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Sample records for factor fgf receptor

  1. A Murine Fibroblast Growth Factor (FGF) Receptor Expressed in CHO Cells is Activated by Basic FGF and Kaposi FGF

    Science.gov (United States)

    Mansukhani, Alka; Moscatelli, David; Talarico, Daniela; Levytska, Vera; Basilico, Claudio

    1990-06-01

    We have cloned a murine cDNA encoding a tyrosine kinase receptor with about 90% similarity to the chicken fibroblast growth factor (FGF) receptor and the human fms-like gene (FLG) tyrosine kinase. This mouse receptor lacks 88 amino acids in the extracellular portion, leaving only two immunoglobulin-like domains compared to three in the chicken FGF receptor. The cDNA was cloned into an expression vector and transfected into receptor-negative CHO cells. We show that cells expressing the receptor can bind both basic FGF and Kaposi FGF. Although the receptor binds basic FGF with a 15- to 20-fold higher affinity, Kaposi FGF is able to induce down-regulation of the receptor to the same extent as basic FGF. The receptor is phosphorylated upon stimulation with both FGFs, DNA synthesis is stimulated, and a proliferative response is produced in cells expressing the receptor, whereas cells expressing the cDNA in the antisense orientation show none of these responses to basic FGF or Kaposi FGF. Thus this receptor can functionally interact with two growth factors of the FGF family.

  2. Expression of fibroblast growth factor (FGF)-8 isoforms and FGF receptors in human ovarian tumors.

    Science.gov (United States)

    Valve, E; Martikainen, P; Seppänen, J; Oksjoki, S; Hinkka, S; Anttila, L; Grenman, S; Klemi, P; Härkönen, P

    2000-12-01

    FGF-8 is a mitogenic growth factor, which is widely expressed during embryonic development but only at a very low level in adult tissues. Alternative splicing of the human FGF-8 gene potentially allows coding for 4 protein isoforms (a, b, e, f), which differ in their transforming capacity. The FGF-8 isoforms preferentially activate the receptors FGFR1IIIc, FGFR2IIIc, FGFR3IIIc and FGFR4. FGF-8 is over-expressed in human breast and prostate cancers. Expression has also been found in RT-PCR studies of human ovarian and testicular cancers. The present study was undertaken to examine which FGF-8 isoforms are expressed in ovarian cancer and whether FGF-8 receptors are also expressed. Specimens from 5 normal human ovaries and 51 ovarian tumors (1 benign tumor, 8 borderline malignancies, 42 malignant tumors of different histopathological types) were studied by RT-PCR and immunohistochemistry. FGF-8 isoform b was expressed in all ovarian tumors and in all 7 ovarian-cancer cell lines studied. Isoform a was co-expressed in 9 malignant ovarian tumors. FGF-8 mRNA was not detected by RT-PCR of 3 normal ovary samples. Immunohistochemical staining localized FGF-8 protein to cancer cells. In general, the increased intensity of FGF-8 staining was associated with loss of differentiation within the tumors (Bowker's test, p = 0.37). FGF-8 staining of surface epithelium observed on 2 normal ovaries was very faint. RT-PCR showed that FGFR1IIIc, FGFR2IIIc and FGFR4 were the FGF-8 receptors expressed in normal ovaries and in ovarian tumors. FGF-8 receptor immunoreactivity was preferentially found in normal ovary surface epithelium and tumor cells but also in some stromal cells. Collectively, our results show that ovarian cancers of a wide variety of histological types expressing receptors for FGF-8 have acquired the capacity of expressing FGF-8. This suggests that FGF-8 has an important role in ovarian tumorigenesis.

  3. Tissue-specific Expression of βKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21*†

    OpenAIRE

    Kurosu, Hiroshi; Choi, Mihwa; Ogawa, Yasushi; Dickson, Addie S.; Goetz, Regina; Eliseenkova, Anna V.; Mohammadi, Moosa; Rosenblatt, Kevin P.; Kliewer, Steven A.; Kuro-o, Makoto

    2007-01-01

    The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1–4). We demonstrated that Klotho and βKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires βKlotho. Both FGF19 and FGF21 c...

  4. Plasticity in interactions of fibroblast growth factor 1 (FGF1) N terminus with FGF receptors underlies promiscuity of FGF1.

    Science.gov (United States)

    Beenken, Andrew; Eliseenkova, Anna V; Ibrahimi, Omar A; Olsen, Shaun K; Mohammadi, Moosa

    2012-01-27

    Tissue-specific alternative splicing in the second half of Ig-like domain 3 (D3) of fibroblast growth factor receptors 1-3 (FGFR1 to -3) generates epithelial FGFR1b-FGFR3b and mesenchymal FGFR1c-FGFR3c splice isoforms. This splicing event establishes a selectivity filter to restrict the ligand binding specificity of FGFRb and FGFRc isoforms to mesenchymally and epithelially derived fibroblast growth factors (FGFs), respectively. FGF1 is termed the "universal FGFR ligand" because it overrides this specificity barrier. To elucidate the molecular basis for FGF1 cross-reactivity with the "b" and "c" splice isoforms of FGFRs, we determined the first crystal structure of FGF1 in complex with an FGFRb isoform, FGFR2b, at 2.1 Å resolution. Comparison of the FGF1-FGFR2b structure with the three previously published FGF1-FGFRc structures reveals that plasticity in the interactions of the N-terminal region of FGF1 with FGFR D3 is the main determinant of FGF1 cross-reactivity with both isoforms of FGFRs. In support of our structural data, we demonstrate that substitution of three N-terminal residues (Gly-19, His-25, and Phe-26) of FGF2 (a ligand that does not bind FGFR2b) for the corresponding residues of FGF1 (Phe-16, Asn-22, and Tyr-23) enables the FGF2 triple mutant to bind and activate FGFR2b. These findings taken together with our previous structural data on receptor binding specificity of FGF2, FGF8, and FGF10 conclusively show that sequence divergence at the N termini of FGFs is the primary regulator of the receptor binding specificity and promiscuity of FGFs.

  5. Fibroblast growth factor (FGF)-21 signals through both FGF receptor-1 and 2

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Fibroblast growth factor (FGF)-21 is a member of the FGF superfamily based on sequence homology. However, unlike most members of this family it does not show any mitogenic activity in all cell types tested. The objective of this study is to identify and characterize receptors for this molecule. Sequencing of the cDNA clones from 3T3-L1 adipocytes indicates that the only isoforms for FGFR-1 and 2 expressed in 3T3-L1 cells are 1IIIc and 2IIIc, respectively, suggesting that FGF-21 regulates glucose metabolism in 3T3-L1 adipocytes through FGFR-1IIIc and FGFR-2IIIc.

  6. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.

    Science.gov (United States)

    Kurosu, Hiroshi; Choi, Mihwa; Ogawa, Yasushi; Dickson, Addie S; Goetz, Regina; Eliseenkova, Anna V; Mohammadi, Moosa; Rosenblatt, Kevin P; Kliewer, Steven A; Kuro-o, Makoto

    2007-09-14

    The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1-4). We demonstrated that Klotho and betaKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires betaKlotho. Both FGF19 and FGF21 can signal through FGFR1-3 bound by betaKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the betaKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of betaKlotho, in combination with particular FGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21.

  7. Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1*

    OpenAIRE

    Beenken, Andrew; Eliseenkova, Anna V.; Ibrahimi, Omar A; Olsen, Shaun K.; Mohammadi, Moosa

    2011-01-01

    Tissue-specific alternative splicing in the second half of Ig-like domain 3 (D3) of fibroblast growth factor receptors 1–3 (FGFR1 to -3) generates epithelial FGFR1b-FGFR3b and mesenchymal FGFR1c-FGFR3c splice isoforms. This splicing event establishes a selectivity filter to restrict the ligand binding specificity of FGFRb and FGFRc isoforms to mesenchymally and epithelially derived fibroblast growth factors (FGFs), respectively. FGF1 is termed the “universal FGFR ligand” because it overrides ...

  8. Membrane and integrative nuclear fibroblastic growth factor receptor (FGFR) regulation of FGF-23.

    Science.gov (United States)

    Han, Xiaobin; Xiao, Zhousheng; Quarles, L Darryl

    2015-04-17

    Fibroblastic growth factor receptor 1 (FGFR1) signaling pathways are implicated in the regulation of FGF-23 gene transcription, but the molecular pathways remain poorly defined. We used low molecular weight (LMW, 18 kDa) FGF-2 and high molecular weight (HMW) FGF-2 isoforms, which, respectively, activate cell surface FGF receptors and intranuclear FGFR1, to determine the roles of membrane FGFRs and integrative nuclear FGFR1 signaling (INFS) in the regulation of FGF-23 gene transcription in osteoblasts. We found that LMW-FGF-2 induced NFAT and Ets1 binding to conserved cis-elements in the proximal FGF-23 promoter and stimulated FGF-23 promoter activity through PLCγ/calcineurin/NFAT and MAPK pathways in SaOS-2 and MC3T3-E1 osteoblasts. In contrast, HMW-FGF-2 stimulated FGF-23 promoter activity in osteoblasts through a cAMP-dependent binding of FGFR1 and cAMP-response element-binding protein (CREB) to a conserved cAMP response element (CRE) contiguous with the NFAT binding site in the FGF-23 promoter. Mutagenesis of the NFAT and CRE binding sites, respectively, inhibited the effects of LMW-FGF-2 and HMW-FGF-23 to stimulate FGF-23 promoter activity. FGF-2 activation of both membrane FGFRs and INFS-dependent FGFR1 pathways may provide a means to integrate systemic and local regulation of FGF-23 transcription under diverse physiological and pathological conditions.

  9. Crosstalk between Fibroblast Growth Factor (FGF Receptor and Integrin through Direct Integrin Binding to FGF and Resulting Integrin-FGF-FGFR Ternary Complex Formation

    Directory of Open Access Journals (Sweden)

    Seiji Mori

    2013-08-01

    Full Text Available Fibroblast growth factors (FGFs play a critical role in diverse physiological processes and the pathogenesis of diseases. Integrins are involved in FGF signaling, since integrin antagonists suppress FGF signaling. This is called integrin-FGF crosstalk, while the specifics of the crosstalk are unclear. This review highlights recent findings that FGF1 directly interacts with integrin αvβ3, and the resulting integrin-FGF-fibroblast growth factor receptor (FGFR ternary complex formation is essential for FGF1-induced cell proliferation, migration and angiogenesis. An integrin-binding defective FGF1 mutant (Arg-50 to Glu, R50E is defective in ternary complex formation and in inducing cell proliferation, migration and angiogenesis, while R50E still binds to the FGF receptor and heparin. In addition, R50E suppressed tumorigenesis in vivo, while wild-type (WT FGF1 enhanced it. Thus, the direct interaction between FGF1 and integrin αvβ3 is a potential therapeutic target, and R50E is a potential therapeutic agent.

  10. Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival.

    Science.gov (United States)

    Tiong, Kai Hung; Tan, Boon Shing; Choo, Heng Lungh; Chung, Felicia Fei-Lei; Hii, Ling-Wei; Tan, Si Hoey; Khor, Nelson Tze Woei; Wong, Shew Fung; See, Sze-Jia; Tan, Yuen-Fen; Rosli, Rozita; Cheong, Soon-Keng; Leong, Chee-Onn

    2016-09-06

    Basal-like breast cancer is an aggressive tumor subtype with poor prognosis. The discovery of underlying mechanisms mediating tumor cell survival, and the development of novel agents to target these pathways, is a priority for patients with basal-like breast cancer. From a functional screen to identify key drivers of basal-like breast cancer cell growth, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of cell survival. We found that FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT. Importantly, a subset of basal-like breast cancer cells also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. siRNA-mediated silencing of FGF19 or neutralization of extracellular FGF19 by anti-FGF19 antibody (1A6) decreases AKT phosphorylation, suppresses cancer cell growth and enhances doxorubicin sensitivity only in the FGFR4+/FGF19+ breast cancer cells. Consistently, FGFR4/FGF19 co-expression was also observed in 82 out of 287 (28.6%) primary breast tumors, and their expression is strongly associated with AKT phosphorylation, Ki-67 staining, higher tumor stage and basal-like phenotype. In summary, our results demonstrated the presence of an FGFR4/FGF19 autocrine signaling that mediates the survival of a subset of basal-like breast cancer cells and suggest that inactivation of this autocrine loop may potentially serve as a novel therapeutic intervention for future treatment of breast cancers.

  11. 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.

  12. Mechanism of FGF receptor dimerization and activation

    Science.gov (United States)

    Sarabipour, Sarvenaz; Hristova, Kalina

    2016-01-01

    Fibroblast growth factors (fgfs) are widely believed to activate their receptors by mediating receptor dimerization. Here we show, however, that the FGF receptors form dimers in the absence of ligand, and that these unliganded dimers are phosphorylated. We further show that ligand binding triggers structural changes in the FGFR dimers, which increase FGFR phosphorylation. The observed effects due to the ligands fgf1 and fgf2 are very different. The fgf2-bound dimer structure ensures the smallest separation between the transmembrane (TM) domains and the highest possible phosphorylation, a conclusion that is supported by a strong correlation between TM helix separation in the dimer and kinase phosphorylation. The pathogenic A391E mutation in FGFR3 TM domain emulates the action of fgf2, trapping the FGFR3 dimer in its most active state. This study establishes the existence of multiple active ligand-bound states, and uncovers a novel molecular mechanism through which FGFR-linked pathologies can arise.

  13. Plasma FGF21 Concentrations, Adipose Fibroblast Growth Factor Receptor-1 and β-Klotho Expression Decrease with Fasting in Northern Elephant Seals

    OpenAIRE

    Suzuki, Miwa; Lee, Andrew; Vázquez-Medina, Jose Pablo; Viscarra, Jose A.; Crocker, Daniel E.; Ortiz, Rudy M.

    2015-01-01

    Fibroblast growth factor (FGF)-21 is secreted from the liver, pancreas, and adipose in response to prolonged fasting/starvation to facilitate lipid and glucose metabolism. Northern elephant seals naturally fast for several months, maintaining a relatively elevated metabolic rate to satisfy their energetic requirements. Thus, to better understand the impact of prolonged food deprivation on FGF21-associated changes, we analyzed the expression of FGF21, FGF receptor-1 (FGFR1), β-klotho (KLB; a c...

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

    Science.gov (United States)

    Cheng, Xingguo; Vispute, Saurabh G; Liu, Jie; Cheng, Christine; Kharitonenkov, Alexei; Klaassen, Curtis D

    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 200μg/kg of TCDD died within 20days, 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.

  15. Plasma FGF21 concentrations, adipose fibroblast growth factor receptor-1 and β-klotho expression decrease with fasting in northern elephant seals.

    Science.gov (United States)

    Suzuki, Miwa; Lee, Andrew Y; Vázquez-Medina, José Pablo; Viscarra, Jose A; Crocker, Daniel E; Ortiz, Rudy M

    2015-05-15

    Fibroblast growth factor (FGF)-21 is secreted from the liver, pancreas, and adipose in response to prolonged fasting/starvation to facilitate lipid and glucose metabolism. Northern elephant seals naturally fast for several months, maintaining a relatively elevated metabolic rate to satisfy their energetic requirements. Thus, to better understand the impact of prolonged food deprivation on FGF21-associated changes, we analyzed the expression of FGF21, FGF receptor-1 (FGFR1), β-klotho (KLB; a co-activator of FGFR) in adipose, and plasma FGF21, glucose and 3-hydroxybutyrate in fasted elephant seal pups. Expression of FGFR1 and KLB mRNA decreased 98% and 43%, respectively, with fasting duration. While the 80% decrease in mean adipose FGF21 mRNA expression with fasting did not reach statistical significance, it paralleled the 39% decrease in plasma FGF21 concentrations suggesting that FGF21 is suppressed with fasting in elephant seals. Data demonstrate an atypical response of FGF21 to prolonged fasting in a mammal suggesting that FGF21-mediated mechanisms have evolved differentially in elephant seals. Furthermore, the typical fasting-induced, FGF21-mediated actions such as the inhibition of lipolysis in adipose may not be required in elephant seals as part of a naturally adapted mechanism to support their unique metabolic demands during prolonged fasting. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. FGF receptor genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Agarwal, D; Pineda, S; Michailidou, K

    2014-01-01

    Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying...... was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.Conclusion:Our results suggest...

  17. Expression of the fibroblast growth factor-2 isoforms and the FGF receptor 1-4 transcripts in the rat model system of Parkinson's disease.

    Science.gov (United States)

    Claus, Peter; Werner, Stefan; Timmer, Marco; Grothe, Claudia

    2004-04-29

    Basic fibroblast growth factor (FGF)-2 occurs in different isoforms representing different translation products of a single mRNA. We have previously shown that the high molecular weight FGF-2 isoforms (21, 23 kD) stimulated survival- and neurite-promoting activities and protective effects on cultured embryonic dopaminergic (DA) neurons of the substantia nigra (Neuroscience 100 (2000) 73). In this study the expression of FGF-2 isoforms in the striatum and substantia nigra was analyzed by Western blot in adult intact rats and following complete unilateral 6-hydroxydopamine (6-OHDA) lesion. In intact rats, all three FGF-2 isoforms (18, 21, 23 kD) are expressed. Neurotoxin-mediated lesion of nigral DA neurons revealed no change of the FGF-2 isoform expression pattern in the nigrostriatal system. Additionally, the FGF receptors 1, 2 and 3 are expressed in these tissues and displayed no alterations after 6-OHDA injection as demonstrated by RT-PCR. The presence of all three FGF-2 isoforms and the FGFR 1-3, together with the previous demonstrated neurotrophic effects of FGF-2 on dopaminergic neurons, suggest a physiological function of the FGF-2 isoforms in the nigrostriatal system.

