Suzuki, Ken; Yashiro, Kenta

    2016-07-26

    A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure. PMID:27396331

  1. GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Hidekazu Ishida

    2016-07-01

    Full Text Available A surface marker that distinctly identifies cardiac progenitors (CPs is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2, specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.

  2. Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase

    Science.gov (United States)

    Shimizu, M.; Wang, W.; Walch, E. T.; Dunne, P. W.; Epstein, H. F.

    2000-01-01

    Myotonic dystrophy protein kinase (DMPK) is a serine-threonine protein kinase encoded by the myotonic dystrophy (DM) locus on human chromosome 19q13.3. It is a close relative of other kinases that interact with members of the Rho family of small GTPases. We show here that the actin cytoskeleton-linked GTPase Rac-1 binds to DMPK, and coexpression of Rac-1 and DMPK activates its transphosphorylation activity in a GTP-sensitive manner. DMPK can also bind Raf-1 kinase, the Ras-activated molecule of the MAP kinase pathway. Purified Raf-1 kinase phosphorylates and activates DMPK. The interaction of DMPK with these distinct signals suggests that it may play a role as a nexus for cross-talk between their respective pathways and may partially explain the remarkable pleiotropy of DM.

  3. Mutations in the VEGFR3 signaling pathway explain 36% of familial lymphedema

    DEFF Research Database (Denmark)

    Mendola, A; Schlögel, M J; Ghalamkarpour, A;

    2013-01-01

    , stratification of treatments and generation of disease models. Interestingly, most of the proteins that are encoded by the genes mutated in primary lymphedema seem to act in a single functional pathway involving VEGFR3 signaling. This underscores the important role this pathway plays in lymphatic development and......Lymphedema is caused by dysfunction of lymphatic vessels, leading to disabling swelling that occurs mostly on the extremities. Lymphedema can be either primary (congenital) or secondary (acquired). Familial primary lymphedema commonly segregates in an autosomal dominant or recessive manner. It can...... also occur in combination with other clinical features. Nine mutated genes have been identified in different isolated or syndromic forms of lymphedema. However, the prevalence of primary lymphedema that can be explained by these genetic alterations is unknown. In this study, we investigated 7 of these...

  4. Hedgehog信号通路与骨发育%Hedgehog signaling pathway and bone development

    Institute of Scientific and Technical Information of China (English)

    邹沙沙; 胡洪亮

    2011-01-01

    背景:Hedgehog作为骨发育中一种重要调控因子,近几年其在骨生长中作用机制的研究备受关注.目的:介绍Hedgehog在软骨组织和骨组织发育中的作用机制及其与骨疾病的关系,从而分析Hedgehog信号通路与骨发育的研究现状及发展趋势.方法:应用计算机检索中国期刊全文数据库和PubMed 数据库,以"Hedgehog,骨发育,间充质干细胞,软骨,成骨,骨缺陷"和"Hedgehog,bone development,mesenchymal stem cells,cartilage,osteogenesis,bone defects"为检索词.最终共纳入31篇文献进行综述.结果与结论:Hedgehog信号与骨发育各阶段密切相关,包括间充质细胞向骨细胞分化,软骨组织和骨组织形成等各方面.其信号通路传导异常会导致各种骨畸形或骨缺陷.但是Hedgehog信号在骨发育中的详细作用机制体系尚未完善,相关动物实验技术尚未成熟,国内外尚未出现相关临床实验.由于Hedgehog即参与骨发育,又参与某些胚胎组织的血管重新形成和成年哺乳动物的血管发生,因而有望在修复骨缺损的同时解决骨组织工程血管化的问题.Hedgehog信号通路的研究在骨组织工程及临床基因干预治疗等领域有广阔的前景.%BACKGROUND: Hedgehog, as an important regulatory factor in bone growth, has been recently focused for its mechanism inbone growth.OBJECTIVE: To introduce the mechanisms of Hedgehog in cartilage and skeleton development and the relationship between thehedgehog signalling pathway and bone disease and to investigate the research progress in Hedgehog signalling pathway in bonedevelopment.METHODS: A computer-based online search in PubMed and CNKI database was performed using key words of “Hedgehog, bonedevelopment, mesenchymal stem cells, cartilage, osteogenesis, bone defects” in English and Chinese respecti vely. The publisheddates are limited between January 1994 and December 2010. Researches related to this review purpose were included

  5. KCTD1 suppresses canonical Wnt signaling pathway by enhancing β-catenin degradation.

    Directory of Open Access Journals (Sweden)

    Xinxin Li

    Full Text Available The canonical Wnt signaling pathway controls normal embryonic development, cellular proliferation and growth, and its aberrant activity results in human carcinogenesis. The core component in regulation of this pathway is β-catenin, but molecular regulation mechanisms of β-catenin stability are not completely known. Here, our recent studies have shown that KCTD1 strongly inhibits TCF/LEF reporter activity. Moreover, KCTD1 interacted with β-catenin both in vivo by co-immunoprecipitation as well as in vitro through GST pull-down assays. We further mapped the interaction regions to the 1-9 armadillo repeats of β-catenin and the BTB domain of KCTD1, especially Position Ala-30 and His-33. Immunofluorescence analysis indicated that KCTD1 promotes the cytoplasmic accumulation of β-catenin. Furthermore, protein stability assays revealed that KCTD1 enhances the ubiquitination/degradation of β-catenin in a concentration-dependent manner in HeLa cells. And the degradation of β-catenin mediated by KCTD1 was alleviated by the proteasome inhibitor, MG132. In addition, KCTD1-mediated β-catenin degradation was dependent on casein kinase 1 (CK1- and glycogen synthase kinase-3β (GSK-3β-mediated phosphorylation and enhanced by the E3 ubiquitin ligase β-transducin repeat-containing protein (β-TrCP. Moreover, KCTD1 suppressed the expression of endogenous Wnt downstream genes and transcription factor AP-2α. Finally, we found that Wnt pathway member APC and tumor suppressor p53 influence KCTD1-mediated downregulation of β-catenin. These results suggest that KCTD1 functions as a novel inhibitor of Wnt signaling pathway.