  18. Fibroblast growth factor (FGF) signaling in development and skeletal diseases.

    Science.gov (United States)

    Teven, Chad M; Farina, Evan M; Rivas, Jane; Reid, Russell R

    2014-12-01

    Fibroblast growth factors (FGF) and their receptors serve many functions in both the developing and adult organism. Humans contain 18 FGF ligands and four FGF receptors (FGFR). FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation, differentiation, and migration, morphogenesis, and patterning. FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton. In particular, the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis. In the adult, FGFs and FGFRs are crucial for tissue repair. FGF signaling generally follows one of three transduction pathways: RAS/MAP kinase, PI3/AKT, or PLCγ. Each pathway likely regulates specific cellular behaviors. Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions, unregulated cell growth, and tumorigenesis. Additionally, aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis. The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years. Recently, work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors. The majority of FGF-related therapy is aimed at age-related disorders. Increased understanding of FGF signaling and biology may reveal additional therapeutic roles, both in utero and postnatally. This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development.

  19. The fibroblast growth factor receptor (FGFR) agonist FGF1 and the neural cell adhesion molecule-derived peptide FGL activate FGFR substrate 2alpha differently

    DEFF Research Database (Denmark)

    Chen, Yongshuo; Li, Shizhong; Berezin, Vladimir

    2010-01-01

    Activation of fibroblast growth factor (FGF) receptors (FGFRs) both by FGFs and by the neural cell adhesion molecule (NCAM) is crucial in the development and function of the nervous system. We found that FGFR substrate 2alpha (FRS2alpha), Src homologous and collagen A (ShcA), and phospholipase......-Cgamma (PLCgamma) were all required for neurite outgrowth from cerebellar granule neurons (CGNs) induced by FGF1 and FGL (an NCAM-derived peptide agonist of FGFR1). Like FGF1, FGL induced tyrosine phosphorylation of FGFR1, FRS2alpha, ShcA, and PLCgamma in a time- and dose-dependent manner. However, the activation...... of FRS2alpha by FGL was significantly lower than the activation by FGF1, indicating a differential signaling profile induced by NCAM compared with the cognate growth factor....

  20. Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression.

    Science.gov (United States)

    Feng, Shu; Dakhova, Olga; Creighton, Chad J; Ittmann, Michael

    2013-04-15

    Prostate cancer is the most common visceral malignancy and the second leading cause of cancer deaths in US men. There is broad evidence that fibroblast growth factor (FGF) receptors are important in prostate cancer initiation and progression, but the contribution of particular FGFs in this disease is not fully understood. The FGF family members FGF19, FGF21, and FGF23 comprise a distinct subfamily that circulate in serum and act in an endocrine manner. These endocrine FGFs require α-Klotho (KL) and/or β-Klotho (KLB), two related single-pass transmembrane proteins restricted in their tissue distribution, to act as coreceptors along with classic FGF receptors (FGFR) to mediate potent biologic activity. Here we show that FGF19 is expressed in primary and metastatic prostate cancer tissues, where it functions as an autocrine growth factor. Exogenous FGF19 promoted the growth, invasion, adhesion, and colony formation of prostate cancer cells at low ligand concentrations. FGF19 silencing in prostate cancer cells expressing autocrine FGF19 decreased invasion and proliferation in vitro and tumor growth in vivo. Consistent with these observations, KL and/or KLB were expressed in prostate cancer cells in vitro and in vivo, raising the possibility that additional endocrine FGFs may also exert biologic effects in prostate cancer. Our findings support the concept that therapies targeting FGFR signaling may have efficacy in prostate cancer and highlight FGF19 as a relevant endocrine FGF in this setting.

  1. Study of the interaction of the Ig2 module of the fibroblast growth factor receptor, FGFR Ig2, with the fibroblast growth factor 1, FGF1, by means of NMR spectroscopy

    DEFF Research Database (Denmark)

    Kochoyan, Artur; Poulsen, Flemming M; Berezin, Vladimir;

    2008-01-01

    Fibroblast growth factor (FGF) receptor (FGFR) consists extracellularly of three immunoglobulin (Ig) modules (Ig1-3). Currently, there are two competing models (symmetric and asymmetric) of the FGF-FGFR-heparin complex based on crystal structures. Indirect evidence exists in support of both models...

  2. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.

    Science.gov (United States)

    Degirolamo, Chiara; Sabbà, Carlo; Moschetta, Antonio

    2016-01-01

    The endocrine fibroblast growth factors (FGFs), FGF19, FGF21 and FGF23, are critical for maintaining whole-body homeostasis, with roles in bile acid, glucose and lipid metabolism, modulation of vitamin D and phosphate homeostasis and metabolic adaptation during fasting. Given these functions, the endocrine FGFs have therapeutic potential in a wide array of chronic human diseases, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. However, the safety and feasibility of chronic endocrine FGF administration has been challenged, and FGF analogues and mimetics are now being investigated. Here, we discuss current knowledge of the complex biology of the endocrine FGFs and assess how this may be harnessed therapeutically.

  3. FGF23-FGF Receptor/Klotho Pathway as a New Drug Target for Disorders of Bone and Mineral Metabolism.

    Science.gov (United States)

    Fukumoto, Seiji

    2016-04-01

    Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone and works by binding to Klotho-FGF receptor complex. Excessive and deficient actions of FGF23 result in hypophosphatemic and hyperphosphatemic diseases, respectively. Therefore, it is reasonable to think that modulating FGF23 activities may be a novel therapeutic measure for these diseases. Several preclinical reports indicate that the inhibition of FGF23 activities ameliorates hypophosphatemic rickets/osteomalacia caused by excessive actions of FGF23. In addition, phase I-II clinical trials of anti-FGF23 antibody in adult patients with X-linked hypophosphatemia rickets, the most prevalent cause of genetic FGF23-related hypophosphatemic rickets, indicated that the antibody enhances renal tubular phosphate reabsorption and increases serum phosphate. However, it is not known whether the inhibition of FGF23 activities actually brings clinical improvement of rickets and osteomalacia. Available data indicate that FGF23-FGF receptor/Klotho pathway can be a new drug target for disorders of phosphate and bone metabolism.

  4. Peptides derived from specific interaction sites of the fibroblast growth factor 2 - FGF receptor complexes induce receptor activation and signaling

    DEFF Research Database (Denmark)

    Manfè, Valentina; Kochoyan, Artur; Bock, Elisabeth

    2010-01-01

    , promoting survival of cerebellar granule neurons induced to undergo apoptosis. Our results suggest that canofins mirror the effect of specific interaction sites in FGF2 for FGFR. Thus, canofins are valuable pharmacological tools to study the functional roles of specific molecular interactions of FGF2...... by canofins, indicating that canofins are partial FGFR agonists. Furthermore, canofins were demonstrated to induce neuronal differentiation determined by neurite outgrowth from cerebellar granule neurons, and this effect was dependent on FGFR activation. Additionally, canofins acted as neuroprotectants...

  5. FGF growth factor analogs

    Science.gov (United States)

    Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY; Takahashi, Kazuyuki [Germantown, MD

    2012-07-24

    The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

  6. FGF19 functions as autocrine growth factor for hepatoblastoma.

    Science.gov (United States)

    Elzi, David J; Song, Meihua; Blackman, Barron; Weintraub, Susan T; López-Terrada, Dolores; Chen, Yidong; Tomlinson, Gail E; Shiio, Yuzuru

    2016-03-01

    Hepatoblastoma is the most common liver cancer in children, accounting for over 65% of all childhood liver malignancies. Hepatoblastoma is distinct from adult liver cancer in that it is not associated with hepatitis virus infection, cirrhosis, or other underlying liver pathology. The paucity of appropriate cell and animal models has been hampering the mechanistic understanding of hepatoblastoma pathogenesis. Consequently, there is no molecularly targeted therapy for hepatoblastoma. To gain insight into cytokine signaling in hepatoblastoma, we employed mass spectrometry to analyze the proteins secreted from Hep293TT hepatoblastoma cell line we established and identified the specific secretion of fibroblast growth factor 19 (FGF19), a growth factor for liver cells. We determined that silencing FGF19 by shRNAs or neutralizing secreted FGF19 by anti-FGF19 antibody inhibits the proliferation of hepatoblastoma cells. Furthermore, blocking FGF19 signaling by an FGF receptor kinase inhibitor suppressed hepatoblastoma growth. RNA expression analysis in hepatoblastoma tumors revealed that the high expression of FGF19 signaling pathway components as well as the low expression of FGF19 signaling repression targets correlates with the aggressiveness of the tumors. These results suggest the role of FGF19 as autocrine growth factor for hepatoblastoma.

  7. Study of the interaction of the Ig2 module of the fibroblast growth factor receptor, FGFR Ig2, with the fibroblast growth factor 1, FGF1, by means of NMR spectroscopy

    DEFF Research Database (Denmark)

    Kochoyan, Artur; Poulsen, Flemming M; Berezin, Vladimir

    2008-01-01

    Fibroblast growth factor (FGF) receptor (FGFR) consists extracellularly of three immunoglobulin (Ig) modules (Ig1-3). Currently, there are two competing models (symmetric and asymmetric) of the FGF-FGFR-heparin complex based on crystal structures. Indirect evidence exists in support of both models....... However, it is not clear which model is physiologically relevant. Our aim was to obtain direct, non-crystallographic evidence in support of them. We found by nuclear magnetic resonance that Ig2 could bind to FGF1 not only via the primary site (present in both models), but also via the secondary site...

  8. Diverse FGF receptor signaling controls astrocyte specification and proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Kyungjun [School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712 (Korea, Republic of); Song, Mi-Ryoung, E-mail: msong@gist.ac.kr [School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712 (Korea, Republic of); Bioimaging Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712 (Korea, Republic of)

    2010-05-07

    During CNS development, pluripotency neuronal progenitor cells give rise in succession to neurons and glia. Fibroblast growth factor-2 (FGF-2), a major signal that maintains neural progenitors in the undifferentiated state, is also thought to influence the transition from neurogenesis to gliogenesis. Here we present evidence that FGF receptors and underlying signaling pathways transmit the FGF-2 signals that regulate astrocyte specification aside from its mitogenic activity. Application of FGF-2 to cortical progenitors suppressed neurogenesis whereas treatment with an FGFR antagonist in vitro promoted neurogenesis. Introduction of chimeric FGFRs with mutated tyrosine residues into cortical progenitors and drug treatments to specifically block individual downstream signaling pathways revealed that the overall activity of FGFR rather than individual autophosphorylation sites is important for delivering signals for glial specification. In contrast, a signal for cell proliferation by FGFR was mainly delivered by MAPK pathway. Together our findings indicate that FGFR activity promotes astrocyte specification in the developing CNS.

  9. C-terminal tail of FGF19 determines its specificity toward Klotho co-receptors.

    Science.gov (United States)

    Wu, Xinle; Lemon, Bryan; Li, XiaoFan; Gupte, Jamila; Weiszmann, Jennifer; Stevens, Jennitte; Hawkins, Nessa; Shen, Wenyan; Lindberg, Richard; Chen, Jin-Long; Tian, Hui; Li, Yang

    2008-11-28

    FGF19 subfamily proteins (FGF19, FGF21, and FGF23) are unique members of fibroblast growth factors (FGFs) that regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis in an endocrine fashion. Their activities require the presence of alpha or betaKlotho, two related single-pass transmembrane proteins, as co-receptors in relevant target tissues. We previously showed that FGF19 can bind to both alpha and betaKlotho, whereas FGF21 and FGF23 can bind only to either betaKlotho or alphaKlotho, respectively in vitro. To determine the mechanism regulating the binding and specificity among FGF19 subfamily members to Klotho family proteins, chimeric proteins between FGF19 subfamily members or chimeric proteins between Klotho family members were constructed to probe the interaction between those two families. Our results showed that a chimera of FGF19 with the FGF21 C-terminal tail interacts only with betaKlotho and a chimera with the FGF23 C-terminal tail interacts only with alphaKlotho. FGF signaling assays also reflected the change of specificity we observed for the chimeras. These results identified the C-terminal tail of FGF19 as a region necessary for its recognition of Klotho family proteins. In addition, chimeras between alpha and betaKlotho were also generated to probe the regions in Klotho proteins that are important for signaling by this FGF subfamily. Both FGF23 and FGF21 require intact alpha or betaKlotho for signaling, respectively, whereas FGF19 can signal through a Klotho chimera consisting of the N terminus of alphaKlotho and the C terminus of betaKlotho. Our results provide the first glimpse of the regions that regulate the binding specificity between this unique family of FGFs and their co-receptors.

  10. 成纤维细胞生长因子(FGF)受体-2参与FGF-21介导的糖代谢活性%Fibroblast Growth Factor Receptor-2 Involved in FGF-21-mediated Glucose Metabolism

    Institute of Scientific and Technical Information of China (English)

    任桂萍; 李璐; 孙国鹏; 侯玉婷; 王文飞; 李德山

    2009-01-01

    最近发现,FGF-21具有很强的调节血糖和血脂的作用,已经成为糖尿病研究领域的新热点,但是其功能受体和作用机制还不清楚.前期结果表明,FGF-21促进3T3 L1脂肪细胞代谢葡萄糖,对前脂肪细胞无作用,说明脂肪细胞表达FGF-功能受体.以3T3L1脂肪细胞为靶标,旨在寻找FGF-21的功能受体.结果表明,FGF-21可与3T3L1脂肪细胞膜蛋白形成FGF-21/受体复合物,免疫检测结果发现,FGF-21/受体复合物中含有FGF受体-2(FGFR-2).为明确FGF-21/FGFR-2的特异性关系,系统研究了FGFR-2对FGF-21刺激后的酪氨酸磷酸化反应.结果表明,虽然前脂肪细胞和脂肪细胞均表达FGFR-2,但是FGF-21只诱导脂肪细胞巾表达的FGFR-2磷酸化,对前脂肪细胞表达的FGFR-2无作用,与葡萄糖吸收试验相符.FGF-21不仅可使原位表达的FGFR-2磷酸化,还可使异位表达的FGFR-2磷酸化.克隆后测序分析结果表明,FGFR-2Ⅲc是3T3 L1脂肪细胞表达的主要FGFR-2类型.这些结果提示,FGFR-2Ⅲc是FGF-21的功能受体,参与FGF-21在脂肪细胞介导的糖代谢活性.此外,系统分析了,FGFR-2在3T3L1分化过程中的筹异表达,为FGF-21在前脂肪细胞和脂肪细胞中的功能差异提供了依据.

  11. Fibroblast Growth Factor (FGF-2 and Its Receptors FGFR-2 and FGFR-3 May Be Putative Biomarkers of Malignant Transformation of Potentially Malignant Oral Lesions into Oral Squamous Cell Carcinoma.

    Directory of Open Access Journals (Sweden)

    Seema Nayak

    Full Text Available There are several factors like angiogenesis, lymphangiogenesis, genetic alterations, mutational factors that are involved in malignant transformation of potentially malignant oral lesions (PMOLs to oral squamous cell carcinoma (OSCC. Fibroblast growth factor-2 (FGF-2 is one of the prototypes of the large family of growth factors that bind heparin. FGF-2 induces angiogenesis and its receptors may play a role in synthesis of collagen. FGFs are involved in transmission of signals between the epithelium and connective tissue, and influence growth and differentiation of a wide variety of tissue including epithelia. The present study was undertaken to analyze expression of FGF-2 and its receptors FGFR-2 and FGFR-3 in 72 PMOLs, 108 OSCC and 52 healthy controls, and their role in risk assessment for malignant transformation of Leukoplakia (LKP and Oral submucous fibrosis (OSMF to OSCC. Immunohistochemistry was performed using antibodies against FGF-2, FGFR-2 and FGFR-3. IHC results were validated by Real Time PCR. Expression of FGF-2, FGFR-2 and FGFR-3 was upregulated from PMOLs to OSCC. While 90% (9/10 of PMOLs which showed malignant transformation (transformed expressed FGF-2, only 24.19% cases (15/62 of PMOLs which were not transformed (untransformed to OSCC expressed FGF-2. Similarly, FGFR-2 expression was seen in 16/62 (25.81% of untransformed PMOLs and 8/10 (80% cases of transformed PMOLs. FGFR-3 expression was observed in 23/62 (37.10% cases of untransformed PMOLs and 6/10 (60% cases of transformed PMOLs. A significant association of FGF-2 and FGFR-2 expression with malignant transformation from PMOLs to OSCC was observed both at phenotypic and molecular level. The results suggest that FGF-2 and FGFR-2 may be useful as biomarkers of malignant transformation in patients with OSMF and LKP.

  12. Fibroblast Growth Factor (FGF-2) and Its Receptors FGFR-2 and FGFR-3 May Be Putative Biomarkers of Malignant Transformation of Potentially Malignant Oral Lesions into Oral Squamous Cell Carcinoma.

    Science.gov (United States)

    Nayak, Seema; Goel, Madhu Mati; Makker, Annu; Bhatia, Vikram; Chandra, Saumya; Kumar, Sandeep; Agarwal, S P

    2015-01-01

    There are several factors like angiogenesis, lymphangiogenesis, genetic alterations, mutational factors that are involved in malignant transformation of potentially malignant oral lesions (PMOLs) to oral squamous cell carcinoma (OSCC). Fibroblast growth factor-2 (FGF-2) is one of the prototypes of the large family of growth factors that bind heparin. FGF-2 induces angiogenesis and its receptors may play a role in synthesis of collagen. FGFs are involved in transmission of signals between the epithelium and connective tissue, and influence growth and differentiation of a wide variety of tissue including epithelia. The present study was undertaken to analyze expression of FGF-2 and its receptors FGFR-2 and FGFR-3 in 72 PMOLs, 108 OSCC and 52 healthy controls, and their role in risk assessment for malignant transformation of Leukoplakia (LKP) and Oral submucous fibrosis (OSMF) to OSCC. Immunohistochemistry was performed using antibodies against FGF-2, FGFR-2 and FGFR-3. IHC results were validated by Real Time PCR. Expression of FGF-2, FGFR-2 and FGFR-3 was upregulated from PMOLs to OSCC. While 90% (9/10) of PMOLs which showed malignant transformation (transformed) expressed FGF-2, only 24.19% cases (15/62) of PMOLs which were not transformed (untransformed) to OSCC expressed FGF-2. Similarly, FGFR-2 expression was seen in 16/62 (25.81%) of untransformed PMOLs and 8/10 (80%) cases of transformed PMOLs. FGFR-3 expression was observed in 23/62 (37.10%) cases of untransformed PMOLs and 6/10 (60%) cases of transformed PMOLs. A significant association of FGF-2 and FGFR-2 expression with malignant transformation from PMOLs to OSCC was observed both at phenotypic and molecular level. The results suggest that FGF-2 and FGFR-2 may be useful as biomarkers of malignant transformation in patients with OSMF and LKP.

  13. FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway

    Institute of Scientific and Technical Information of China (English)

    Wenchao Zhou; Xiujing Feng; Yingjie Wu; Johannes Benge; Zhe Zhang; Zhengjun Chen

    2009-01-01

    Fibroblast growth factor (FGF) receptor substrate 2α (FRS2α) is the main mediator of signaling in the FGF path-way. Recent studies have shown that n/itogen-activated protein kinase (MAPK) phosphorylates serine and threonine residues in FRS2, negatively affecting FGF-induced tyrosine phosphorylation (PY) of FRS2. Several kinds of stimuli can induce serine/threonine phosphorylation (PS/T) of FRS2, indicating that FRS2 may be useful for studying cross-talk between growth factor signaling pathways. Here, we report that FGF-induced PY of FRS2 can be attenuated by EGF co-stimulation in PC12cells; this inhibitory effect could be completely reversed by U0126, an inhibitor of MEK. We further identified the ERK1/2-binding motif in FRS2 and generated FRS2-3KL, a mutant lacking MAPK binding and PT upon FGF and/or EGF stimulation. Unlike wild-type (WT) FRS2, FGF-induced PY of FRS2-3KL could not be inhibited by EGF co-stimulation, and FRS2-3KL-expressing PC12 cells exhibited more differentiating potential than FRS2-WT-expressing cells in response to FGF treatment. These results suggest that PSfr of FRS2 mediated by the FRS2-MAPK negative regulatory loop may function as a molecular switch integrating negative regulatory signals from other pathways into FGFR-generated signal transduction.

  14. Expression of Fibroblast growth factor 19 (Fgf19) during chicken embryogenesis and eye development, compared with Fgf15 expression in the mouse.

    Science.gov (United States)

    Kurose, Hitomi; Bito, Takaaki; Adachi, Taro; Shimizu, Miyuki; Noji, Sumihare; Ohuchi, Hideyo

    2004-10-01

    The normal development of eyes relies on proper signaling through Fibroblast growth factor (FGF) receptors, but the source and identity of cognate ligands have remained largely unknown. We have found that Fgf19 is expressed in the developing chicken retina. In situ hybridization discloses dynamic expression patterns for Fgf19 in the optic vesicle, lens primordia and retinal horizontal cells. Overall expression pattern of Fgf19 during chicken embryogenesis was also examined: Fgf19 is expressed in the regions associated with cranial placodes induction, boundary regions of rhombomeres, somites, specific groups of neural cells in midbrain, hindbrain, and those derived from epibranchial placodes, and the apical ectodermal ridge of limb buds. Expression pattern of the Fgf19-orthologous gene Fgf15 was further examined in the mouse developing eye. Fgf15 is expressed in the optic vesicle, a subset of progenitor cells of neural retina, and emerging ganglion and amacrine cells during retinogenesis.

  15. FGF5 as an oncogenic factor in human glioblastoma multiforme: autocrine and paracrine activities.

    Science.gov (United States)

    Allerstorfer, S; Sonvilla, G; Fischer, H; Spiegl-Kreinecker, S; Gauglhofer, C; Setinek, U; Czech, T; Marosi, C; Buchroithner, J; Pichler, J; Silye, R; Mohr, T; Holzmann, K; Grasl-Kraupp, B; Marian, B; Grusch, M; Fischer, J; Micksche, M; Berger, W

    2008-07-10

    Fibroblast growth factor 5 (FGF5) is widely expressed in embryonic but scarcely in adult tissues. Here we report simultaneous overexpression of FGF5 and its predominant high-affinity receptor (FGFR1 IIIc) in astrocytic brain tumour specimens (N=49) and cell cultures (N=49). The levels of both ligand and receptor increased with enhanced malignancy in vivo and in vitro. Furthermore, secreted FGF5 protein was generally present in the supernatants of glioblastoma (GBM) cells. siRNA-mediated FGF5 downmodulation reduced moderately but significantly GBM cell proliferation while recombinant FGF5 (rFGF5) increased this parameter preferentially in cell lines with low endogenous expression levels. Apoptosis induction by prolonged serum starvation was significantly prevented by rFGF5. Moreover, tumour cell migration was distinctly stimulated by rFGF5 but attenuated by FGF5 siRNA. Blockade of FGFR1-mediated signals by pharmacological FGFR inhibitors or a dominant-negative FGFR1 IIIc protein inhibited GBM cell proliferation and/or induced apoptotic cell death. Moreover, rFGF5 and supernatants of highly FGF5-positive GBM cell lines specifically stimulated proliferation, migration and tube formation of human umbilical vein endothelial cells. In summary, we demonstrate for the first time that FGF5 contributes to the malignant progression of human astrocytic brain tumours by both autocrine and paracrine effects.

  16. Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs

    DEFF Research Database (Denmark)

    Francavilla, Chiara; Rigbolt, Kristoffer T.G.; Emdal, Kristina B

    2013-01-01

    The stimulation of fibroblast growth factor receptors (FGFRs) with distinct FGF ligands generates specific cellular responses. However, the mechanisms underlying this paradigm have remained elusive. Here, we show that FGF-7 stimulation leads to FGFR2b degradation and, ultimately, cell proliferation......, whereas FGF-10 promotes receptor recycling and cell migration. By combining mass-spectrometry-based quantitative proteomics with fluorescence microscopy and biochemical methods, we find that FGF-10 specifically induces the rapid phosphorylation of tyrosine (Y) 734 on FGFR2b, which leads to PI3K and SH3BP4...... recruitment. This complex is crucial for FGFR2b recycling and responses, given that FGF-10 stimulation of either FGFR2b_Y734F mutant- or SH3BP4-depleted cells switches the receptor endocytic route to degradation, resulting in decreased breast cancer cell migration and the inhibition of epithelial branching...

  17. The single fgf receptor gene in the beetle Tribolium castaneum codes for two isoforms that integrate FGF8- and Branchless-dependent signals.

    Science.gov (United States)

    Sharma, Rahul; Beer, Katharina; Iwanov, Katharina; Schmöhl, Felix; Beckmann, Paula Indigo; Schröder, Reinhard

    2015-06-15

    The precise regulation of cell-cell communication by numerous signal-transduction pathways is fundamental for many different processes during embryonic development. One important signalling pathway is the evolutionary conserved fibroblast-growth-factor (FGF)-pathway that controls processes like cell migration, axis specification and mesoderm formation in vertebrate and invertebrate animals. In the model insect Drosophila, the FGF ligand / receptor combinations of FGF8 (Pyramus and Thisbe) / Heartless (Htl) and Branchless (Bnl) / Breathless (Btl) are required for the migration of mesodermal cells and for the formation of the tracheal network respectively with both the receptors functioning independently of each other. However, only a single fgf-receptor gene (Tc-fgfr) has been identified in the genome of the beetle Tribolium. We therefore asked whether both the ligands Fgf8 and Bnl could transduce their signal through a common FGF-receptor in Tribolium. Indeed, we found that the function of the single Tc-fgfr gene is essential for mesoderm differentiation as well as for the formation of the tracheal network during early development. Ligand specific RNAi for Tc-fgf8 and Tc-bnl resulted in two distinct non-overlapping phenotypes of impaired mesoderm differentiation and abnormal formation of the tracheal network in Tc-fgf8- and Tc-bnl(RNAi) embryos respectively. We further show that the single Tc-fgfr gene encodes at least two different receptor isoforms that are generated through alternative splicing. We in addition demonstrate through exon-specific RNAi their distinct tissue-specific functions. Finally, we discuss the structure of the fgf-receptor gene from an evolutionary perspective.

  18. Functions and Mechanisms of Fibroblast Growth Factor (FGF Signalling in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Hans-Arno J. Müller

    2013-03-01

    Full Text Available Intercellular signalling via growth factors plays an important role in controlling cell differentiation and cell movements during the development of multicellular animals. Fibroblast Growth Factor (FGF signalling induces changes in cellular behaviour allowing cells in the embryo to move, to survive, to divide or to differentiate. Several examples argue that FGF signalling is used in multi-step morphogenetic processes to achieve and maintain a transitional state of the cells required for the control of cell fate. In the genetic model Drosophila melanogaster, FGF signalling via the receptor tyrosine kinases Heartless (Htl and Breathless (Btl is particularly well studied. These FGF receptors affect gene expression, cell shape and cell–cell interactions during mesoderm layer formation, caudal visceral muscle (CVM formation, tracheal morphogenesis and glia differentiation. Here, we will address the current knowledge of the biological functions of FGF signalling in the fly on the tissue, at a cellular and molecular level.

  19. mRNA and protein expression of FGF-1, FGF-2 and their receptors in the porcine umbilical cord during pregnancy.

    Directory of Open Access Journals (Sweden)

    R Rekawiecki

    2011-04-01

    Full Text Available The fibroblast growth factors (FGFs are multifunctional proteins that, among other roles, regulate structural reorganization of uterine and placental vascular bed during pregnancy. Thus, we analyzed mRNA and protein expression and immunohistochemical localization of FGF-1 and FGF-2, and their receptors (FGFR-1 and FGFR-2 in the developing umbilical cord (UC on days 40, 60, 75 and 90 of pregnancy and after the physiological delivery in the pig (day 114. qPCR analysis demonstrated an increase in FGF-1 and FGF-2 mRNA levels beginning on day 75 and on day 114 of pregnancy, respectively. In addition, significantly increased FGFR-1IIIc mRNA expression was also found on day 114. On the other hand, no significant changes in FGFR-2IIIb mRNA expression were observed. Western Blot analysis revealed a decrease in FGF-1 and FGFR-2 protein expression after day 40. Beside an increased protein expression of FGF-2 on day 60, no significant changes in FGFR-1 protein expression were detected. Immunohistochemical staining enabled detection of FGF-FGFR system, with different intensity of immunoreaction in endothelial and tunica media cells of the umbilical vessels and in allantoic duct and amniotic epithelium as well as in myofibroblasts. In conclusion, our results show that members of FGF-FGFR system are expressed specifically in UC structures. Furthermore their day of pregnancy-related expression suggest that they may be an important players during UC formation and development.

  20. Fibroblast growth factor (Fgf) signaling pathway regulates liver homeostasis in zebrafish.

    Science.gov (United States)

    Tsai, Su-Mei; Liu, Da-Wei; Wang, Wen-Pin

    2013-04-01

    In mammals, fibroblast growth factor (FGF) signaling controls liver specification and regulates the metabolism of lipids, cholesterol, and bile acids. FGF signaling also promotes hepatocyte proliferation, and helps detoxify hepatotoxin during liver regeneration after partial hepatectomy. However, the function of Fgf in zebrafish liver is not yet well understood, specifically for postnatal homeostasis. The current study analyzed the expression of fgf receptors (fgfrs) in the liver of zebrafish. We then investigated the function of Fgf signaling in the zebrafish liver by expressing a dominant-negative Fgf receptor in hepatocytes (lfabp:dnfgfr1-egfp, lf:dnfr). Histological analysis showed that our genetic intervention resulted in a small liver size with defected medial expansion of developing livers in transgenic (Tg) larvae. Morphologically, the liver lobe of lf:dnfr adult fish was shorter than that of control. Ballooning degeneration of hepatocytes was observed in fish as young as 3 months. Further examination revealed the development of hepatic steatosis and cholestasis. In adult Tg fish, we unexpectedly observed increased liver-to-body-weight ratios, with higher percentages of proliferating hepatocytes. Considering all these findings, we concluded that as in mammals, in adult zebrafish the metabolism of lipid and bile acids in the liver are regulated by Fgf signaling. Disruption of the Fgf signal-mediated metabolism might indirectly affect hepatocyte proliferation.

  1. Transient global ischemia induces dynamic changes in the expression of bFGF and the FGF receptor.

    Science.gov (United States)

    Endoh, M; Pulsinelli, W A; Wagner, J A

    1994-03-01

    To study the roles of bFGF and its receptor in the process of neuronal cell death and the wound repair response, we induced 10 min of transient global cerebral ischemia in rats and measured changes in expression of both bFGF and the FGF receptor, flg. CA1 pyramidal cells are selectively vulnerable to ischemia and die one to 3 days after 10 min of ischemia. In these cells, bFGF mRNA was induced by 6 hours, reached a maximal level by 24 h after ischemia, and subsequently decreased. Message for the FGF receptor, flg, was present in the pyramidal cells layer, and vanished almost completely in parallel with neuronal death. In the granule cell layer of dentate gyrus, the expression of bFGF mRNA increased more rapidly. It was maximal by 6 h and returned to the basal level by 3 days. In the hilus of the dentate gyrus, bFGF expression was maximal at 24 h and returned to control levels by 3 days. Despite the rapid changes in expression of bFGF mRNA, there was no significant change of bFGF immunoreactivity in either the CA1 pyramidal cell layer or in the granule cell layer of dentate gyrus within 3 days after ischemia. The apparent failure of the message to be efficiently translated supports the idea that translation is impaired under conditions where ischemia leads to delayed neuronal cell death. Expression of bFGF mRNA, FGFR mRNA and bFGF immunoreactivity increased dramatically in a broad area of CA1 subfield from 7 days until 30 days after ischemia because of increased expression by reactive glial cells. We suggest that these rapid and complex changes in the expression of bFGF mRNA and bFGF protein may be part of a coordinated response to ischemic injury that is designed to minimize the severity of neuron death.

  2. FGF15/FGFR4 integrates growth factor signaling with hepatic bile acid metabolism and insulin action.

    Science.gov (United States)

    Shin, Dong-Ju; Osborne, Timothy F

    2009-04-24

    The current studies show FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation. The bile acid receptor FXR (farnesoid X receptor) activates expression of fibroblast growth factor (FGF) 15 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7alpha hydroxylase (CYP7A1) and limit bile acid production. Because FoxO1 activity and CYP7A1 gene expression are both increased by fasting, we hypothesized CYP7A1 might be a FoxO1 target gene. Consistent with recently reported results, we show CYP7A1 is a direct target of FoxO1. Additionally, we show that the PI 3-kinase pathway is key for both the induction of CYP7A1 by fasting and the suppression by FGF15. FGFR4 is the major hepatic FGF receptor isoform and is responsible for the hepatic effects of FGF15. We also show that expression of FGFR4 in liver was decreased by fasting, increased by insulin, and reduced by streptozotocin-induced diabetes, implicating FGFR4 as a primary target of insulin regulation. Because insulin and FGF both target the PI 3-kinase pathway, these observations suggest FoxO1 is a key node in the convergence of FGF and insulin signaling pathways and functions as a key integrator for the regulation of glucose and bile acid metabolism.

  3. Up-regulation of fibroblast growth factor (FGF) 9 expression and FGF-WNT/β-catenin signaling in laser-induced wound healing.

    Science.gov (United States)

    Zheng, Zhenlong; Kang, Hye-Young; Lee, Sunha; Kang, Shin-Wook; Goo, Boncheol; Cho, Sung Bin

    2014-01-01

    Fibroblast growth factor (FGF) 9 is secreted by both mesothelial and epithelial cells, and plays important roles in organ development and wound healing via WNT/β-catenin signaling. The aim of this study was to evaluate FGF9 expression and FGF-WNT/β-catenin signaling during wound healing of the skin. We investigated FGF9 expression and FGF-WNT/β-catenin signaling after laser ablation of mouse skin and adult human skin, as well as in cultured normal human epidermal keratinocytes (NHEKs) upon stimulation with recombinant human (rh) FGF9 and rh-transforming growth factor (TGF)-β1. Our results showed that laser ablation of both mouse skin and human skin leads to marked overexpression of FGF9 and FGF9 mRNA. Control NHEKs constitutively expressed FGF9, WNT7b, WNT2, and β-catenin, but did not show Snail or FGF receptor (FGFR) 2 expression. We also found that FGFR2 was significantly induced in NHEKs by rhFGF9 stimulation, and observed that FGFR2 expression was slightly up-regulated on particular days during the wound healing process after ablative laser therapy. Both WNT7b and WNT2 showed up-regulated protein expression during the laser-induced wound healing process in mouse skin; moreover, we discerned that the stimulatory effect of rhFGF9 and rhTGF-β1 activates WNT/β-catenin signaling via WNT7b in cultured NHEKs. Our data indicated that rhFGF9 and/or rhTGF-β1 up-regulate FGFR2, WNT7b, and β-catenin, but not FGF9 and Snail; pretreatment with rh dickkopf-1 significantly inhibited the up-regulation of FGFR2, WNT7b, and β-catenin. Our results suggested that FGF9 and FGF-WNT/β-catenin signaling may play important roles in ablative laser-induced wound healing processes. © 2014 by the Wound Healing Society.

  4. Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations.

    Science.gov (United States)

    Wilkie, Andrew O M

    2005-04-01

    The discovery in 1994 that highly specific mutations of fibroblast growth factor (FGF) receptor 3 caused the most common form of human short-limbed dwarfism, achondroplasia, heralded a new era in FGF receptor (FGFR) biology. A decade later, the purpose of this review is to survey how the study of humans with FGFR mutations continues to provide insights into FGFR function in health and disease, and the clinical applications of these findings. Amongst the most interesting recent discoveries have been the description of novel phenotypes associated with FGFR1 and FGFR3 mutations; identification of fundamental differences in the cellular mechanisms of mutant FGFR2 and FGFR3 action; and the direct identification of FGFR2 and FGFR3 mutations in sperm. These clinical observations illustrate the pleiotropism of FGFR action and fuel ongoing efforts to understand the rich biology and pathophysiology of the FGF signalling system.

  5. Identification of soluble forms of the fibroblast growth factor receptor in blood.

    OpenAIRE

    Hanneken, A; Ying, W; Ling, N; Baird, A.

    1994-01-01

    We have purified three acidic (FGF-1) and basic (FGF-2) fibroblast growth factor binding proteins (FGF-BP1, FGF-BP2, and FGF-BP3) from human plasma and calf serum and demonstrate the presence of these circulating FGF-BPs in blood. Each are truncated forms of the high-affinity FGF receptor (FGFR-1). FGF-BP1 and FGF-BP2 have estimated molecular masses of 70-85 kDa and 55-60 kDa, respectively, and are detected by using 125I-labeled FGF-2 ligand blotting. Immunoblotting with four distinct antibod...