  6. Identification of small molecule compounds that inhibit the HIF-1 signaling pathway

    Directory of Open Access Journals (Sweden)

    Sun Yi

    2009-12-01

    Full Text Available Abstract Background Hypoxia-inducible factor-1 (HIF-1 is the major hypoxia-regulated transcription factor that regulates cellular responses to low oxygen environments. HIF-1 is composed of two subunits: hypoxia-inducible HIF-1α and constitutively-expressed HIF-1β. During hypoxic conditions, HIF-1α heterodimerizes with HIF-1β and translocates to the nucleus where the HIF-1 complex binds to the hypoxia-response element (HRE and activates expression of target genes implicated in cell growth and survival. HIF-1α protein expression is elevated in many solid tumors, including those of the cervix and brain, where cells that are the greatest distance from blood vessels, and therefore the most hypoxic, express the highest levels of HIF-1α. Therapeutic blockade of the HIF-1 signaling pathway in cancer cells therefore provides an attractive strategy for development of anticancer drugs. To identify small molecule inhibitors of the HIF-1 pathway, we have developed a cell-based reporter gene assay and screened a large compound library by using a quantitative high-throughput screening (qHTS approach. Results The assay is based upon a β-lactamase reporter under the control of a HRE. We have screened approximate 73,000 compounds by qHTS, with each compound tested over a range of seven to fifteen concentrations. After qHTS we have rapidly identified three novel structural series of HIF-1 pathway Inhibitors. Selected compounds in these series were also confirmed as inhibitors in a HRE β-lactamase reporter gene assay induced by low oxygen and in a VEGF secretion assay. Three of the four selected compounds tested showed significant inhibition of hypoxia-induced HIF-1α accumulation by western blot analysis. Conclusion The use of β-lactamase reporter gene assays, in combination with qHTS, enabled the rapid identification and prioritization of inhibitors specific to the hypoxia induced signaling pathway.

  7. Hedgehog signaling pathway and lung cancer%Hedgehog信号转导通路与肺癌

    Institute of Scientific and Technical Information of China (English)

    白晓燕

    2011-01-01

    Hedgehog (Hh) pathway plays a critical role in embryonic development period,which regulates cell proliferation and differentiation,and coordinates the key step of organs' development process such as skin,brain,neural tube,bowels,appendage and lung.In the adult stage,Hh signaling regulates proliferation of stem cells.At this time,Hh signaling is strictly controlled by time and space.In recent years,studies have shown aberrant activation of the Hh pathway is closely related to various types of malignancies,and would be a new therapeutic target of tumor treatment.This paper will review the characteristic of Hh signaling pathway and its research status in lung cancer.%Hedgehog(Hh)信号通路在胚胎发育期起关键作用,调节细胞的增殖、分化,协调组织器官如皮肤、脑、神经管、肠、附肢及肺等发育过程中的关键步骤.在成年期,Hh通路调控干细胞的增殖,此时Hh通路受到严格的时空限制.近年来研究表明Hh信号通路异常激活与包括肺癌在内的多种肿瘤的发生、发展密切相关,因此可能会成为肿瘤治疗的一个新靶点.现对Hh信号通路的特性及其在肺癌中的研究现状作一综述.

  8. Blocking lhh Signaling Pathway Inhibits the Proliferation and Pro-motes the Apoptosis of PSCs

    Institute of Scientific and Technical Information of China (English)

    Kai XU; Fengjing GUO; Shuwei ZHANG; Cheng LIU; Feixiong WANG; Zhiguo ZHOU; Anmin CHEN

    2009-01-01

    The roles of Indian hedgehog (Ihh) signaling pathway in the proliferation and apoptosis of precartilaginous stem cells (PSCs) were investigated.PSCs,labeled with fibroblast growth factor receptor 3 (FGFR-3),were isolated from neonatal rats by immanomagnetic separation.After identifi-cation with FGFR-3 and Col Ⅱ,the cells were incubated with different concentrations of cyclopamine (cyclo),the specific inhibitor of lhh signaling pathway.The morphologic changes of the cells were observed under the inverted phase contrast microscope.The mRNA expression levels of Ibh,para-thyroid hormonerelated peptide (PTHrP),protein Patched (Ptch),Bcl-2 and p21 were detected by RT-PCR.The protein expression levels of Ihh and Ptch were measured by Western blot.MTT assay was used to examine the effects of cyclo on proliferation of PSCs.Apoptosis rate of PSCs was exam-ined by Annexin V/PI assay of flow cytometric analyses.After PSCs were incubated with cyclo,ob-vious morphologic changes were observed as compared with the control group.The mRNA expres-sion levels of PTHrP,Ptch and Bcl-2 were decreased to varying degrees in a cyclo dose-dependent manner.However,the expression levels of lhh and p21 mRNA were increased.The protein expres-sion of Ptch and Ihh had the same change as the mRNA expression.Meanwhile,cyclo could obvi-ously inhibit the proliferation and promote the apoptosis of PSCs.The results indicated that Ihh sig-naling pathway plays an important role in regulating the proliferation and apoptosis of PSCs,which is probably mediated by Bcl-2 and p21.