  6. Effects of FGF receptor peptide agonists on animal behavior under normal and pathological conditions

    DEFF Research Database (Denmark)

    Rudenko, Olga; Tkach, Vadym; Berezin, Vladimir

    2010-01-01

    Hexafins are recently identified low-molecular-weight peptide agonists of the fibroblast growth factor receptor (FGFR), derived from the ß6–ß7 loop region of various FGFs. Synthetic hexafin peptides have been shown to bind to and induce tyrosine phosphorylation of FGFR1, stimulate neurite outgrowth......, and promote neuronal survival in vitro. Thus, the pronounced biological activities of hexafins in vitro make them attractive compounds for pharmacological studies in vivo. The present study investigated the effects of subcutaneous administration of hexafin1 and hexafin2 (peptides derived from FGF1 and FGF2...

  7. TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition.

    Science.gov (United States)

    Shirakihara, Takuya; Horiguchi, Kana; Miyazawa, Keiji; Ehata, Shogo; Shibata, Tatsuhiro; Morita, Ikuo; Miyazono, Kohei; Saitoh, Masao

    2011-02-16

    The epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair, and cancer progression in adult tissues. Here, we demonstrate that transforming growth factor (TGF)-β induced EMT and that long-term exposure to TGF-β elicited the epithelial-myofibroblastic transition (EMyoT) by inactivating the MEK-Erk pathway. During the EMT process, TGF-β induced isoform switching of fibroblast growth factor (FGF) receptors, causing the cells to become sensitive to FGF-2. Addition of FGF-2 to TGF-β-treated cells perturbed EMyoT by reactivating the MEK-Erk pathway and subsequently enhanced EMT through the formation of MEK-Erk-dependent complexes of the transcription factor δEF1/ZEB1 with the transcriptional corepressor CtBP1. Consequently, normal epithelial cells that have undergone EMT as a result of combined TGF-β and FGF-2 stimulation promoted the invasion of cancer cells. Thus, TGF-β and FGF-2 may cooperate with each other and may regulate EMT of various kinds of cells in cancer microenvironment during cancer progression.

  8. Expression of VEGF, b-FGF, and their receptors after injection of VEGF on ischemic heart muscle

    Institute of Scientific and Technical Information of China (English)

    XU Xun-yu; SUN Lin; HAN Tao; CHEN Wen-hong; CUI Yong; LI Yan

    2004-01-01

    Objective: To study the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) and their receptors after injection of external VEGF on ischemic heart muscle and to investigate the mechanism of therapeutic myocardial angiogenesis of VEGF. Methods: Standard experimental pigs underwent placement of a left circumflex artery ameroid occluder. Six weeks later, the animals in the experimental group were treated with VEGF (20μg) by direct epicardial injection ( n = 8) and other animals in the control group did not receive any treatment ( n = 8).Four weeks after therapy, the animals were evaluated with regard to mRNA and protein expression of VEGF and b-FGF and their receptors by RT-PCR and Western blotting. Results: The mRNA expression of VEGF and b-FGF and their receptors by RT-PCR expressing as percentage of density ratio to the GAPDH control was increased in experimental group versus control group. The protein expression of VEGF and b-FGF and their receptors by Western blot expressing as percentage of density ratio to the Commassie Blue control was increased in experimental group versus control Group. Conclusion: Exogenous VEGF can induce the expression of endogenous VEGF, b-FGF, and their receptors; b-FGF may play a role in the angiogenesis of VEGF.

  9. Applications of basic fibroblastic growth factor (FGF-2, bFGF) in dentistry.

    Science.gov (United States)

    Sonmez, Ayse B; Castelnuovo, Jacopo

    2014-04-01

    Recent developments in research have been based on the maintenance and regeneration of natural organs and tissues; among such developments is the use of growth factors (GFs). The use of basic fibroblastic growth factors (bFGF) may be indicated in different disciplines of dentistry such as periodontics and dental traumatology. These cells' ability to induce proliferation and differentiation of cells may make GFs a useful source for the development of natural structures. This mini-review will discuss how bFGF can be beneficial to dentistry in relation to 1) re-implantation/autotransplantation of avulsed teeth and 2) periodontal regeneration.

  10. Effect of mammogenic hormones on the expression of FGF7, FGF10 and their receptor in mouse mammary gland

    Institute of Scientific and Technical Information of China (English)

    CUI Yingdun; LI QingZhang

    2008-01-01

    To investigate the regulation of estrogen, progesterone and prolactin stimulating the development of mammary gland, the Kunming mice were used as experimental animals in this study. Through the ex-periment in vitro, the effect of mammogenic hormones were systematically investigated on expression of FGF7 and FGF10 and their receptor in different periods. The results are as follows: in mammary glands of mice, 17 beta-estradiol increased the expression of FGF7; progesterone did not affect the expression of FGF7; prolactin up-regulated the expression of FGF7 significantly in pregnancy and lac-tation. 17 beta-estradiol increased the expression of FGF10; progesterone and prolactin reduced the expression of FGF10 significantly in virgin; prolactin significantly increased the expression of FGF10 in pregnancy. When 17 beta-estradiol in the body was in relatively high proportion, it would lower the ex-pression of KGFR; while 17 beta-estradiol in the body was in relatively low proportion, it would increase the expression of KGFR. Low concentration of progesterone increased the expression of KGFR and high progesterone did not affect the expression of KGFR. Prolactin increased the expression of KGFR significantly in pregnancy and lactation.

  11. Nuclear fibroblast growth factor 2 (FGF2) isoforms inhibit bone marrow stromal cell mineralization through FGF23/FGFR/MAPK in vitro.

    Science.gov (United States)

    Xiao, Liping; Esliger, Alycia; Hurley, Marja M

    2013-01-01

    Fibroblast growth factor 23 (FGF23) is responsible for phosphate wasting and the phenotypic changes observed in human diseases such as X-linked hypophosphatemia (XLH). Targeted overexpression of nuclear high-molecular weight fibroblast growth factor 2 isoforms (HMW isoforms) in osteoblasts resulted in a transgenic mouse with phenotypic changes similar to XLH, including increased FGF23, hypophosphatemia, and rickets/osteomalacia. The goal of this study was to assess whether HMW isoforms also reduced mineralized bone formation via phosphate-independent effects in bone marrow stromal cells (BMSCs) by modulating FGF23/FGF receptor (FGFR)/extracellular signal-regulated kinase (ERK) signaling. To determine if decreased bone formation in BMSC cultures from HMW transgenic mice could be rescued by blocking this pathway, an FGF23 neutralizing antibody, the FGFR tyrosine kinase inhibitor SU5402 and the mitogen-activated protein kinase (MAPK) inhibitor PD98059 were used. FGF23 levels in the conditioned medium of HMW BMSC cultures were dramatically increased compared to BMSC from control (Vector) mice. Mineralized nodule formation was significantly decreased in HMW BMSC cultures compared with control cultures. The decreased nodule formation in HMW cultures was partially rescued by the FGF23 neutralizing antibody, SU5402 and PD98059. mRNA levels for the osteoblast-related genes, osteocalcin, Runt-related transcription factor 2 (Runx2), and osterix, and the osteocyte-related gene dentin matrix acidic phosphoprotein 1 (Dmp1) were significantly decreased in HMW cultures compared with control cultures, and the decreases were partially rescued by SU5402 or PD98059 treatment. Matrix-gla-protein (Mgp) mRNA was significantly higher in HMW cultures compared with control cultures, reduced by SU5402, but further increased by PD98059. Our results suggest that phosphate-independent effects of HMW isoforms in vitro may be directly mediated in part via FGF23 and that HMW isoforms signal via

  12. Neuron-glia interactions through the Heartless FGF receptor signaling pathway mediate morphogenesis of Drosophila astrocytes.

    Science.gov (United States)

    Stork, Tobias; Sheehan, Amy; Tasdemir-Yilmaz, Ozge E; Freeman, Marc R

    2014-07-16

    Astrocytes are critically important for neuronal circuit assembly and function. Mammalian protoplasmic astrocytes develop a dense ramified meshwork of cellular processes to form intimate contacts with neuronal cell bodies, neurites, and synapses. This close neuron-glia morphological relationship is essential for astrocyte function, but it remains unclear how astrocytes establish their intricate morphology, organize spatial domains, and associate with neurons and synapses in vivo. Here we characterize a Drosophila glial subtype that shows striking morphological and functional similarities to mammalian astrocytes. We demonstrate that the Fibroblast growth factor (FGF) receptor Heartless autonomously controls astrocyte membrane growth, and the FGFs Pyramus and Thisbe direct astrocyte processes to ramify specifically in CNS synaptic regions. We further show that the shape and size of individual astrocytes are dynamically sculpted through inhibitory or competitive astrocyte-astrocyte interactions and Heartless FGF signaling. Our data identify FGF signaling through Heartless as a key regulator of astrocyte morphological elaboration in vivo.

  13. FGF receptor antagonism does not affect adipose tissue development in nutritionally induced obesity.

    Science.gov (United States)

    Scroyen, Ilse; Vranckx, Christine; Lijnen, Henri Roger

    2014-01-01

    The fibroblast growth factor (FGF)-FGF receptor (FGFR) system plays a role in angiogenesis and maintenance of vascular integrity, but its potential role in adipose tissue related angiogenesis and development is still unknown. Administration of SSR, a low molecular weight inhibitor of multiple FGFRs, did not significantly affect body weight nor weight of subcutaneous or gonadal (GON) fat, as compared with pair-fed control mice. Adipocyte hypertrophy and reduced adipocyte density were only observed in GON adipose tissues of treated mice. Adipose tissue angiogenesis was not affected by SSR treatment, as normalized blood vessel density was comparable in adipose tissues of both groups. Blocking the FGF-FGFR system in vivo does not markedly affect adipose tissue development in mice with nutritionally induced obesity.

  14. Characterization of FGF family growth factors concerning branching morphogenesis of mouse lung epithelium.

    Science.gov (United States)

    Goto, Asami; Yamazaki, Naohiro; Nogawa, Hiroyuki

    2014-05-01

    Mouse lung rudiments express eight members of fibroblast growth factor (FGF) family genes from embryonic day 10 (E10) to E13. Some of these are expressed in either the epithelium or mesenchyme, while others are expressed in both. Incorporating the results of our previous study, we characterized the branch-inducing activities of all of FGFs expressed in the early lung rudiment. Of these, FGF1, FGF2, FGF7, FGF9 and FGF10 induced branching morphogenesis in Matrigel-embedded E11 epithelium, and their effective concentrations varied (10 nM, 10 nM, 3 nM, 1 nM, and 100 nM, respectively). Whereas shaking culture dishes containing medium supplemented with FGF7 or FGF10 showed reduced branching morphogenesis, those supplemented with FGF1, FGF2, or FGF9 did not, suggesting the involvement of autocrine growth factor(s) in branching morphogenesis induced by FGF7 or FGF10. In the presence of heparin, a well-known activator of FGF signaling, cystic morphology with lumen expansion was observed in cultures containing FGF1, FGF7, or FGF10, but growth arrest was observed in cultures containing FGF2 or FGF9. These results indicate that several paracrine and autocrine FGFs function during branching morphogenesis of lung epithelium.

  15. FGF19 and cancer.

    Science.gov (United States)

    Lin, Benjamin C; Desnoyers, Luc R

    2012-01-01

    Fibroblast growth factors (FGFs) and their cognate receptors, FGF receptors (FGFRs), play critical roles in a variety of normal developmental and physiological processes. Numerous reports support a role for deregulation of FGF-FGFR signaling, whether it is at the ligand and/or receptor level, in tumor development and progression. The FGF19-FGFR4 signaling axis has been implicated in the pathogenesis of several cancers, including hepatocellular carcinomas in mice and potentially in humans. This chapter focuses on recent progress in the understanding of the molecular mechanisms of FGF19 action and its potential involvement in cancer.

  16. Nuclear isoforms of fibroblast growth factor 2 are novel inducers of hypophosphatemia via modulation of FGF23 and KLOTHO.

    Science.gov (United States)

    Xiao, Liping; Naganawa, Takahiro; Lorenzo, Joseph; Carpenter, Thomas O; Coffin, J Douglas; Hurley, Marja M

    2010-01-22

    FGF2 transgenic mice were developed in which type I collagen regulatory sequences drive the nuclear high molecular weight FGF2 isoforms in osteoblasts (TgHMW). The phenotype of TgHMW mice included dwarfism, decreased bone mineral density (BMD), osteomalacia, and decreased serum phosphate (P(i)). When TgHMW mice were fed a high P(i) diet, BMD was increased, and dwarfism was partially reversed. The TgHMW phenotype was similar to mice overexpressing FGF23. Serum FGF23 was increased in TgHMW mice. Fgf23 mRNA in bones and fibroblast growth factor receptors 1c and 3c and Klotho mRNAs in kidneys were increased in TgHMW mice, whereas the renal Na(+)/P(i) co-transporter Npt2a mRNA was decreased. Immunohistochemistry and Western blot analyses of TgHMW kidneys showed increased KLOTHO and decreased NPT2a protein. The results suggest that overexpression of HMW FGF2 increases FGF23/FGFR/KLOTHO signaling to down-regulate NPT2a, causing P(i) wasting, osteomalacia, and decreased BMD. We assessed whether HMW FGF2 expression was altered in the Hyp mouse, a mouse homolog of the human disease X-linked hypophosphatemic rickets/osteomalacia. Fgf2 mRNA was increased in bones, and Western blots showed increased FGF2 protein in nuclear fractions from osteoblasts of Hyp mice. In addition, immunohistochemistry demonstrated co-localization of FGF23 and HMW FGF2 protein in osteoblasts and osteocytes from Hyp mice. This study reveals a novel mechanism of regulation of the FGF23-P(i) homeostatic axis.

  17. Age-Related Changes in FGF-2, Fibroblast Growth Factor Receptors and β-Catenin Expression in Human Mesenchyme-Derived Progenitor Cells.

    Science.gov (United States)

    Hurley, Marja M; Gronowicz, Gloria; Zhu, Li; Kuhn, Liisa T; Rodner, Craig; Xiao, Liping

    2016-03-01

    FGF-2 stimulates preosteoblast replication, and knockout of the FGF-2 gene in mice resulted in osteopenia with age, associated with decreased Wnt-β-Catenin signaling. In addition, targeted expression of FGF-2 in osteoblast progenitors increased bone mass in mice via Wnt-β-Catenin signaling. We posited that diminution of the intrinsic proliferative capacity of human mesenchyme-derived progenitor cells (HMDPCs) with age is due in part to reduction in FGF-2. To test this hypothesis HMDPCs from young (27-38), middle aged (47-56), and old (65-76) female human subjects were isolated from bone discarded after orthopedic procedures. HMDPCs cultures were mostly homogeneous with greater than 90% mesenchymal progenitor cells, determined by fluorescence-activated cell sorting. There was a progressive decrease in FGF-2 and FGFR1 mRNA and protein in HMDPCs with age. Since FGF-2 activates β-catenin, which can enhance bone formation, we also assessed its age-related expression in HMDPCs. An age-related decrease in total-β-Catenin mRNA and protein expression was observed. However there were increased levels of p-β-Catenin and decreased levels of activated-β-Catenin in old HMDSCs. FGF-2 treatment increased FGFR1 and β-Catenin protein, reduced the level of p-β-Catenin and increased activated-β-Catenin in aged HMDPCs. In conclusion, reduction in FGF-2 expression could contribute to age-related impaired function of HMDPCs via modulation of Wnt-β-catenin signaling.

  18. Chronic Over-expression of Fibroblast Growth Factor 21 Increases Bile Acid Biosynthesis by Opposing FGF15/19 Action

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    2017-02-01

    Full Text Available Pharmacological doses of fibroblast growth factor (FGF 21 effectively normalize glucose, lipid and energy homeostasis in multiple animal models with many benefits translating to obese humans with type 2 diabetes. However, a role for FGF21 in the regulation of bile acid metabolism has not been reported. Herein, we demonstrate AAV-mediated FGF21 overexpression in mice increases liver expression of the key bile acid producing enzyme, Cyp7a1, resulting in an increased bile acid pool. Furthermore, in cholecystectomized mice, FGF21-mediated bile acid pool increase led to increased transit of bile acids into colon. We elucidate that the mechanism of FGF21 induced bile acid changes is mainly through antagonizing FGF15/19 function on liver βKlotho/FGFR4 receptor complex; thus inhibiting FGF15/19-mediated suppression of Cyp7a1 expression. In conclusion, these data reveal a previously unidentified role for FGF21 on bile acid metabolism and may be relevant to understand the effects of FGF21 analogs in clinical studies.

  19. High fibroblast growth factor 19 (FGF19) expression predicts worse prognosis in invasive ductal carcinoma of breast.

    Science.gov (United States)

    Buhmeida, Abdelbaset; Dallol, Ashraf; Merdad, Adnan; Al-Maghrabi, Jaudah; Gari, Mamdooh A; Abu-Elmagd, Muhammad M; Chaudhary, Adeel G; Abuzenadah, Adel M; Nedjadi, Taoufik; Ermiah, Eramah; Al-Thubaity, Fatima; Al-Qahtani, Mohammed H

    2014-03-01

    Metabolic diseases like diabetes and obesity are major risk factors for breast cancer. Aberrant expression of metabolic effectors such as fibroblast growth factor 19 (FGF19) could be therefore associated with the disease. The expression of FGF19 was examined in 193 archival breast tumor samples by immunohistochemistry and evaluated semi-quantitatively by determining the staining index and correlating it with clinicopathological parameters using Fisher's exact test. The correlation between FGF19 expression and 5-year disease-specific survival rate was determined using the univariate Kaplan-Meier analysis. The prognostic value of FGF19 expression was evaluated using the multivariate Cox regression analysis. Of the 193 tumors analyzed, 40% were classified with low FGF19 expression, whereas 60% were categorized as tumors with high FGF19 expression. There was a highly significant correlation between high FGF19 expression and patients' age (p = 0.008) as well as 5-year disease-specific survival (p = 0.001). However, FGF19 expression did not show any significant correlations with other clinicopathological parameters, including hormonal status, tumor grade, tumor size, or lymph node status. Univariate Kaplan-Meier log rank analysis showed that patients with high FGF19 expression exhibited a significantly shorter disease-specific 5-year survival (p = 0.007). This effect was exacerbated by lymph node metastasis (p = 0.001), negative estrogen receptor (ER) status (p = 0.002), or old age (p = 0.013). Multivariate analysis showed that high FGF19 expression could be an independent prognostic marker of disease-specific survival in breast cancer patients (p = 0.030). Quantification of FGF19 expression appears to provide valuable prognostic information in breast cancer, particularly in older patients with lymph node metastasis and negative ER status.

  20. Fibroblast growth factor 23 and its receptors.

    Science.gov (United States)

    Yu, Xijie; White, Kenneth E

    2005-08-01

    Fibroblast growth factor 23 (FGF23) is a circulating factor that plays critical roles in phosphate and vitamin D metabolism, as evidenced by the fact that FGF23 missense mutations cause autosomal dominant hypophosphatemic rickets (ADHR). Autosomal dominant hypophosphatemic rickets is characterized by hypophosphatemia with inappropriately normal 1,25-dihydroxyvitamin D concentrations, as well as bone pain, fracture and rickets. This phenotype parallels that of patients with tumor induced osteomalacia (TIO), X-linked hypophosphatemic rickets (XLH), and fibrous dysplasia (FD), in whom elevated serum FGF23 levels are often observed. The fibroblast growth factor receptors (FGFR1-4) play key roles in skeletal development, as well as in normal metabolic processes. Several FGFR isoforms that potentially mediate the activity of FGF23 have been implicated. In the short term, these findings will lead to further understanding of FGF23 function, and potentially in the long term, to targeted therapies in disorders of hypo- and hyperphosphatemia that involve FGF23.

  1. Fibronectin type III (FN3) modules of the neuronal cell adhesion molecule L1 interact directly with the fibroblast growth factor (FGF) receptor

    DEFF Research Database (Denmark)

    Kulahin, Nikolaj; Li, Shizhong; Hinsby, Anders Mørkeberg

    2008-01-01

    The neuronal cell adhesion molecule (CAM) L1 promotes axonal outgrowth, presumably through an interaction with the fibroblast growth factor receptor (FGFR). The present study demonstrates a direct interaction between L1 fibronectin type III (FN3) modules I-V and FGFR1 immunoglobulin (Ig) modules ...

  2. Syndecan-1 and FGF-2, but not FGF receptor-1, share a common transport route and co-localize with heparanase in the nuclei of mesenchymal tumor cells.

    Directory of Open Access Journals (Sweden)

    Fang Zong

    Full Text Available Syndecan-1 forms complexes with growth factors and their cognate receptors in the cell membrane. We have previously reported a tubulin-mediated translocation of syndecan-1 to the nucleus. The transport route and functional significance of nuclear syndecan-1 is still incompletely understood. Here we investigate the sub-cellular distribution of syndecan-1, FGF-2, FGFR-1 and heparanase in malignant mesenchymal tumor cells, and explore the possibility of their coordinated translocation to the nucleus. To elucidate a structural requirement for this nuclear transport, we have transfected cells with a syndecan-1/EGFP construct or with a short truncated version containing only the tubulin binding RMKKK sequence. The sub-cellular distribution of the EGFP fusion proteins was monitored by fluorescence microscopy. Our data indicate that syndecan-1, FGF-2 and heparanase co-localize in the nucleus, whereas FGFR-1 is enriched mainly in the perinuclear area. Overexpression of syndecan-1 results in increased nuclear accumulation of FGF-2, demonstrating the functional importance of syndecan-1 for this nuclear transport. Interestingly, exogenously added FGF-2 does not follow the route taken by endogenous FGF-2. Furthermore, we prove that the RMKKK sequence of syndecan-1 is necessary and sufficient for nuclear translocation, acting as a nuclear localization signal, and the Arginine residue is vital for this localization. We conclude that syndecan-1 and FGF-2, but not FGFR-1 share a common transport route and co-localize with heparanase in the nucleus, and this transport is mediated by the RMKKK motif in syndecan-1. Our study opens a new perspective in the proteoglycan field and provides more evidence of nuclear interactions of syndecan-1.

  3. Exercise increases serum fibroblast growth factor 21 (FGF21 levels.

    Directory of Open Access Journals (Sweden)

    Daniel Cuevas-Ramos

    Full Text Available BACKGROUND: Fibroblast growth factor 21 (FGF21 increases glucose uptake. It is unknown if FGF21 serum levels are affected by exercise. METHODOLOGY/PRINCIPAL FINDINGS: This was a comparative longitudinal study. Anthropometric and biochemical evaluation were carried out before and after a bout of exercise and repeated after two weeks of daily supervised exercise. The study sample was composed of 60 sedentary young healthy women. The mean age was 24±3.7 years old, and the mean BMI was 21.4±7.0 kg/m². The anthropometric characteristics did not change after two weeks of exercise. FGF21 levels significantly increased after two weeks of exercise (276.8 ng/l (142.8-568.6 vs. (460.8 (298.2-742.1, p<0.0001. The delta (final-basal log of serum FGF21, adjusted for BMI, showed a significant positive correlation with basal glucose (r = 0.23, p = 0.04, mean maximal heart rate (MHR (r = 0.54, p<0.0001, mean METs (r = 0.40, p = 0.002, delta plasma epinephrine (r = 0.53, p<0.0001 and delta plasma FFAs (r = 0.35, p = 0.006. A stepwise linear regression model showed that glucose, MHR, METs, FFAs, and epinephrine, were factors independently associated with the increment in FGF21 after the exercise program (F = 4.32; r² = 0.64, p<0.0001. CONCLUSIONS: Serum FGF21 levels significantly increased after two weeks of physical activity. This increment correlated positively with clinical parameters related to the adrenergic and lipolytic response to exercise. TRIAL REGISTRATION: ClinicalTrials.gov NCT01512368.

  4. FGF19-induced Hepatocyte Proliferation Is Mediated through FGFR4 Activation

    OpenAIRE

    Wu, Xinle; Ge, Hongfei; Lemon, Bryan; Vonderfecht, Steven; Weiszmann, Jennifer; Hecht, Randy; Gupte, Jamila; Hager, Todd; Wang, Zhulun; Lindberg, Richard; Li, Yang

    2009-01-01

    FGF19 and FGF21, unique members of the fibroblast growth factor (FGF) family, are hormones that regulate glucose, lipid, and energy homeostasis. Increased hepatocyte proliferation and liver tumor formation have also been observed in FGF19 transgenic mice. Here, we report that, in contrast to FGF19, FGF21 does not induce hepatocyte proliferation in vivo. To identify the mechanism for FGF19-induced hepatocyte proliferation, we explored similarities and differences in receptor specificity betwee...

  5. Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19).

    Science.gov (United States)

    Wu, Xinle; Ge, Hongfei; Lemon, Bryan; Vonderfecht, Steven; Baribault, Helene; Weiszmann, Jennifer; Gupte, Jamila; Gardner, Jonitha; Lindberg, Richard; Wang, Zhulun; Li, Yang

    2010-08-10

    FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Their potent effects on normalizing glucose, lipid, and energy homeostasis in disease models have made them an interesting focus of research for combating the growing epidemics of diabetes and obesity. Despite overlapping functions, FGF19 and FGF21 have many discrete effects, the most important being that FGF19 has both metabolic and proliferative effects, whereas FGF21 has only metabolic effects. Here we identify the structural determinants dictating differential receptor interactions that explain and distinguish these two physiological functions. We also have generated FGF19 variants that have lost the ability to induce hepatocyte proliferation but that still are effective in lowering plasma glucose levels and improving insulin sensitivity in mice. Our results add valuable insight into the structure-function relationship of FGF19/FGF21 and identify the structural basis underpinning the distinct proliferative feature of FGF19 compared with FGF21. In addition, these studies provide a road map for engineering FGF19 as a potential therapeutic candidate for treating diabetes and obesity.

  6. Expression and function of fibroblast growth factor (FGF) 9 in hepatic stellate cells and its role in toxic liver injury.

    Science.gov (United States)

    Antoine, Marianne; Wirz, Werner; Tag, Carmen G; Gressner, Axel M; Marvituna, Meltem; Wycislo, Mathias; Hellerbrand, Claus; Kiefer, Paul

    2007-09-21

    Hepatic injury and regeneration of the liver are associated with activation of hepatic stellate cells (HSC). Fibroblast growth factors (FGFs) and their receptors are important regulators of repair in various tissues. HSC express FGFR3IIIc as well as FGFGR4 and different spliced FGFR1IIIc and FGFR2IIIc isoforms which differ in the presence or absence of the acid box and of the first Ig-like domain. Expression of FGF9, known to be capable to activate the HSC FGFR2/3-isoforms, was increased in HSC in liver slice cultures after exposition to carbon tetrachloride, as an acute liver injury model. FGF9 significantly stimulated 3-H thymidine incorporation of hepatocytes, but failed to induce DNA synthesis in HSC despite the fact that FGF9 induced a sustained activation of extracellular signal-related kinases (ERK) 1/2. FGF9 induced an increased phosphorylation of Tyr436 of the fibroblast growth factor receptor substrate (FRS) 2, while phosphorylation of Tyr196 which is required for efficient Grb2 recruitment remained unchanged. Our findings suggest that HSC FGF9 provide a paracrine mitogenic signal to hepatocytes during acute liver injury, while the autocrine FGF9 signaling appears to be not sufficient to induce cell proliferation.

  7. Dual blockade of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) exhibits potent anti-angiogenic effects.

    Science.gov (United States)

    Li, Dong; Xie, Kun; Zhang, Longzhen; Yao, Xuejing; Li, Hongwen; Xu, Qiaoyu; Wang, Xin; Jiang, Jing; Fang, Jianmin

    2016-07-28

    Both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF or FGF-2) are potent pro-angiogenic factors and play a critical role in cancer development and progression. Clinical anti-VEGF therapy trials had a major challenge due to upregulated expression of other pro-angiogenic factor, like FGF-2. This study developed a novel chimeric decoy receptor VF-Trap fusion protein to simultaneously block activity of both VEGF and FGF pathways in order to achieve an additive or synergistic anti-tumor effect. Our in vitro data showed that VF-Trap potently blocked proliferation and migration of both VEGF- and FGF-2-induced vascular endothelial cells. In animal models, treatment of xenograft tumors with VF-Trap resulted in significant inhibition of tumor growth compared to blockage of the single molecule, like VEGF or FGF blocker. In addition, VF-Trap was also more potent in inhibition of ocular angiogenesis in a mouse oxygen-induced retinopathy (OIR) model. These data demonstrated the potent anti-angiogenic effects of this novel VF-Trap fusion protein on blockage of VEGF and FGF-2 activity in vitro and in animal models. Further study will assess its effects in clinic as a therapeutic agent for angiogenesis-related disorders, such as cancer and ocular vascular diseases.

  8. Lower cerebrospinal fluid/plasma fibroblast growth factor 21 (FGF21 ratios and placental FGF21 production in gestational diabetes.

    Directory of Open Access Journals (Sweden)

    Bee K Tan

    Full Text Available OBJECTIVES: Circulating Fibroblast Growth Factor 21 (FGF21 levels are increased in insulin resistant states such as obesity, type 2 diabetes mellitus and gestational diabetes mellitus (GDM. In addition, GDM is associated with serious maternal and fetal complications. We sought to study human cerebrospinal fluid (CSF and corresponding circulating FGF21 levels in women with gestational diabetes mellitus (GDM and in age and BMI matched control subjects. We also assessed FGF21 secretion from GDM and control human placental explants. DESIGN: CSF and corresponding plasma FGF21 levels of 24 women were measured by ELISA [12 GDM (age: 26-47 years, BMI: 24.3-36.3 kg/m(2 and 12 controls (age: 22-40 years, BMI: 30.1-37.0 kg/m(2]. FGF21 levels in conditioned media were secretion from GDM and control human placental explants were also measured by ELISA. RESULTS: Glucose, HOMA-IR and circulating NEFA levels were significantly higher in women with GDM compared to control subjects. Plasma FGF21 levels were significantly higher in women with GDM compared to control subjects [234.3 (150.2-352.7 vs. 115.5 (60.5-188.7 pg/ml; P<0.05]. However, there was no significant difference in CSF FGF21 levels in women with GDM compared to control subjects. Interestingly, CSF/Plasma FGF21 ratio was significantly lower in women with GDM compared to control subjects [0.4 (0.3-0.6 vs. 0.8 (0.5-1.6; P<0.05]. FGF21 secretion into conditioned media was significantly lower in human placental explants from women with GDM compared to control subjects (P<0.05. CONCLUSIONS: The central actions of FGF21 in GDM subjects maybe pivotal in the pathogenesis of insulin resistance in GDM subjects. The significance of FGF21 produced by the placenta remains uncharted and maybe crucial in our understanding of the patho-physiology of GDM and its associated maternal and fetal complications. Future research should seek to elucidate these points.

  9. Differential expression of specific FGF ligands and receptor isoforms during osteogenic differentiation of mouse Adipose-derived Stem Cells (mASCs) recapitulates the in vivo osteogenic pattern.

    Science.gov (United States)

    Quarto, Natalina; Longaker, Michael T

    2008-11-15

    The ability of Adipose-derived Stem Cells (ASCs) to differentiate into various tissues in vitro and in vivo, a function known as "stem cell plasticity", makes them an appealing cell source for tissue engineering. Our laboratory is particularly focused on the potential role of adipose tissue as a readily available postnatal source of osteoprogenitor. Fibroblast growth factors (FGF) and their receptors (FGFR) are important regulators of osteogenesis. The goal of this study was to elucidate how changes in temporal expression patterns of individual components of the fibroblast growth factor (FGF) signaling axis correlate with osteogenic differentiation of mASCs. Our results indicate that FGF ligand genes, such as Fgf-2, -4, -8, and -18, displayed a differential and dynamic profile during mouse ASC (mASC) osteogenesis. Fgf-2 transcript was down-regulated, while Fgf-18 transcript level was strongly up-regulated. Interestingly, a drift in the ratio of different FGF-2 protein forms, with translation favoring the HMWFGF-2 forms, occurred during osteogenic differentiation, whereas, the expression of LMWFGF-2 form was down-regulated. This finding shares similarity with a previous study suggesting that preferential expression of the HMWFGF-2 forms is associated with a more osteogenic differentiated state of calvarial osteoblast. Moreover, a differential expression of Fgf Receptor 1 and 2 resembling that previously found in in vivo osteogenic study was observed. Thus, mASCs undergoing osteogenesis recapitulate the in vivo osteogenic differentiation expression pattern of FGF ligands and receptors of calvarial mesenchymal cells during their own osteogenic differentiation. Indeed, this observation further validates ASCs as a suitable resource for skeletal tissue engineering.

  10. FGF19 (fibroblast growth factor 19) as a novel target gene for activating transcription factor 4 in response to endoplasmic reticulum stress.

    Science.gov (United States)

    Shimizu, Makoto; Li, Juan; Maruyama, Ryuto; Inoue, Jun; Sato, Ryuichiro

    2013-02-15

    FGF19 (fibroblast growth factor 19), expressed in the small intestine, acts as an enterohepatic hormone by mediating inhibitory effects on the bile acid synthetic pathway and regulating carbohydrate and lipid metabolism. In an attempt to identify novel agents other than bile acids that induce increased FGF19 expression, we found that some ER (endoplasmic reticulum) stress inducers were effective. When intestinal epithelial Caco-2 cells were incubated with thapsigargin, marked increases were observed in the mRNA and secreted protein levels of FGF19. This was not associated with the farnesoid X receptor. Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress. EMSAs (electrophoretic mobility-shift assays) and ChIP (chromatin immunoprecipitation) assays showed that ATF4 bound to this site and enhanced FGF19 expression. Overexpression of ATF4 in Caco-2 cells induced increased FGF19 mRNA expression, whereas shRNA (short hairpin RNA)-mediated depletion of ATF4 significantly attenuated a thapsigargin-induced increase in FGF19 mRNA.

  11. Effect of mammogenic hormones on the expression of dFGF7, FGF10 and their receptor in mouse mammary gland

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    To investigate the regulation of estrogen, progesterone and prolactin stimulating the development of mammary gland, the Kunming mice were used as experimental animals in this study.Through the ex-periment in vitro, the effect of mammogenic hormones were systematically investigated on expression of FGF7 and FGF10 and their receptor in different periods.The results are as follows:in mammary glands of mice, 17 beta-estradiol increased the expression of FGF7;progesterone did not affect the expression of FGF7;prolactin up-regulated the expression of FGF7 significantly in pregnancy and lac-tation.17 beta-estradiol increased the expression of FGF10;progesterone and prolactin reduced the expression of FGF10 significantly in virgin;prolactin significantly increased the expression of FGF10 in pregnancy.When 17 beta-estradiol in the body was in relatively high proportion, it would lower the ex-pression of KGFR;while 17 beta-estradiol in the body was in relatively low proportion, it would increase the expression of KGFR.Low concentration of progesterone increased the expression of KGFR and high progesterone did not affect the expression of KGFR.Prolactin increased the expression of KGFR significantly in pregnancy and lactation.

  12. Effects of insulin and exercise training on FGF21, its receptors and target genes in obesity and type 2 diabetes

    DEFF Research Database (Denmark)

    Sørensen, Rikke Kruse; Vienberg, Sara Gry; Vind, Birgitte F

    2017-01-01

    that insulin and exercise increase FGF21 in plasma. Obesity and type 2 diabetes are potentially FGF21-resistant states, but to what extent FGF21 responses to insulin and exercise training are preserved, and whether FGF21, its receptors and target genes are altered, remains to be established. METHODS......: The effects of insulin during euglycaemic-hyperinsulinaemic clamps and 10 week endurance training on serum FGF21 were examined in individuals with type 2 diabetes and in glucose tolerant overweight/obese and lean individuals. Gene expression of FGF21, its receptors and target genes in muscle and WAT biopsies...... obesity with and without type 2 diabetes led to reduced expression of KLB, but increased FGFR1c expression. However, the expression of most FGF21 target genes was unaltered except for reduced CIDEA expression in individuals with type 2 diabetes. CONCLUSIONS...