  9. Integrated analysis of breast cancer cell lines reveals unique signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Heiser, Laura M.; Wang, Nicholas J.; Talcott, Carolyn L.; Laderoute, Keith R.; Knapp, Merrill; Guan, Yinghui; Hu, Zhi; Ziyad, Safiyyah; Weber, Barbara L.; Laquerre, Sylvie; Jackson, Jeffrey R.; Wooster, Richard F.; Kuo, Wen-Lin; Gray, Joe W.; Spellman, Paul T.

    2009-03-31

    Cancer is a heterogeneous disease resulting from the accumulation of genetic defects that negatively impact control of cell division, motility, adhesion and apoptosis. Deregulation in signaling along the EGFR-MAPK pathway is common in breast cancer, though the manner in which deregulation occurs varies between both individuals and cancer subtypes. We were interested in identifying subnetworks within the EGFR-MAPK pathway that are similarly deregulated across subsets of breast cancers. To that end, we mapped genomic, transcriptional and proteomic profiles for 30 breast cancer cell lines onto a curated Pathway Logic symbolic systems model of EGFR-MEK signaling. This model was comprised of 539 molecular states and 396 rules governing signaling between active states. We analyzed these models and identified several subtype specific subnetworks, including one that suggested PAK1 is particularly important in regulating the MAPK cascade when it is over-expressed. We hypothesized that PAK1 overexpressing cell lines would have increased sensitivity to MEK inhibitors. We tested this experimentally by measuring quantitative responses of 20 breast cancer cell lines to three MEK inhibitors. We found that PAK1 over-expressing luminal breast cancer cell lines are significantly more sensitive to MEK inhibition as compared to those that express PAK1 at low levels. This indicates that PAK1 over-expression may be a useful clinical marker to identify patient populations that may be sensitive to MEK inhibitors. All together, our results support the utility of symbolic system biology models for identification of therapeutic approaches that will be effective against breast cancer subsets.

  10. Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression

    Directory of Open Access Journals (Sweden)

    Stephen A. Rosenberg

    2015-02-01

    Full Text Available Our group has previously reported that the majority of human melanomas (>60% express the metabotropic glutamate receptor 1 (GRM1 and that the glutamate release inhibitor riluzole, a drug currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo. Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy.

  11. Development of Drugs Targeting the PI3K Signalling Pathway in Leukaemias and Lymphomas

    Directory of Open Access Journals (Sweden)

    Alexandre Arcaro

    2015-03-01

    Full Text Available The phosphoinositide 3-kinase (PI3K family of signalling enzymes play a key role in the transduction of signals from activated cell surface receptors controlling cell growth and proliferation, survival, metabolism, and migration. The intracellular signalling pathway from activated receptors to PI3K and its downstream targets v-akt murine thymoma viral oncogene homolog (Akt and mechanistic target of rapamycin (mTOR is very frequently deregulated by genetic and epigenetic mechanisms in human cancer, including leukaemia and lymphoma. In the past decade, an arsenal of small molecule inhibitors of key enzymes in this pathway has been developed and evaluated in pre-clinical studies and clinical trials in cancer patients. These include pharmacological inhibitors of Akt, mTOR, and PI3K, some of which are approved for the treatment of leukaemia and lymphoma. The PI3K family comprises eight different catalytic isoforms in humans, which have been subdivided into three classes. Class I PI3K isoforms have been extensively studied in the context of human cancer, and the isoforms p110α and p110δ are validated drug targets. The recent approval of a p110δ-specific PI3K inhibitor (idelalisib/Zydelig® for the treatment of selected B cell malignancies represents the first success in developing these molecules into anti-cancer drugs. In addition to PI3K inhibitors, mTOR inhibitors are intensively studied in leukaemia and lymphoma, and temsirolimus (Torisel® is approved for the treatment of a type of lymphoma. Based on these promising results it is hoped that additional novel PI3K pathway inhibitors will in the near future be further developed into new drugs for leukaemia and lymphoma.

  12. Curcumin synergizes with resveratrol to stimulate the MAPK signaling pathway in human articular chondrocytes in vitro.

    Science.gov (United States)

    Shakibaei, Mehdi; Mobasheri, Ali; Buhrmann, Constanze

    2011-05-01

    The mitogen-activated protein kinase (MAPK) pathway is stimulated in differentiated chondrocytes and is an important signaling cascade for chondrocyte differentiation and survival. Pro-inflammatory cytokines such as interleukin 1β (IL-1β) play important roles in the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA). In this study, we investigated whether curcumin and resveratrol can synergistically inhibit the catabolic effects of IL-1β, specifically the inhibition of the MAPK and subsequent apoptosis in human articular chondrocytes. Chondrocytes were either left untreated or treated with 10 ng/ml IL-1β or 1 μM U0126, a specific inhibitor of MAPK pathway alone for the indicated time periods or pre-treated with 10 μM curcumin, 10 μM resveratrol or 10 μM resveratrol and 10 μM curcumin for 4 h followed by co-treatment with 10 ng/ml IL-1β or 1 μM U0126 and 10 μM resveratrol, 10 μM curcumin or 10 μM resveratrol and 10 μM curcumin for the indicated time periods. Cultures were evaluated by immunoblotting and transmission electron microscopy. Incubation of chondrocytes with IL-1β resulted in induction of apoptosis, downregulation of β1-integrins and the extracellular signal-regulated kinase 1/2 (Erk1/2). Interestingly, U0126 induced apoptosis and blocked the above-mentioned proteins in a similar way to IL-1β. Furthermore, curcumin and resveratrol inhibited IL-1β- or U0126-induced apoptosis and downregulation of β1-integrins and Erk1/2 in human articular chondrocytes. These results suggest that combining these two natural compounds activates MEK/Erk signaling, a pathway that is involved in the maintenance of chondrocyte differentiation and survival. PMID:21484156