  13. Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress.

    Science.gov (United States)

    Shimizu, Makoto; Morimoto, Hitomi; Maruyama, Ryuto; Inoue, Jun; Sato, Ryuichiro

    2015-01-01

    Fibroblast growth factor 19 (FGF19) and FGF21 are members of a subfamily of the FGFs called endocrine FGFs. FGF19 regulates the bile acid synthetic pathway. FGF19 expression is induced by farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids in the small intestine. FGF21 plays an important role in lipolysis that occurs in white adipose tissue. FGF21 expression is stimulated by the nuclear fatty acid receptor peroxisome proliferator-activated receptor α (PPARα) in the liver. FGF19 and FGF21 were recently identified as targets of activating transcription factor 4 (ATF4), which is activated in response to endoplasmic reticulum (ER) stress. ATF4 is also activated by oxidative stress and amino acid deprivation. In this study, we investigated FGF19 and FGF21 expression in response to oxidative stress and amino acid deprivation. We found that FGF19 mRNA is induced by oxidative stress inducers in Caco-2 cells, which are derived from the human intestinal epithelium, and rat intestinal epithelial IEC6 cells. In contrast, ileal FGF15 expression, the rodent ortholog of human FGF19, is not increased by oxidative stress. No notable changes in expression of FGF15/19 took place under amino acid deprivation either in vitro or in vivo. In contrast, FGF21 expression is induced by oxidative stress and amino acid deprivation both in vitro and in vivo. These results indicate distinctive patterns of regulation of FGF19 expression by ER stress, and FGF21 expression by ER stress, oxidative stress, and amino acid deprivation through ATF4 activation.

  14. FGF23 fails to inhibit uremic parathyroid glands.

    Science.gov (United States)

    Canalejo, Rocío; Canalejo, Antonio; Martinez-Moreno, Julio Manuel; Rodriguez-Ortiz, M Encarnacion; Estepa, Jose C; Mendoza, Francisco Javier; Munoz-Castaneda, Juan Rafael; Shalhoub, Victoria; Almaden, Yolanda; Rodriguez, Mariano

    2010-07-01

    Fibroblast growth factor 23 (FGF23) modulates mineral metabolism by promoting phosphaturia and decreasing the production of 1,25-dihydroxyvitamin D(3). FGF23 decreases parathyroid hormone (PTH) mRNA and secretion, but despite a marked elevation in FGF23 in uremia, PTH production increases. Here, we investigated the effect of FGF23 on parathyroid function in normal and uremic hyperplastic parathyroid glands in rats. In normal parathyroid glands, FGF23 decreased PTH production, increased expression of both the parathyroid calcium-sensing receptor and the vitamin D receptor, and reduced cell proliferation. Furthermore, FGF23 induced phosphorylation of extracellular signal-regulated kinase 1/2, which mediates the action of FGF23. In contrast, in hyperplastic parathyroid glands, FGF23 did not reduce PTH production, did not affect expression of the calcium-sensing receptor or vitamin D receptor, and did not affect cell proliferation. In addition, FGF23 failed to activate the extracellular signal-regulated kinase 1/2-mitogen-activated protein kinase pathway in hyperplastic parathyroid glands. We observed very low expression of the FGF23 receptor 1 and the co-receptor Klotho in uremic hyperplastic parathyroid glands, which may explain the lack of response to FGF23 in this tissue. In conclusion, in hyperparathyroidism secondary to renal failure, the parathyroid cells resist the inhibitory effects of FGF23, perhaps as a result of the low expression of FGF23 receptor 1 and Klotho in this condition.

  15. FGF19-FGFR4 signaling elaborates lens induction with the FGF8-L-Maf cascade in the chick embryo.

    Science.gov (United States)

    Kurose, Hitomi; Okamoto, Mayumi; Shimizu, Miyuki; Bito, Takaaki; Marcelle, Cristophe; Noji, Sumihare; Ohuchi, Hideyo

    2005-05-01

    The fibroblast growth factor (FGF) family is known to be involved in vertebrate eye development. However, distinct roles of individual FGF members during eye development remain largely elusive. Here, we show a detailed expression pattern of Fgf19 in chick lens development. Fgf19 expression initiated in the forebrain, and then became restricted to the distal portion of the optic vesicle abutting the future lens placode, where FGF receptor 4 (Fgfr4), a receptor for FGF19, was expressed. Fgf8, a positive regulator for L-Maf, was expressed in a portion of the optic vesicle. To examine the role of FGF19 signaling during early eye development, Fgf19 was misexpressed near the presumptive lens ectoderm; however, no alteration in the expression of lens marker genes was observed. Conversely, a secreted form of FGFR4 was misexpressed to inhibit an FGF19 signal, resulting in the induction of L-Maf expression. To further define the relationship between L-Maf and Fgf19, L-Maf misexpression was performed, resulting in ectopic induction of Fgf19 expression by Hamburger and Hamilton's stage 12/13. Furthermore, misexpression of Fgf8 induced Fgf19 expression in addition to L-Maf. These results suggest that FGF19-FGFR4 signaling plays a role in early lens development in collaboration with FGF8 signaling and L-Maf transcriptional system.

  16. Expression of osteoclastogenic factor transcripts in osteoblast-like UMR-106 cells after exposure to FGF-23 or FGF-23 combined with parathyroid hormone.

    Science.gov (United States)

    Teerapornpuntakit, Jarinthorn; Wongdee, Kannikar; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2016-03-01

    As a bone-derived hormone, fibroblast growth factor-23 (FGF-23) negatively regulates phosphate and calcium metabolism, while retaining growth-promoting action for mesenchymal cell differentiation. Elevated FGF-23 levels, together with hyperparathyroidism, are often observed in chronic kidney disease, which is associated with impaired bone mineralization and enhanced bone resorption. Although overexpression of osteoblast-derived osteoclastogenic cytokines might contribute to this metabolic bone disease, whether FGF-23 alone and FGF-23 plus parathyroid hormone (PTH) directly modulated the expression of osteoblast-derived osteoclastogenic genes remained elusive. Herein, we demonstrated the direct effects of FGF-23 on proliferation and mRNA expression of osteoblast-specific differentiation and osteoclastogenic markers in rat osteoblast-like UMR-106 cells in the presence or absence of PTH. FGF-23 was found to suppress UMR-106 cell proliferation, while increasing FGF-23 expression, the latter of which suggested the presence of positive feedback regulation of FGF-23 expression in osteoblasts. FGF-23 also upregulated the mRNA expression of osteoblast differentiation markers (e.g., Runx2, osterix, AJ18, Dlx5, alkaline phosphatase, and osteopontin), osteoclastogenic factors (e.g., MCSF, MCP-1, IL-6, and TNF-α), and bone resorption regulators (RANKL and osteoprotegerin). However, combined PTH and FGF-23 exposure did not alter the levels of FGF-23-induced transcripts, suggesting that both hormones had no additive effect. In conclusion, FGF-23 directly suppressed osteoblast proliferation, while inducing osteoclastogenic gene expression in UMR-106 cells, and the FGF-23-induced transcripts were not altered by long-standing PTH exposure.

  17. Fibroblast Growth Factor 23 (FGF23 and Disorders of Phosphate Metabolism

    Directory of Open Access Journals (Sweden)

    Tasuku Saito

    2009-01-01

    Full Text Available Derangements in serum phosphate level result in rickets/osteomalacia or ectopic calcification indicating that healthy people without these abnormalities maintain serum phosphate within certain ranges. These results indicate that there must be a regulatory mechanism of serum phosphate level. Fibroblast growth factor 23 (FGF23 was identified as the last member of FGF family. FGF23 is produced by bone and reduces serum phosphate level by suppressing phosphate reabsorption in proximal tubules and intestinal phosphate absorption through lowering 1,25-dihydroxyvitamin D level. It has been shown that excess and deficient actions of FGF23 result in hypophosphatemic rickets/osteomalacia and hyperphosphatemic tumoral calcinosis, respectively. These results indicate that FGF23 works as a hormone, and several disorders of phosphate metabolism can be viewed as endocrine diseases. It may become possible to treat patients with abnormal phosphate metabolism by pharmacologically modifying the activity of FGF23.

  18. The expression characteristics and biological significance of bFGF, EGF,TGF-β isoforms and their receptors in skins from fetus and adult

    Institute of Scientific and Technical Information of China (English)

    Chen Wei; Fu Xiaobing; Sun Xiaoqing; Sun Tongzhu; Zhao Zhili; Sheng Zhiyong

    2002-01-01

    To observe the localization and expression characteristics of alpha-smooth muscle actin (AS-MA), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), transforming growth factor-β(TGF-β) isoforms, and their receptors in fetal and adult skins in order to explore their potential biological significance.Methods: The expression and the distribution of ASMA, bFGF, EGF, TGF-βisoforms, and their receptors were detected with immunohistochemistry and histopathology methods in 36 skin specimens. Among them, 30 specimens belonged to fetuses at different developmental stages and 6 were from adults. Results:Positive immunohistochemical signals of ASMA, bFGF, EGF, and TGF-βisoforms and their receptors could be found in fetal and postnatal skins.These factors were mainly distributed in the cytoplasm and extracellular matrix of epidermal cells, endothelial cells,hair follicle epithelial cells and some fibroblasts. Receptors of these factors were mostly located in the cellular membrane of the above mentioned cells, while protein particles of ASMA could be observed in myofibroblasts and sweat gland cells. Along with ascent in gestational age, the positive cellular rates of bFGF, EGF, TGF-βisoforms, their receptors, and ASMA in skin were elevated progressively. In skins specimens obtained from fetuses of late-trimester (29-31 week gestation) and adult, the positive rates of these proteins were significantly raised in comparison with skin of fetuses of early-trimester. Conclusion: The endogenous bFGF, EGF, three TGF-βisoforms and their receptors might be involved in the development of the skin in embryonic stage and in the cutaneous structure and function,and also wound healing in adult stage. The relative lack of these factors and their receptors might be one reason why the wound of fetus heal by regeneration rather than by scarring.

  19. Receptor-mediated gene delivery using polyethylenimine (PEI)coupled with polypeptides targeting FGF receptors on cells surface

    Institute of Scientific and Technical Information of China (English)

    LI Da; WANG Qing-qing; TANG Gu-ping; HUANG Hong-liang; SHEN Fen-ping; LI Jing-zhong; YU Hai

    2006-01-01

    Objective: To construct a novel kind ofnonviral gene delivery vector based on polyethylenimine (PEI) conjugated with polypeptides derived from ligand FGF with high transfection efficiency and according to tumor targeting ability. Methods:The synthetic polypeptides CR16 for binding FGF receptors was conjugated to PEI and the characters of the polypeptides including DNA condensing and particle size were determined. Enhanced efficiency and the targeting specificity of the synthesized vector were investigated in vitro and in vivo. Results: The polypeptides were successfully coupled to PEI. The new vectors PEI-CR16 could efficiently condense pDNA into particles with around 200 nm diameter. The PEI-CR16/pDNA polyplexes showed significantly greater transgene activity than PEI/pDNA in FGF receptors positive tumor cells in vitro and in vivo gene transfer, while no difference was observed in FGF receptors negative tumor cells. The enhanced transfection efficiency of PEI-CR16 could be blocked by excess free polypeptides. Conclusion: The synthesized vector could improve the efficiency of gene transfer and targeting specificity in FGF receptors positive cells. The vector had good prospect for use in cancer gene therapy.

  20. Actions and mode of actions of FGF19 subfamily members.

    Science.gov (United States)

    Fukumoto, Seiji

    2008-03-01

    Fibroblast growth factors (FGFs) are humoral factors with diverse biological functions. While most FGFs were shown to work as local factors regulating cell growth and differentiation, recent investigations indicated that FGF19 subfamily members, FGF15/19, FGF21 and FGF23 work as systemic factors. FGF15/19 produced by intestine inhibits bile acid synthesis and FGF21from liver is involved in carbohydrate and lipid metabolism. In addition, FGF23 was shown to be produced by bone and regulate phosphate and vitamin D metabolism. Furthermore, these FGFs require klotho or betaklotho for their actions in addition to canonical FGF receptors. It is possible that these FGFs together with their receptor systems might be targets for novel therapeutic measures in the future.

  1. THE RELATIONS AMONG FIBROBLAST GROWTH FACTOR-1 FIBROBLAST GROWTH FACTOR RECEPTOR-1 AND THE PATHOLOGICAL GRADING IN HUMAN MENINGIOMAS%FGF-1及FGFR-1与人脑膜瘤病理分级的关系

    Institute of Scientific and Technical Information of China (English)

    姚曙光; 袁贤瑞

    2009-01-01

    Objective To study the ralations among the expressions of FGF-1,FGFR-1 and the pathological grading in human meningiomas by immunohistochemical staining method.Methods According to the hematoxylin and eosin staining,All of the 68 cases were assorted into 4 groups.The numbers of tumor cells immunohistochemically stained by FGF-1 and FGFR-1 were counted and analized.Results As to the expression of FGF-1,the differences between the two adjacent groups(Grade 0~Ⅰ,Ⅰ~Ⅱ and Ⅱ~Ⅲ) showed no significance(P>0.05),but significant diffences were found in other groups(P<0.01).As to the expression of FGFR-1,all groups except the groups of GradeⅡ~Ⅲ showed significant differences(P<0.05).Pearson correlations were significant at the 0.05 level between the expressions of FGF-1/FGFR-1 and the pathological grading,though partial correlation between FGF-1 and FGFR-1 was insignificant.Conclusion The expressions of FGF-1 and FGFR-1 have close relations to the pathological grading of human meningiomas.They may reflect the proliferative activities of meningioma cells but there is no correlation between them.%目的 应用免疫组织化学方法研究成纤维细胞生长因子-1(FGF-1)和成纤维细胞生长因子受体-1(FGFR-1)在人正常脑组织和脑膜瘤组织中的表达及其与人脑膜瘤病理分级的关系和二者间的相关关系.方法 68例标本常规HE染色,依据WHO 1990年脑膜瘤分型标准分为0~3级4组.按照石蜡切片微波修复抗原染色程序分别作FGF-1和FGFR-1免疫组织化学染色,观察其表达情况,计数阳性和阴性细胞,进行统计学分析.结果 病理级别相邻组间FGF-1表达阳性率的差别P>0.05,相隔组间FGF-1表达阳性率的差别P0.05,其它各组间FGFR-1表达阳性率的差别P0.05.结论 人脑膜瘤中FGF-1和FGFR-1的表达与其病理分级密切相关,可在一定程度上反应人脑膜瘤的恶性程度,恶性程度越高,表达越强;但FGF-1和FGFR-1二者间并无相关关系.

  2. The structural biology of the FGF19 subfamily.

    Science.gov (United States)

    Beenken, Andrew; Mohammadi, Moosa

    2012-01-01

    The ability of the Fibroblast Growth Factor (FGF) 19 subfamily to signal in an endocrine fashion sets this subfamily apart from the remaining five FGF subfamilies known for their paracrine functions during embryonic development. Compared to the members of paracrine FGF subfamiles, the three members of the FGF19 subfamily, namely FGF19, FGF21 and FGF23, have poor affinity for heparan sulfate (HS) and therefore can diffuse freely in the HS-rich extracellular matrix to enter into the bloodstream. In further contrast to paracrine FGFs, FGF19 subfamily members have unusually poor affinity for their cognate FGF receptors (FGFRs) and therefore cannot bind and activate them in a solely HS-dependent fashion. As a result, the FGF19 subfamily requires α/βklotho coreceptor proteins in order to bind, dimerize and activate their cognate FGFRs. This klotho-dependency also determines the tissue specificity of endocrine FGFs. Recent structural and biochemical studies have begun to shed light onto the molecular basis for the klotho-dependent endocrine mode of action of the FGF19 subfamily. Crystal structures of FGF19 and FGF23 show that the topology of the HS binding site (HBS) of FGF19 subfamily members deviates drastically from the common topology adopted by the paracrine FGFs. The distinct topologies of the HBS of FGF19 and FGF23 prevent HS from direct hydrogen bonding with the backbone atoms of the HBS of these ligands and accordingly decrease the HS binding affinity of this subfamily. Recent biochemical data reveal that the ?klotho ectodomain binds avidly to the ectodomain of FGFR1c, the main cognate FGFR of FGF23, creating a de novo high affinity binding site for the C-terminal tail of FGF23. The isolated FGF23 C-terminus can be used to effectively inhibit the formation of the FGF23-FGFR1c-αklotho complex and alleviate hypophosphatemia in renal phosphate disorders due to elevated levels of FGF23.

  3. Exploiting Surface Plasmon Resonance (SPR Technology for the Identification of Fibroblast Growth Factor-2 (FGF2 Antagonists Endowed with Antiangiogenic Activity

    Directory of Open Access Journals (Sweden)

    Marco Presta

    2009-08-01

    Full Text Available Angiogenesis, the process of new blood vessel formation, is implicated in various physiological/pathological conditions, including embryonic development, inflammation and tumor growth. Fibroblast growth factor-2 (FGF2 is a heparin-binding angiogenic growth factor involved in various physiopathological processes, including tumor neovascularization. Accordingly, FGF2 is considered a target for antiangiogenic therapies. Thus, numerous natural/synthetic compounds have been tested for their capacity to bind and sequester FGF2 in the extracellular environment preventing its interaction with cellular receptors. We have exploited surface plasmon resonance (SPR technique in search for antiangiogenic FGF2 binders/antagonists. In this review we will summarize our experience in SPR-based angiogenesis research, with the aim to validate SPR as a first line screening for the identification of antiangiogenic compounds.

  4. Mouse FGF15 is the ortholog of human and chick FGF19, but is not uniquely required for otic induction.

    Science.gov (United States)

    Wright, Tracy J; Ladher, Raj; McWhirter, John; Murre, Cornelis; Schoenwolf, Gary C; Mansour, Suzanne L

    2004-05-01

    The inner ear develops from an ectodermal placode that is specified by inductive signals from the adjacent neurectoderm and underlying mesoderm. In chick, fibroblast growth factor (Fgf)-19 is expressed in mesoderm underlying the presumptive otic placode, and human FGF19 induces expression of otic markers in a tissue explant containing neural plate and surface ectoderm. We show here that mouse Fgf15 is the sequence homolog of chick and human Fgf19/FGF19. In addition, we show that FGF15, like FGF19, is sufficient to induce expression of otic markers in a chick explant assay, suggesting that these FGFs are orthologs. Mouse embryos lacking Fgf15, however, do not have otic abnormalities at E9.5-E10.5, suggesting that Fgf15 is not uniquely required for otic induction or early patterning of the otocyst. To compare FGF15 and FGF19 signaling components and assess where signals potentially redundant with FGF15 might function, we determined the expression patterns of Fgf15 and Fgf19. Unlike Fgf19, Fgf15 is not expressed in mesoderm underlying the presumptive otic placode, but is expressed in the adjacent neurectoderm. Fgfr4, which encodes the likely receptor for both FGF19 and FGF15, is expressed in the neurectoderm of both species, and is also expressed in the mesoderm only in chick. These results suggest the hypotheses that during otic induction, FGF19 signals in either an autocrine fashion to the mesoderm or a paracrine fashion to the neurectoderm, whereas FGF15 signals in an autocrine fashion to the neurectoderm. Thus, the FGFs that signal to the neurectoderm are the best potential candidates for redundancy with FGF15 during mouse otic development.

  5. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation.

    Science.gov (United States)

    Wu, Xinle; Ge, Hongfei; Lemon, Bryan; Vonderfecht, Steven; Weiszmann, Jennifer; Hecht, Randy; Gupte, Jamila; Hager, Todd; Wang, Zhulun; Lindberg, Richard; Li, Yang

    2010-02-19

    FGF19 and FGF21, unique members of the fibroblast growth factor (FGF) family, are hormones that regulate glucose, lipid, and energy homeostasis. Increased hepatocyte proliferation and liver tumor formation have also been observed in FGF19 transgenic mice. Here, we report that, in contrast to FGF19, FGF21 does not induce hepatocyte proliferation in vivo. To identify the mechanism for FGF19-induced hepatocyte proliferation, we explored similarities and differences in receptor specificity between FGF19 and FGF21. We find that although both are able to activate FGF receptors (FGFRs) 1c, 2c, and 3c, only FGF19 activates FGFR4, the predominant receptor in the liver. Using a C-terminal truncation mutant of FGF19 and a series of FGF19/FGF21 chimeric molecules, we determined that amino acids residues 38-42 of FGF19 are sufficient to confer both FGFR4 activation and increased hepatocyte proliferation in vivo to FGF21. These data suggest that activation of FGFR4 is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation.

  6. Fundamentals of FGF19 & FGF21 action in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Andrew C Adams

    Full Text Available Fibroblast growth factors 19 (FGF19 and 21 (FGF21 have emerged as key regulators of energy metabolism. Several studies have been conducted to understand the mechanism of FGF19 and FGF21 action, however, the data presented has often been inconsistent and at times contradictory. Here in a single study we compare the mechanisms mediating FGF19/FGF21 actions, and how similarities/differences in actions at the cellular level between these two factors translate to common/divergent physiological outputs. Firstly, we show that in cell culture FGF19/FGF21 are very similar, however, key differences are still observed differentiating the two. In vitro we found that both FGF's activate FGFRs in the context of βKlotho (KLB expression. Furthermore, both factors alter ERK phosphorylation and glucose uptake with comparable potency. Combination treatment of cells with both factors did not have additive effects and treatment with a competitive inhibitor, the FGF21 delta N17 mutant, also blocked FGF19's effects, suggestive of a shared receptor activation mechanism. The key differences between FGF21/FGF19 were noted at the receptor interaction level, specifically the unique ability of FGF19 to bind/signal directly via FGFR4. To determine if differential effects on energy homeostasis and hepatic mitogenicity exist we treated DIO and ob/ob mice with FGF19/FGF21. We find comparable efficacy of the two proteins to correct body weight and serum glucose in both DIO and ob/ob mice. Nevertheless, FGF21 and FGF19 had distinctly different effects on proliferation in the liver. Interestingly, in vivo blockade of FGF21 signaling in mice using ΔN17 caused profound changes in glycemia indicative of the critical role KLB and FGF21 play in the regulation of glucose homeostasis. Overall, our data demonstrate that while subtle differences exist in vitro the metabolic effects in vivo of FGF19/FGF21 are indistinguishable, supporting a shared mechanism of action for these two

  7. Fundamentals of FGF19 & FGF21 action in vitro and in vivo.

    Science.gov (United States)

    Adams, Andrew C; Coskun, Tamer; Rovira, Armando R Irizarry; Schneider, Michael A; Raches, David W; Micanovic, Radmila; Bina, Holly A; Dunbar, James D; Kharitonenkov, Alexei

    2012-01-01

    Fibroblast growth factors 19 (FGF19) and 21 (FGF21) have emerged as key regulators of energy metabolism. Several studies have been conducted to understand the mechanism of FGF19 and FGF21 action, however, the data presented has often been inconsistent and at times contradictory. Here in a single study we compare the mechanisms mediating FGF19/FGF21 actions, and how similarities/differences in actions at the cellular level between these two factors translate to common/divergent physiological outputs. Firstly, we show that in cell culture FGF19/FGF21 are very similar, however, key differences are still observed differentiating the two. In vitro we found that both FGF's activate FGFRs in the context of βKlotho (KLB) expression. Furthermore, both factors alter ERK phosphorylation and glucose uptake with comparable potency. Combination treatment of cells with both factors did not have additive effects and treatment with a competitive inhibitor, the FGF21 delta N17 mutant, also blocked FGF19's effects, suggestive of a shared receptor activation mechanism. The key differences between FGF21/FGF19 were noted at the receptor interaction level, specifically the unique ability of FGF19 to bind/signal directly via FGFR4. To determine if differential effects on energy homeostasis and hepatic mitogenicity exist we treated DIO and ob/ob mice with FGF19/FGF21. We find comparable efficacy of the two proteins to correct body weight and serum glucose in both DIO and ob/ob mice. Nevertheless, FGF21 and FGF19 had distinctly different effects on proliferation in the liver. Interestingly, in vivo blockade of FGF21 signaling in mice using ΔN17 caused profound changes in glycemia indicative of the critical role KLB and FGF21 play in the regulation of glucose homeostasis. Overall, our data demonstrate that while subtle differences exist in vitro the metabolic effects in vivo of FGF19/FGF21 are indistinguishable, supporting a shared mechanism of action for these two hormones in the

  8. Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice.

    Science.gov (United States)

    Wang, Hongwei; Venkatesh, Madhukumar; Li, Hao; Goetz, Regina; Mukherjee, Subhajit; Biswas, Arunima; Zhu, Liang; Kaubisch, Andreas; Wang, Lei; Pullman, James; Whitney, Kathleen; Kuro-o, Makoto; Roig, Andres I; Shay, Jerry W; Mohammadi, Moosa; Mani, Sridhar

    2011-08-01

    The nuclear receptor pregnane X receptor (PXR) is activated by a range of xenochemicals, including chemotherapeutic drugs, and has been suggested to play a role in the development of tumor cell resistance to anticancer drugs. PXR also has been implicated as a regulator of the growth and apoptosis of colon tumors. Here, we have used a xenograft model of colon cancer to define a molecular mechanism that might underlie PXR-driven colon tumor growth and malignancy. Activation of PXR was found to be sufficient to enhance the neoplastic characteristics, including cell growth, invasion, and metastasis, of both human colon tumor cell lines and primary human colon cancer tissue xenografted into immunodeficient mice. Furthermore, we were able to show that this PXR-mediated phenotype required FGF19 signaling. PXR bound to the FGF19 promoter in both human colon tumor cells and "normal" intestinal crypt cells. However, while both cell types proliferated in response to PXR ligands, the FGF19 promoter was activated by PXR only in cancer cells. Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas.

  9. Basic Fibroblast Growth Factor and Fibroblast Growth Factor Receptor-1in Human Meningiomas

    Institute of Scientific and Technical Information of China (English)

    YI Wei; CHEN Jian; Filimon H. Golwa; XUE Delin

    2005-01-01

    The expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) in human meningiomas and the relationships between their expression and the tumors' histological features and angiogenesis were investigated by means of immunohistochemical technique. The expression of bFGF and FGFR-1 was detected by antibody of bFGF or FGFR-1.The tumors' angiogenesis was evaluated by microvascular density (MVD) and, which was observed by use of CD34-antibody immunohistochemically. The results showed that there were varied degrees of the expression of bFGF and FGFR-1 proteins in meningiomas. The expression was correlated with the tumors' histological characters and angiogenesis. It was concluded that bFGF and FGFR-1 might play important roles in meningiomas' angiogenesis and proliferation. The expression positive rate of bFGF and FGFR-1 may provide an indication of evaluating the histological and malignant degree of the tumor.

  10. Transitory FGF treatment results in the long-lasting suppression of the proliferative response to repeated FGF stimulation.

    Science.gov (United States)

    Poole, Ashleigh; Knowland, Nicholas; Cooper, Emily; Cole, Rebecca; Wang, Hongchuan; Booth, Lucas; Kacer, Doreen; Tarantini, Francesca; Friesel, Robert; Prudovsky, Igor

    2014-05-01

    FGF applied as a single growth factor to quiescent mouse fibroblasts induces a round of DNA replication, however continuous stimulation results in arrest in the G1 phase of the next cell cycle. We hypothesized that FGF stimulation induces the establishment of cell memory, which prevents the proliferative response to repeated or continuous FGF application. When a 2-5 days quiescence period was introduced between primary and repeated FGF treatments, fibroblasts failed to efficiently replicate in response to secondary FGF application. The establishment of "FGF memory" during the first FGF stimulation did not require DNA synthesis, but was dependent on the activity of FGF receptors, MEK, p38 MAPK and NFκB signaling, and protein synthesis. While secondary stimulation resulted in strongly decreased replication rate, we did not observe any attenuation of morphological changes, Erk1/2 phosphorylation and cyclin D1 induction. However, secondary FGF stimulation failed to induce the expression of cyclin A, which is critical for the progression from G1 to S phase. Treatment of cells with a broad range histone deacetylase inhibitor during the primary FGF stimulation rescued the proliferative response to the secondary FGF treatment suggesting that the establishment of "FGF memory" may be based on epigenetic changes. We suggest that "FGF memory" can prevent the hyperplastic response to cell damage and inflammation, which are associated with an enhanced FGF production and secretion. "FGF memory" may present a natural obstacle to the efficient application of recombinant FGFs for the treatment of ulcers, ischemias, and wounds.

  11. Sustained Inhibition of Proliferative Response After Transient FGF Stimulation Is Mediated by Interleukin 1 Signaling.

    Science.gov (United States)

    Poole, Ashleigh; Kacer, Doreen; Cooper, Emily; Tarantini, Francesca; Prudovsky, Igor

    2016-03-01

    Transient FGF stimulation of various cell types results in FGF memory--a sustained blockage of efficient proliferative response to FGF and other growth factors. FGF memory establishment requires HDAC activity, indicating its epigenetic character. FGF treatment stimulates proinflammatory NFκB signaling, which is also critical for FGF memory formation. The search for FGF-induced mediators of FGF memory revealed that FGF stimulates HDAC-dependent expression of the inflammatory cytokine IL1α. Similarly to FGF, transient cell treatment with recombinant IL1α inhibits the proliferative response to further FGF and EGF stimulation, but does not prevent FGF receptor-mediated signaling. Interestingly, like cells pretreated with FGF1, cells pretreated with IL1α exhibit enhanced restructuring of actin cytoskeleton and increased migration in response to FGF stimulation. IRAP, a specific inhibitor of IL 1 receptor, and a neutralizing anti-IL1α antibody prevent the formation of FGF memory and rescue an efficient proliferative response to FGF restimulation. A similar effect results following treatment with the anti-inflammatory agents aspirin and dexamethasone. Thus, FGF memory is mediated by proinflammatory IL1 signaling. It may play a role in the limitation of proliferative response to tissue damage and prevention of wound-induced hyperplasia.

  12. Effects of central fibroblast growth factor 21 (FGF21) in energy balance.

    Science.gov (United States)

    Recinella, L; Leone, S; Ferrante, C; Chiavaroli, A; Di Nisio, C; Martinotti, S; Vacca, M; Brunetti, L; Orlando, G

    Fibroblast growth factor 21 (FGF21) is known as a major metabolic regulator of glucose and lipid homeostasis. Continuous intracerebroventricular (i.c.v.) administration of FGF21 was found to modulate feeding and energy expenditure in rats with diet-induced obesity, suggesting a central effect by the peptide. In this context, in the present work, we studied the effects of a single central FGF21 administration (0.5-5 µg) on feeding and energy expenditure by evaluating locomotor activity, interscapular brown adipose tissue (BAT) weight, gene expression of uncoupling protein-1 (UCP-1) in BAT and plasma norepinephrine (NE) levels in Sprague-Dawley fed rats. In addition, we evaluated the effects of FGF21 on orexigenic [agouti-related peptide (AgRP) and neuropeptide Y (NPY)] and anorexigenic [cocaine and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC)] peptides, in the hypothalamus, and dopamine (DA) and serotonin (5-hydroxytriptamine, 5-HT) levels in nucleus accumbens (NAc). We confirmed that central FGF21 administration induced a significant increase in food intake, possibly mediated by increased NPY and AgRP, and decreased POMC and CART gene expression. Moreover, FGF21 could modulate the motivational aspects of feeding, possibly through stimulated NAc DA levels. On the other hand, our findings of decreased locomotor activity, BAT weight, UCP-1 gene expression and plasma NE levels support a role for FGF21 in decreasing energy expenditure.

  13. FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro.

    Science.gov (United States)

    Joannes, Audrey; Brayer, Stéphanie; Besnard, Valérie; Marchal-Sommé, Joëlle; Jaillet, Madeleine; Mordant, Pierre; Mal, Hervé; Borie, Raphael; Crestani, Bruno; Mailleux, Arnaud A

    2016-04-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by an accumulation of extracellular matrix proteins and fibroblasts in the distal airways. Key developmental lung signaling pathways are reactivated in IPF. For instance, fibroblast growth factor 9 (FGF9) and FGF18, involved in epithelial-mesenchymal interactions, are critical for lung development. We evaluated the expression of FGF9, FGF18, and FGF receptors (FGFRs) in lung tissue from controls and IPF patients and assessed their effect on proliferation, survival, migration, and differentiation of control and IPF human lung fibroblasts (HLFs). FGF9, FGF18, and all FGFRs were present in the remodeled alveolar epithelium close to the fibroblast foci in IPF lungs. FGFR3 was generally detected in fibroblast foci by immunohistochemistry. In vitro, HLFs mainly expressed mesenchyme-associated FGFR isoforms (FGFR1c and FGFR3c) and FGFR4. FGF9 did not affect fibroblast proliferation, whereas FGF18 inhibited cell growth in control fibroblasts. FGF9 and FGF18 decreased Fas-ligand-induced apoptosis in control but not in IPF fibroblasts. FGF9 prevented transforming growth factor β1-induced myofibroblast differentiation. FGF9 and FGF18 increased the migratory capacities of HLF, and FGF9 actively modulated matrix metalloproteinase activity. In addition, FGFR3 inhibition by small interfering RNA impacted p-ERK activation by FGF9 and FGF18 and their effects on differentiation and migration. These results identify FGF9 as an antiapoptotic and promigratory growth factor on HLF, maintaining fibroblasts in an undifferentiated state. The biological effects of FGF9 and FGF18 were partially driven by FGFR3. FGF18 was a less potent molecule. Both growth factors likely contribute to the fibrotic process in vivo.

  14. FAP finds FGF21 easy to digest

    DEFF Research Database (Denmark)

    Gillum, Matthew P; Potthoff, Matthew J

    2016-01-01

    Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates carbohydrate and lipid metabolism. In humans, circulating FGF21 is inactivated by proteolytic cleavage of its C-terminus, thereby preventing signalling through a receptor complex. The mechanism for this cleavage event...... and the factors contributing to the post-translational regulation of FGF21 activity has previously been unknown. In a recent issue of the Biochemical Journal, Zhen et al. have identified fibroblast activation protein (FAP) as the endopeptidase responsible for this site-specific cleavage of human FGF21 (hFGF21......), and propose that inhibition of FAP may be a therapeutic strategy to increase endogenous levels of active FGF21....

  15. Cubilin, a High Affinity Receptor for Fibroblast Growth Factor 8, Is Required for Cell Survival in the Developing Vertebrate Head*

    Science.gov (United States)

    Cases, Olivier; Perea-Gomez, Aitana; Aguiar, Diego P.; Nykjaer, Anders; Amsellem, Sabine; Chandellier, Jacqueline; Umbhauer, Muriel; Cereghini, Silvia; Madsen, Mette; Collignon, Jérôme; Verroust, Pierre; Riou, Jean-François; Creuzet, Sophie E.; Kozyraki, Renata

    2013-01-01

    Cubilin (Cubn) is a multiligand endocytic receptor critical for the intestinal absorption of vitamin B12 and renal protein reabsorption. During mouse development, Cubn is expressed in both embryonic and extra-embryonic tissues, and Cubn gene inactivation results in early embryo lethality most likely due to the impairment of the function of extra-embryonic Cubn. Here, we focus on the developmental role of Cubn expressed in the embryonic head. We report that Cubn is a novel, interspecies-conserved Fgf receptor. Epiblast-specific inactivation of Cubn in the mouse embryo as well as Cubn silencing in the anterior head of frog or the cephalic neural crest of chick embryos show that Cubn is required during early somite stages to convey survival signals in the developing vertebrate head. Surface plasmon resonance analysis reveals that fibroblast growth factor 8 (Fgf8), a key mediator of cell survival, migration, proliferation, and patterning in the developing head, is a high affinity ligand for Cubn. Cell uptake studies show that binding to Cubn is necessary for the phosphorylation of the Fgf signaling mediators MAPK and Smad1. Although Cubn may not form stable ternary complexes with Fgf receptors (FgfRs), it acts together with and/or is necessary for optimal FgfR activity. We propose that plasma membrane binding of Fgf8, and most likely of the Fgf8 family members Fgf17 and Fgf18, to Cubn improves Fgf ligand endocytosis and availability to FgfRs, thus modulating Fgf signaling activity. PMID:23592779

  16. Cubilin, a high affinity receptor for fibroblast growth factor 8, is required for cell survival in the developing vertebrate head.