  13. PAQR3 regulates Golgi vesicle fission and transport via the Gβγ-PKD signaling pathway.

    Science.gov (United States)

    Hewavitharana, Thamara; Wedegaertner, Philip B

    2015-12-01

    Heterotrimeric G proteins function at diverse subcellular locations, in addition to canonical signaling at the plasma membrane (PM). Gβγ signals at the Golgi, via protein kinase D (PKD), to regulate fission of PM-destined vesicles. However, the mechanism by which Gβγ is regulated at the Golgi in this process remains elusive. Recent studies have revealed that PAQR3 (Progestin and AdipoQ Receptor 3), also called RKTG (Raf Kinase Trapping to the Golgi), interacts with the Gβ subunit and localizes Gβ to the Golgi thereby inhibiting Gβγ signaling at the PM. Herein we show that, in contrast to this inhibition of canonical Gβγ signaling at the PM, PAQR3 promotes Gβγ signaling at the Golgi. Expression of PAQR3 causes fragmentation of the Golgi, while a Gβ binding-deficient mutant of PAQR3 does not cause Golgi fragmentation. Also, a C-terminal fragment of GRK2 (GRK2ct), which interacts with Gβγ and inhibits Gβγ signaling, and gallein, a small molecule inhibitor of Gβγ, are both able to inhibit PAQR3-mediated Golgi fragmentation. Furthermore, a dominant negative form of PKD (PKD-DN) and a pharmacological inhibitor of PKD, Gö6976, also inhibit PAQR3-mediated fragmentation of the Golgi. Importantly, expression of the Gβ binding-deficient mutant of PAQR3 inhibits the constitutive transport of the model cargo protein VSV-G from the Golgi to the PM, indicating the involvement of PAQR3 in Golgi-to PM vesicle transport and a dominant negative role for this mutant. Collectively, these results reveal a novel role for the newly characterized, Golgi-localized PAQR3 in regulating Gβγ at the non-canonical subcellular location of the Golgi and thus for controlling Golgi-to-PM protein transport via the Gβγ-PKD signaling pathway. PMID:26327583

  14. Drosophila fatty acid taste signals through the PLC pathway in sugar-sensing neurons.

    Directory of Open Access Journals (Sweden)

    Pavel Masek

    Full Text Available Taste is the primary sensory system for detecting food quality and palatability. Drosophila detects five distinct taste modalities that include sweet, bitter, salt, water, and the taste of carbonation. Of these, sweet-sensing neurons appear to have utility for the detection of nutritionally rich food while bitter-sensing neurons signal toxicity and confer repulsion. Growing evidence in mammals suggests that taste for fatty acids (FAs signals the presence of dietary lipids and promotes feeding. While flies appear to be attracted to fatty acids, the neural basis for fatty acid detection and attraction are unclear. Here, we demonstrate that a range of FAs are detected by the fly gustatory system and elicit a robust feeding response. Flies lacking olfactory organs respond robustly to FAs, confirming that FA attraction is mediated through the gustatory system. Furthermore, flies detect FAs independent of pH, suggesting the molecular basis for FA taste is not due to acidity. We show that low and medium concentrations of FAs serve as an appetitive signal and they are detected exclusively through the same subset of neurons that sense appetitive sweet substances, including most sugars. In mammals, taste perception of sweet and bitter substances is dependent on phospholipase C (PLC signaling in specialized taste buds. We find that flies mutant for norpA, a Drosophila ortholog of PLC, fail to respond to FAs. Intriguingly, norpA mutants respond normally to other tastants, including sucrose and yeast. The defect of norpA mutants can be rescued by selectively restoring norpA expression in sweet-sensing neurons, corroborating that FAs signal through sweet-sensing neurons, and suggesting PLC signaling in the gustatory system is specifically involved in FA taste. Taken together, these findings reveal that PLC function in Drosophila sweet-sensing neurons is a conserved molecular signaling pathway that confers attraction to fatty acids.

  15. Comprehensive logic based analyses of Toll-like receptor 4 signal transduction pathway.

    Directory of Open Access Journals (Sweden)

    Mahesh Kumar Padwal

    Full Text Available Among the 13 TLRs in the vertebrate systems, only TLR4 utilizes both Myeloid differentiation factor 88 (MyD88 and Toll/Interleukin-1 receptor (TIR-domain-containing adapter interferon-β-inducing Factor (TRIF adaptors to transduce signals triggering host-protective immune responses. Earlier studies on the pathway combined various experimental data in the form of one comprehensive map of TLR signaling. But in the absence of adequate kinetic parameters quantitative mathematical models that reveal emerging systems level properties and dynamic inter-regulation among the kinases/phosphatases of the TLR4 network are not yet available. So, here we used reaction stoichiometry-based and parameter independent logical modeling formalism to build the TLR4 signaling network model that captured the feedback regulations, interdependencies between signaling kinases and phosphatases and the outcome of simulated infections. The analyses of the TLR4 signaling network revealed 360 feedback loops, 157 negative and 203 positive; of which, 334 loops had the phosphatase PP1 as an essential component. The network elements' interdependency (positive or negative dependencies in perturbation conditions such as the phosphatase knockout conditions revealed interdependencies between the dual-specific phosphatases MKP-1 and MKP-3 and the kinases in MAPK modules and the role of PP2A in the auto-regulation of Calmodulin kinase-II. Our simulations under the specific kinase or phosphatase gene-deficiency or inhibition conditions corroborated with several previously reported experimental data. The simulations to mimic Yersinia pestis and E. coli infections identified the key perturbation in the network and potential drug targets. Thus, our analyses of TLR4 signaling highlights the role of phosphatases as key regulatory factors in determining the global interdependencies among the network elements; uncovers novel signaling connections; identifies potential drug targets for

  16. Role of NO-cGMP signalling pathway in mediation of ischemia-reperfusion lung injury

    OpenAIRE

    Egemnazarov, Bakytbek

    2008-01-01

    Ischemia reperfusion (I/R) lung injury is a complex pathological process, which occurs in many clinical situations. Previous studies reported equivocal results about the role of nitric oxide (NO) synthase isoforms in the mediation of the injury and their possible mechanisms of action. Therefore, the aim of our study was to evaluate the role of NO synthase isoforms and NO-cGMP signaling pathway on I/R injury of the lung in an isolated perfused organ model employing rabbits as well as wild type...

  17. Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway

    OpenAIRE

    Jie Zheng; Dong Ju Son; Sun Mi Gu; Ju Rang Woo; Young Wan Ham; Hee Pom Lee; Wun Jae Kim; Jae Kyung Jung; Jin Tae Hong

    2016-01-01

    Piperlongumine has anti-cancer activity in numerous cancer cell lines via various signaling pathways. But there has been no study regarding the mechanisms of PL on the lung cancer yet. Thus, we evaluated the anti-cancer effects and possible mechanisms of PL on non-small cell lung cancer (NSCLC) cells in vivo and in vitro. Our findings showed that PL induced apoptotic cell death and suppressed the DNA binding activity of NF-κB in a concentration dependent manner (0–15 μM) in NSCLC cells. Docki...

  18. Role of FGF-2/FGFR signaling pathway in cancer and its signification in breast cancer

    Institute of Scientific and Technical Information of China (English)

    FANG Jianwu; HUANG Siluo; LIU Huisheng; M. Crepin; XU Tao; LIU Jianfeng

    2003-01-01

    Fibroblast growth factor-2 (FGF-2) is a member of a large family of proteins that bind heparin and heparan sulfate and modulate the function of a wide range of cell types. It has been proved that FGF-2 stimulates the growth and development of new blood vessels (angiogenesis) that contribute to the pathogenesis of several diseases (i.e. cancer, atherosclerosis). However, many of the biological activities of FGF-2 have been found to depend on its receptor's intrinsic tyrosine kinase activity and second messengers such as the mitogen activated protein kinases. This review will focus on the mechanism of FGF-2/FGFR induced signaling pathway in tumor and human breast cancer.

  19. Plant ubiquitin-proteasome pathway and its role in gibberellin signaling

    Institute of Scientific and Technical Information of China (English)

    Feng Wang; Xing Wang Deng

    2011-01-01

    The ubiquitin-proteasome system (UPS) in plants,like in other eukaryotes,targets numerous intracellular regulators and thus modulates almost every aspect of growth and development.The well-known and best-characterized outcome of ubiquitination is mediating target protein degradation via the 26S proteasome,which represents the major selective protein degradation pathway conserved among eukaryotes.In this review,we will discuss the molecular composition,regulation and function of plant UPS,with a major focus on how DELLA protein degradation acts as a key in gibberellin signal transduction and its implication in the regulation of plant growth.

  20. Reducing progression of experimental lupus nephritis via inhibition of the B7/CD28 signaling pathway.

    Science.gov (United States)

    Huang, Li; Kong, Yong; Wang, Jing; Sun, Jie; Shi, Qin; Qiu, Yu-Hua

    2015-09-01

    The aim of the present study was to evaluate the effects of the B7/cluster of differentiation (CD)28 signaling pathway on experimental lupus nephritis and examine the molecular mechanism involved by inhibiting the B7/CD28 signaling pathway. A lupus nephritis model in C57BL/6 J mice was induced via intraperitoneal injection of pristane. A recombinant B7‑1 short hairpin RNA (shRNA) lentivirus vector was constructed by synthesis and splicing. A neutralizing mouse anti‑human B7‑1 antibody termed 4E5 was also prepared. The mouse model of lupus nephritis was treated with B7‑1 shRNA and 4E5 via injection through the tail vein. The silencing effects of B7‑1 shRNA lentiviral infection on target molecules were evaluated using immunofluorescence and flow cytometry. The levels of protein in the urine were detected using Albustix test paper each month over 10 months. The concentration of interleukin (IL)‑4 and interferon‑γ in the serum was determined using an ELISA. The immune complex (IC) deposits in the kidney were analyzed using direct immunofluorescence. The results demonstrated that the C57BL/6 J mouse lupus nephritis model was successfully constructed with immune cells activated in the spleen of the mice, increases in the concentration of anti‑nuclear antibody (ANA) and anti‑double stranded DNA antibodies as well as positive IC formation. Following B7‑1 shRNA lentivirus or 4E5 treatment, CD11b+B7‑1+, CD11c+B7‑1+ and CD21+B7‑1+ cells in the spleen of the mice were significantly reduced. The concentration of ANA and IL‑4 in the serum was also decreased. The concentration of urine protein was reduced and it was at its lowest level in the 4E5 early intervention group. It was also revealed that the immunofluorescence intensity of the IC deposits was weak in the 4E5 early intervention group. In conclusion, inhibiting the B7‑1/CD28 signaling pathway is able to alleviate experimental lupus nephritis and provides an experimental basis for the

  1. The Architecture of the TIR Domain Signalosome in the Toll-like Receptor-4 Signaling Pathway

    OpenAIRE

    Emine Guven-Maiorov; Ozlem Keskin; Attila Gursoy; Carter VanWaes; Zhong Chen; Chung-Jung Tsai; Ruth Nussinov

    2015-01-01

    Scientific Reports | 5:13128 | DOI: 10.1038/srep13128 1 www.nature.com/scientificreports The Architecture of the TIR Domain Signalosome in the Toll-like Receptor-4 Signaling Pathway Emine Guven-Maiorov1,2, Ozlem Keskin1,2, Attila Gursoy2,3, Carter VanWaes4, Zhong Chen4, Chung-Jung Tsai5 & Ruth Nussinov5,6 Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro- and anti-tumor responses. The organization of the assembly is critical to the understandin...

  2. Dual Role of Signaling Pathways Leading to Ca2+ and Cyclic AMP Elevation in Host Cell Invasion by Trypanosoma cruzi

    OpenAIRE

    Caler, Elisabet V.; Morty, Rory E; Burleigh, Barbara A.; Andrews, Norma W.

    2000-01-01

    Cell invasion by the protozoan parasite Trypanosoma cruzi involves activation of host signaling pathways and the recruitment and fusion of lysosomes at the parasite entry site. A major signaling pathway regulating invasion of fibroblasts, epithelial cells, and myoblasts involves mobilization of Ca2+ from intracellular stores and requires the activity of a T. cruzi serine peptidase, oligopeptidase B (OPB). Deletion of the OPB gene results in a marked defect in trypomastigote virulence, consist...

  3. 1,25-Vitamin-D3 Promotes Cardiac Differentiation through Modulation of the Wnt Signaling Pathway

    OpenAIRE

    Hlaing, Su M.; Garcia, Leah A.; Contreras, Jaime R.; Norris, Keith C.; Ferrini, Monica G.; Artaza, Jorge N.

    2014-01-01

    Cardiovascular disease (CV) remains the leading cause of death worldwide. Low levels of vitamin D are associated with high risk of myocardial infarction, even after controlling for factors associated with coronary artery disease. A growing body of evidence suggests that vitamin D plays an important role in CV related signaling pathways. However, little is known about the molecular mechanism by which vitamin D modulates cardiac development. The Wnt signaling pathway plays a pivotal role in tis...

  4. Evaluation of the ‘Hedgehog’ signaling pathways in squamous and basal cell carcinomas of the eyelids and conjunctiva

    OpenAIRE

    Celebi, Ali Riza Cenk; Kiratli, Hayyam; SOYLEMEZOGLU, FIGEN

    2016-01-01

    The purpose of the present study was to assess the role of hedgehog signaling pathway in the carcinogenesis of eyelid skin and conjunctival epithelial malignant tumors. The study was conducted on specimens from 41 patients with cutaneous eyelid basal cell carcinoma, 22 with bulbar conjunctival squamous cell carcinoma, 12 with bulbar conjunctival intraepithelial neoplasia. Major molecules of Hedgehog signaling pathway (Sonic Hedgehog [Shh] and Patched-1 [Ptch-1] and Glioma-associated oncogene ...

  5. Active β-Catenin Signaling Is an Inhibitory Pathway for Human Immunodeficiency Virus Replication in Peripheral Blood Mononuclear Cells▿

    OpenAIRE

    Kumar, Anvita; Zloza, Andrew; Moon, Randall T.; Watts, Jeffrey; Tenorio, Allan R.; Al-Harthi, Lena

    2008-01-01

    The Wnt/β-catenin pathway is involved in cell functions governing development and disease. In modeling postentry restriction of human immunodeficiency virus (HIV) replication in astrocytes, we reported that part of this natural resistance to productive replication of HIV in astrocytes involved expression of proteins of the Wnt/β-catenin signaling pathway. We determined here whether induction of β-catenin signaling in peripheral blood mononuclear cells (PBMCs) can modulate HIV replication. Giv...

  6. Naringin Stimulates Osteogenic Differentiation of Rat Bone Marrow Stromal Cells via Activation of the Notch Signaling Pathway

    OpenAIRE

    Guo-yong Yu; Gui-zhou Zheng; Bo Chang; Qin-xiao Hu; Fei-xiang Lin; De-zhong Liu; Chu-cheng Wu; Shi-xin Du; Xue-dong Li

    2016-01-01

    Naringin is a major flavonoid found in grapefruit and is an active compound extracted from the Chinese herbal medicine Rhizoma Drynariae. Naringin is a potent stimulator of osteogenic differentiation and has potential application in preventing bone loss. However, the signaling pathway underlying its osteogenic effect remains unclear. We hypothesized that the osteogenic activity of naringin involves the Notch signaling pathway. Rat bone marrow stromal cells (BMSCs) were cultured in osteogenic ...

  7. Wnt/β-Catenin and Retinoic Acid Receptor Signaling Pathways Interact to Regulate Chondrocyte Function and Matrix Turnover*

    OpenAIRE

    Yasuhara, Rika; Yuasa, Takahito; Williams, Julie A.; Byers, Stephen W.; Shah, Salim; Pacifici, Maurizio; Iwamoto, Masahiro; Enomoto-Iwamoto, Motomi

    2009-01-01

    Activation of the Wnt/β-catenin and retinoid signaling pathways is known to tilt cartilage matrix homeostasis toward catabolism. Here, we investigated possible interactions between these pathways. We found that all-trans-retinoic acid (RA) treatment of mouse epiphyseal chondrocytes in culture did increase Wnt/β-catenin signaling in the absence or presence of exogenous Wnt3a, as revealed by lymphoid enhancer factor/T-cell factor/β-catenin reporter activity and β-catenin nuclear accumulation. T...

  8. Antroquinonol Targets FAK-Signaling Pathway Suppressed Cell Migration, Invasion, and Tumor Growth of C6 Glioma

    OpenAIRE

    Varadharajan Thiyagarajan; May-Jywan Tsai; Ching-Feng Weng

    2015-01-01

    Focal adhesion kinase (FAK) is a non-receptor protein tyrosine that is overexpressed in many types of tumors and plays a pivotal role in multiple cell signaling pathways involved in cell survival, migration, and proliferation. This study attempts to determine the effect of synthesized antroquinonol on the modulation of FAK signaling pathways and explore their underlying mechanisms. Antroquinonol significantly inhibits cell viability with an MTT assay in both N18 neuroblastoma and C6 glioma ce...

  9. Lithium inhibits tumorigenic potential of PDA cells through targeting hedgehog-GLI signaling pathway.

    Directory of Open Access Journals (Sweden)

    Zhonglu Peng

    Full Text Available Hedgehog signaling pathway plays a critical role in the initiation and development of pancreatic ductal adenocarcinoma (PDA and represents an attractive target for PDA treatment. Lithium, a clinical mood stabilizer for mental disorders, potently inhibits the activity of glycogen synthase kinase 3β (GSK3β that promotes the ubiquitin-dependent proteasome degradation of GLI1, an important downstream component of hedgehog signaling. Herein, we report that lithium inhibits cell proliferation, blocks G1/S cell-cycle progression, induces cell apoptosis and suppresses tumorigenic potential of PDA cells through down-regulation of the expression and activity of GLI1. Moreover, lithium synergistically enhances the anti-cancer effect of gemcitabine. These findings further our knowledge of mechanisms of action for lithium and provide a potentially new therapeutic strategy for PDA through targeting GLI1.

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

    DEFF Research Database (Denmark)

    Saeed, Hamid; Qiu, Weimin; Chen, Li;

    2015-01-01

    The contribution of deficient telomerase activity to age-related decline in osteoblast functions and bone formation is poorly studied. We have previously demonstrated that telomerase over-expression led to enhanced osteoblast differentiation of human bone marrow skeletal (stromal) stem cells (h......MSC) in vitro and in vivo. Here, we investigated the signaling pathways underlying the regulatory functions of telomerase in osteoblastic cells. Comparative microarray analysis and Western blot analysis of telomerase-over expressing hMSC (hMSC-TERT) versus primary hMSC revealed significant up....... 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...

  11. Peptides interfering with protein-protein interactions in the ethylene signaling pathway delay tomato fruit ripening.

    Science.gov (United States)

    Bisson, Melanie M A; Kessenbrock, Mareike; Müller, Lena; Hofmann, Alexander; Schmitz, Florian; Cristescu, Simona M; Groth, Georg

    2016-01-01

    The plant hormone ethylene is involved in the regulation of several processes with high importance for agricultural applications, e.g. ripening, aging and senescence. Previous work in our group has identified a small peptide (NOP-1) derived from the nuclear localization signal of the Arabidopsis ethylene regulator ETHYLENE INSENSITIVE-2 (EIN2) C-terminal part as efficient inhibitor of ethylene responses. Here, we show that NOP-1 is also able to efficiently disrupt EIN2-ETR1 complex formation in tomato, indicating that the NOP-1 inhibition mode is conserved across plant species. Surface application of NOP-1 on green tomato fruits delays ripening similar to known inhibitors of ethylene perception (MCP) and ethylene biosynthesis (AVG). Fruits treated with NOP-1 showed similar ethylene production as untreated controls underlining that NOP-1 blocks ethylene signaling by targeting an essential interaction in this pathway, while having no effect on ethylene biosynthesis. PMID:27477591

  12. From carrot to clinic: an overview of the retinoic acid signaling pathway.

    Science.gov (United States)

    Theodosiou, Maria; Laudet, Vincent; Schubert, Michael

    2010-05-01

    Vitamin A is essential for the formation and maintenance of many body tissues. It is also important for embryonic growth and development and can act as a teratogen at critical periods of development. Retinoic acid (RA) is the biologically active form of vitamin A and its signaling is mediated by the RA and retinoid X receptors. In addition to its role as an important molecule during development, RA has also been implicated in clinical applications, both as a potential anti-tumor agent as well as for the treatment of skin diseases. This review presents an overview of how dietary retinoids are converted to RA, hence presenting the major players in RA metabolism and signaling, and highlights examples of treatment applications of retinoids. Moreover, we discuss the origin and diversification of the retinoid pathway, which are important factors for understanding the evolution of ligand-specificity among retinoid receptors. PMID:20140749

  13. Signalling pathways implicated in early mammary gland morphogenesis and breast cancer.

    Directory of Open Access Journals (Sweden)

    Beatrice Howard

    2006-08-01

    Full Text Available Specification of mammary epithelial cell fate occurs during embryogenesis as cells aggregate to form the mammary anlage. Within the embryonic mammary bud, a population of epithelial cells exists that will subsequently proliferate to form a ductal tree filling the stromal compartment, and which can produce milk upon terminal differentiation after birth. Subsequently, these structures can be remodelled and returned to a basal state after weaning before regenerating in future pregnancies. The plasticity of the mammary epithelial cell, and its responsiveness to hormone receptors, facilitates this amazing biological feat, but aberrant signalling may also result in unintended consequences in the form of frequent malignancies. Reflecting this intimate connection, a considerable number of signalling pathways have been implicated in both mammary gland morphogenesis and carcinogenesis.

  14. Wnt signaling pathway improves central inhibitory synaptic transmission in a mouse model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Fuenzalida, Marco; Espinoza, Claudia; Pérez, Miguel Ángel; Tapia-Rojas, Cheril; Cuitino, Loreto; Brandan, Enrique; Inestrosa, Nibaldo C

    2016-02-01

    The dystrophin-associated glycoprotein complex (DGC) that connects the cytoskeleton, plasma membrane and the extracellular matrix has been related to the maintenance and stabilization of channels and synaptic receptors, which are both essential for synaptogenesis and synaptic transmission. The dystrophin-deficient (mdx) mouse model of Duchenne muscular dystrophy (DMD) exhibits a significant reduction in hippocampal GABA efficacy, which may underlie the altered synaptic function and abnormal hippocampal long-term plasticity exhibited by mdx mice. Emerging studies have implicated Wnt signaling in the modulation of synaptic efficacy, neuronal plasticity and cognitive function. We report here that the activation of the non-canonical Wnt-5a pathway and Andrographolide, improves hippocampal mdx GABAergic efficacy by increasing the number of inhibitory synapses and GABA(A) receptors or GABA release. These results indicate that Wnt signaling modulates GABA synaptic efficacy and could be a promising novel target for DMD cognitive therapy. PMID:26626079

  15. The Tumor Suppressor BCL7B Functions in the Wnt Signaling Pathway.

    Directory of Open Access Journals (Sweden)

    Tomoko Uehara

    2015-01-01

    Full Text Available Human BCL7 gene family consists of BCL7A, BCL7B, and BCL7C. A number of clinical studies have reported that BCL7 family is involved in cancer incidence, progression, and development. Among them, BCL7B, located on chromosome 7q11.23, is one of the deleted genes in patients with Williams-Beuren syndrome. Although several studies have suggested that malignant diseases occurring in patients with Williams-Beuren syndrome are associated with aberrations in BCL7B, little is known regarding the function of this gene at the cellular level. In this study, we focused on bcl-7, which is the only homolog of BCL7 gene family in Caenorhabditis elegans, and analyzed bcl-7 deletion mutants. As a result, we found that bcl-7 is required for the asymmetric differentiation of epithelial seam cells, which have self-renewal properties as stem cells and divide asymmetrically through the WNT pathway. Distal tip cell development, which is regulated by the WNT pathway in Caenorhabditis elegans, was also affected in bcl-7-knockout mutants. Interestingly, bcl-7 mutants exhibited nuclear enlargement, reminiscent of the anaplastic features of malignant cells. Furthermore, in KATOIII human gastric cancer cells, BCL7B knockdown induced nuclear enlargement, promoted the multinuclei phenotype and suppressed cell death. In addition, this study showed that BCL7B negatively regulates the Wnt-signaling pathway and positively regulates the apoptotic pathway. Taken together, our data indicate that BCL7B/BCL-7 has some roles in maintaining the structure of nuclei and is involved in the modulation of multiple pathways, including Wnt and apoptosis. This study may implicate a risk of malignancies with BCL7B-deficiency, such as Williams-Beuren syndrome.

  16. Dual intracellular signaling pathways mediated by the human cannabinoid CB1 receptor.

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    Calandra, B; Portier, M; Kernéis, A; Delpech, M; Carillon, C; Le Fur, G; Ferrara, P; Shire, D

    1999-06-25

    It has long been established that the cannabinoid CB1 receptor transduces signals through a pertussis toxin-sensitive Gi/Go inhibitory pathway. Although there have been reports that the cannabinoid CB1 receptor can also mediate an increase in cyclic AMP levels, in most cases the presence of an adenylyl cyclase costimulant or the use of very high amounts of agonist was necessary. Here, we present evidence for dual coupling of the cannabinoid CB receptor to the classical pathway and to a pertussis toxin-insensitive adenylyl cyclase stimulatory pathway initiated with low quantities of agonist in the absence of any costimulant. Treatment of Chinese hamster ovary (CHO) cells expressing the cannabinoid CB1 receptor with the cannabinoid CP 55,940, {(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hyd roxypropyl) cyclohexan-1-ol} resulted in cyclic AMP accumulation in a dose-response manner, an accumulation blocked by the cannabinoid CB1 receptor-specific antagonist SR 141716A, {N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride}. In CHO cells coexpressing the cannabinoid CB1 receptor and a cyclic AMP response element (CRE)-luciferase reporter gene system, CP 55,940 induced luciferase expression by a pathway blocked by the protein kinase A inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-89). Under the same conditions the peripheral cannabinoid CB2 receptor proved to be incapable of inducing cAMP accumulation or luciferase activity. This incapacity allowed us to study the luciferase activation mediated by CB /CB2 chimeric constructs, from which we determined that the first and second internal loop regions of the cannabinoid CB1 receptor were involved in transducing the pathway leading to luciferase gene expression. PMID:10422789

  17. EDF-1 downregulates the CaM/Cn/NFAT signaling pathway during adipogenesis