    Science.gov (United States)

    Cases, Olivier; Perea-Gomez, Aitana; Aguiar, Diego P; Nykjaer, Anders; Amsellem, Sabine; Chandellier, Jacqueline; Umbhauer, Muriel; Cereghini, Silvia; Madsen, Mette; Collignon, Jérôme; Verroust, Pierre; Riou, Jean-François; Creuzet, Sophie E; Kozyraki, Renata

    2013-06-07

    Cubilin (Cubn) is a multiligand endocytic receptor critical for the intestinal absorption of vitamin B12 and renal protein reabsorption. During mouse development, Cubn is expressed in both embryonic and extra-embryonic tissues, and Cubn gene inactivation results in early embryo lethality most likely due to the impairment of the function of extra-embryonic Cubn. Here, we focus on the developmental role of Cubn expressed in the embryonic head. We report that Cubn is a novel, interspecies-conserved Fgf receptor. Epiblast-specific inactivation of Cubn in the mouse embryo as well as Cubn silencing in the anterior head of frog or the cephalic neural crest of chick embryos show that Cubn is required during early somite stages to convey survival signals in the developing vertebrate head. Surface plasmon resonance analysis reveals that fibroblast growth factor 8 (Fgf8), a key mediator of cell survival, migration, proliferation, and patterning in the developing head, is a high affinity ligand for Cubn. Cell uptake studies show that binding to Cubn is necessary for the phosphorylation of the Fgf signaling mediators MAPK and Smad1. Although Cubn may not form stable ternary complexes with Fgf receptors (FgfRs), it acts together with and/or is necessary for optimal FgfR activity. We propose that plasma membrane binding of Fgf8, and most likely of the Fgf8 family members Fgf17 and Fgf18, to Cubn improves Fgf ligand endocytosis and availability to FgfRs, thus modulating Fgf signaling activity.

  17. Fibroblast Growth Factor 10-Fibroblast Growth Factor Receptor 2b Mediated Signaling Is Not Required for Adult Glandular Stomach Homeostasis

    Science.gov (United States)

    Sala, Frederic G.; Ford, Henri R.; Bellusci, Saverio; Grikscheit, Tracy C.

    2012-01-01

    The signaling pathways that are essential for gastric organogenesis have been studied in some detail; however, those that regulate the maintenance of the gastric epithelium during adult homeostasis remain unclear. In this study, we investigated the role of Fibroblast growth factor 10 (FGF10) and its main receptor, Fibroblast growth factor receptor 2b (FGFR2b), in adult glandular stomach homeostasis. We first showed that mouse adult glandular stomach expressed Fgf10, its receptors, Fgfr1b and Fgfr2b, and most of the other FGFR2b ligands (Fgf1, Fgf7, Fgf22) except for Fgf3 and Fgf20. Fgf10 expression was mesenchymal whereas FGFR1 and FGFR2 expression were mostly epithelial. Studying double transgenic mice that allow inducible overexpression of Fgf10 in adult mice, we showed that Fgf10 overexpression in normal adult glandular stomach increased epithelial proliferation, drove mucous neck cell differentiation, and reduced parietal and chief cell differentiation. Although a similar phenotype can be associated with the development of metaplasia, we found that Fgf10 overexpression for a short duration does not cause metaplasia. Finally, investigating double transgenic mice that allow the expression of a soluble form of Fgfr2b, FGF10's main receptor, which acts as a dominant negative, we found no significant changes in gastric epithelial proliferation or differentiation in the mutants. Our work provides evidence, for the first time, that the FGF10-FGFR2b signaling pathway is not required for epithelial proliferation and differentiation during adult glandular stomach homeostasis. PMID:23133671

  18. Fibroblast growth factor 10-fibroblast growth factor receptor 2b mediated signaling is not required for adult glandular stomach homeostasis.

    Directory of Open Access Journals (Sweden)

    Allison L Speer

    Full Text Available The signaling pathways that are essential for gastric organogenesis have been studied in some detail; however, those that regulate the maintenance of the gastric epithelium during adult homeostasis remain unclear. In this study, we investigated the role of Fibroblast growth factor 10 (FGF10 and its main receptor, Fibroblast growth factor receptor 2b (FGFR2b, in adult glandular stomach homeostasis. We first showed that mouse adult glandular stomach expressed Fgf10, its receptors, Fgfr1b and Fgfr2b, and most of the other FGFR2b ligands (Fgf1, Fgf7, Fgf22 except for Fgf3 and Fgf20. Fgf10 expression was mesenchymal whereas FGFR1 and FGFR2 expression were mostly epithelial. Studying double transgenic mice that allow inducible overexpression of Fgf10 in adult mice, we showed that Fgf10 overexpression in normal adult glandular stomach increased epithelial proliferation, drove mucous neck cell differentiation, and reduced parietal and chief cell differentiation. Although a similar phenotype can be associated with the development of metaplasia, we found that Fgf10 overexpression for a short duration does not cause metaplasia. Finally, investigating double transgenic mice that allow the expression of a soluble form of Fgfr2b, FGF10's main receptor, which acts as a dominant negative, we found no significant changes in gastric epithelial proliferation or differentiation in the mutants. Our work provides evidence, for the first time, that the FGF10-FGFR2b signaling pathway is not required for epithelial proliferation and differentiation during adult glandular stomach homeostasis.

  19. Fibroblast growth factor 10-fibroblast growth factor receptor 2b mediated signaling is not required for adult glandular stomach homeostasis.

    Science.gov (United States)

    Speer, Allison L; Al Alam, Denise; Sala, Frederic G; Ford, Henri R; Bellusci, Saverio; Grikscheit, Tracy C

    2012-01-01

    The signaling pathways that are essential for gastric organogenesis have been studied in some detail; however, those that regulate the maintenance of the gastric epithelium during adult homeostasis remain unclear. In this study, we investigated the role of Fibroblast growth factor 10 (FGF10) and its main receptor, Fibroblast growth factor receptor 2b (FGFR2b), in adult glandular stomach homeostasis. We first showed that mouse adult glandular stomach expressed Fgf10, its receptors, Fgfr1b and Fgfr2b, and most of the other FGFR2b ligands (Fgf1, Fgf7, Fgf22) except for Fgf3 and Fgf20. Fgf10 expression was mesenchymal whereas FGFR1 and FGFR2 expression were mostly epithelial. Studying double transgenic mice that allow inducible overexpression of Fgf10 in adult mice, we showed that Fgf10 overexpression in normal adult glandular stomach increased epithelial proliferation, drove mucous neck cell differentiation, and reduced parietal and chief cell differentiation. Although a similar phenotype can be associated with the development of metaplasia, we found that Fgf10 overexpression for a short duration does not cause metaplasia. Finally, investigating double transgenic mice that allow the expression of a soluble form of Fgfr2b, FGF10's main receptor, which acts as a dominant negative, we found no significant changes in gastric epithelial proliferation or differentiation in the mutants. Our work provides evidence, for the first time, that the FGF10-FGFR2b signaling pathway is not required for epithelial proliferation and differentiation during adult glandular stomach homeostasis.

  20. FGF signaling repertoire of the indirect developing hemichordate Ptychodera flava.

    Science.gov (United States)

    Fan, Tzu-Pei; Su, Yi-Hsien

    2015-12-01

    Fibroblast growth factors (FGFs) are a group of ligands that play multiple roles during development by transducing signals through FGF receptors (FGFRs) to downstream factors. At least 22 FGF ligands and 4 receptors have been identified in vertebrates, while six to eight FGF ligands and a single FGFR are present in invertebrate chordates, such as tunicates and amphioxus. The chordate FGFs can be categorized into at least seven subfamilies, and the members of which expanded during the evolution of early vertebrates. In contrast, only one FGF and two FGFRs have been found in sea urchins. Thus, it is unclear whether the FGF subfamilies duplicated in the lineage leading to the chordates, or sea urchins lost several fgf genes. Analyses of the FGF signaling repertoire in hemichordates, which together with echinoderms form the closest group to the chordates, may provide insights into the evolution of FGF signaling in deuterostomes. In this study, we identified five FGFs and three FGFRs from Ptychodera flava, an indirect-developing hemichordate acorn worm. Phylogenetic analyses revealed that hemichordates possess a conserved FGF8/17/18 in addition to several putative hemichordate-specific FGFs. Analyses of sequence similarity and protein domain organizations suggested that the sea urchin and hemichordate FGFRs arose from independent lineage-specific duplications. Furthermore, the acorn worm fgf and fgfr genes were demonstrated to be expressed during P. flava embryogenesis. These results set the foundations for further functional studies of FGF signaling in hemichordates and provided insights into the evolutionary history of the FGF repertoire.

  1. A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21 modified with polyethylene glycol.

    Directory of Open Access Journals (Sweden)

    Zhifeng Huang

    Full Text Available As one of fibroblast growth factor (FGF family members, FGF21 has been extensively investigated for its potential as a drug candidate to combat metabolic diseases. In the present study, recombinant human FGF21 (rhFGF21 was modified with polyethylene glycol (PEGylation in order to increase its in vivo biostabilities and therapeutic potency. At N-terminal residue rhFGF21 was site-selectively PEGylated with mPEG20 kDa-butyraldehyde. The PEGylated rhFGF21 was purified to near homogeneity by Q Sepharose anion-exchange chromatography. The general structural and biochemical features as well as anti-diabetic effects of PEGylated rhFGF21 in a type 2 diabetic rat model were evaluated. By N-terminal sequencing and MALDI-TOF mass spectrometry, we confirmed that PEG molecule was conjugated only to the N-terminus of rhFGF21. The mono-PEGylated rhFGF21 retained the secondary structure, consistent with the native rhFGF21, but its biostabilities, including the resistance to physiological temperature and trypsinization, were significantly enhanced. The in vivo immunogenicity of PEGylated rhFGF21 was significantly decreased, and in vivo half-life time was significantly elongated. Compared to the native form, the PEGylated rhFGF21 had a similar capacity of stimulating glucose uptake in 3T3-L1 cells in vitro, but afforded a significantly long effect on reducing blood glucose and triglyceride levels in the type 2 diabetic animals. These results suggest that the PEGylated rhFGF21 is a better and more effective anti-diabetic drug candidate than the native rhFGF21 currently available. Therefore, the PEGylated rhFGF21 may be potentially applied in clinics to improve the metabolic syndrome for type 2 diabetic patients.

  2. Immunohistochemical localization and mRNA expression of basic fibroblast growth factor(bFGF) and FGF receptors in rat salivary glands%bFGF及其受体FGFRS在成年大鼠唾液腺中的免疫组化定位和mRNA表达

    Institute of Scientific and Technical Information of China (English)

    黄永清; 曲延征; 马敏; 何涛; 陈伟辉

    2004-01-01

    目的本文研究碱性成纤维细胞生长因子[basic fibroblast growth factor(bFGF)]和成纤维细胞生长因子受体1、2、3和4(FGFR1、FGFR2、FGFR3和FGFR4)在大鼠唾液腺中分布及表达特点.方法应用免疫组化和RT-PCR的方法研究bFGF和FGFR1,FGFR2,FGFR3和FGFR4在成年大鼠腮腺和颌下腺中的免疫组化定位和mRNA表达.结果bFGF和FGFR1,FGFR2,FGFR3和FGFR4在成年大鼠腮腺和颌下腺的各级腺管上皮细胞均有较强的特异性免疫染色.在成年大鼠腮腺和颌下腺可以检测到bFGF和FGFR1,FGFR2,FGFR3 mRNA表达.结论成年大鼠腮腺和颌下腺是合成、分泌bFGF的重要源泉.

  3. Fibroblast Growth Factor 21 (FGF-21 in Peritoneal Dialysis Patients: Natural History and Metabolic Implications.

    Directory of Open Access Journals (Sweden)

    Elena González

    Full Text Available Human fibroblast growth factor 21 (FGF-21 is an endocrine liver hormone that stimulates adipocyte glucose uptake independently of insulin, suppresses hepatic glucose production and is involved in the regulation of body fat. Peritoneal dialysis (PD patients suffer potential interference with FGF-21 status with as yet unknown repercussions.The aim of this study was to define the natural history of FGF-21 in PD patients, to analyze its relationship with glucose homeostasis parameters and to study the influence of residual renal function and peritoneal functional parameters on FGF-21 levels and their variation over time.We studied 48 patients with uremia undergoing PD. Plasma samples were routinely obtained from each patient at baseline and at 1, 2 and 3 years after starting PD therapy.Plasma FGF-21 levels substantially increased over the first year and were maintained at high levels during the remainder of the study period (253 pg/ml (59; 685 at baseline; 582 pg/ml (60.5-949 at first year and 647 pg/ml (120.5-1116.6 at third year (p<0.01. We found a positive correlation between time on dialysis and FGF-21 levels (p<0.001, and also, those patients with residual renal function (RRF had significantly lower levels of FGF-21 than those without RRF (ρ -0.484, p<0.05. Lastly, there was also a significant association between FGF-21 levels and peritoneal protein losses (PPL, independent of the time on dialysis (ρ 0.410, p<0.05.Our study shows that FGF-21 plasma levels in incident PD patients significantly increase during the first 3 years. This increment is dependent on or is associated with RRF and PPL (higher levels in patients with lower RRF and higher PPL. FGF-21 might be an important endocrine agent in PD patients and could act as hormonal signaling to maintain glucose homeostasis and prevent potential insulin resistance. These preliminary results suggest that FGF-21 might play a protective role as against the development of insulin resistance over

  4. Comprehensive analysis of fibroblast growth factor receptor expression patterns during chick forelimb development.

    Science.gov (United States)

    Sheeba, Caroline J; Andrade, Raquel P; Duprez, Delphine; Palmeirim, Isabel

    2010-01-01

    Specific interactions between fibroblast growth factors (Fgf1-22) and their tyrosine kinase receptors (FgfR1-4) activate different signalling pathways that are responsible for the biological processes in which Fgf signalling is implicated during embryonic development. In the chick, several Fgf ligands (Fgf2, 4, 8, 9, 10, 12, 13 and 18) and the four FgfRs (FgfR 1, 2, 3 and 4) have been reported to be expressed in the developing limb. The precise spatial and temporal expression of these transcripts is important to guide the limb bud to develop into a wing/leg. In this paper, we present a detailed and systematic analysis of the expression patterns of FgfR1, 2, 3 and 4 throughout chick wing development, by in situ hybridisation on whole mounts and sections. Moreover, we characterize for the first time the different isoforms of FGFR1-3 by analysing their differential expression in limb ectoderm and mesodermal tissues, using RT-PCR and in situ hybridisation on sections. Finally, isoform-specific sequences for FgfR1IIIb, FgfR1IIIc, FgfR3IIIb and FgfR3IIIc were determined and deposited in GenBank with the following accession numbers: GU053725, GU065444, GU053726, GU065445, respectively.

  5. Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors.

    Science.gov (United States)

    Yeh, Brian K; Igarashi, Makoto; Eliseenkova, Anna V; Plotnikov, Alexander N; Sher, Ifat; Ron, Dina; Aaronson, Stuart A; Mohammadi, Moosa

    2003-03-04

    Binding specificity between fibroblast growth factors (FGFs) and their receptors (FGFRs) is essential for mammalian development and is regulated primarily by two alternatively spliced exons, IIIb ("b") and IIIc ("c"), that encode the second half of Ig-like domain 3 (D3) of FGFRs. FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b). Here, we report the crystal structure of the ligand-binding portion of FGFR2b bound to FGF10. Unique contacts between divergent regions in FGF10 and two b-specific loops in D3 reveal the structural basis by which alternative splicing provides FGF10-FGFR2b specificity. Structure-based mutagenesis of FGF10 confirms the importance of the observed contacts for FGF10 biological activity. Interestingly, FGF10 binding induces a previously unobserved rotation of receptor Ig domain 2 (D2) to introduce specific contacts with FGF10. Hence, both D2 and D3 of FGFR2b contribute to the exceptional specificity between FGF10 and FGFR2b. We propose that ligand-induced conformational change in FGFRs may also play an important role in determining specificity for other FGF-FGFR complexes.

  6. [The process of heme synthesis in bone marrow mesenchymal stem cells cultured under fibroblast growth factor bFGF and hypoxic conditions].

    Science.gov (United States)

    Poleshko, A G; Lobanok, E S; Mezhevikina, L M; Fesenko, E E; Volotkovskiĭ, I D

    2014-01-01

    It was demonstrated that fibroblast growth factor bFGF influences the process of heme synthesis, the proliferation activity and viability of bone marrow mesenchymal stem cells in culture under hypoxic conditions. The addition of fibroblast growth factor bFGF (7 ng/ml) to the medium under above conditions led to the accumulation of aminolevulinic acid--an early porphyrin and heme precursor, an increase in CD 71 expression--a transferrin receptor, and also a decrease in porphyrin pigments and heme contents--a late precursor and end products of heme synthesis, respectively. It was found that cultivation of the cells under hypoxic conditions and bFGF is an optimum to maintain high viability and proliferation capacity of the mesenchymal stem cells.

  7. Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism.

    Directory of Open Access Journals (Sweden)

    Hongfei Ge

    Full Text Available Diabetes and associated metabolic conditions have reached pandemic proportions worldwide, and there is a clear unmet medical need for new therapies that are both effective and safe. FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Both have potent effects on normalizing glucose, lipid, and energy homeostasis, and therefore, represent attractive potential next generation therapies for combating the growing epidemics of type 2 diabetes and obesity. The mechanism responsible for these impressive metabolic effects remains unknown. While both FGF19 and FGF21 can activate FGFRs 1c, 2c, and 3c in the presence of co-receptor βKlotho in vitro, which receptor is responsible for the metabolic activities observed in vivo remains unknown. Here we have generated a variant of FGF19, FGF19-7, that has altered receptor specificity with a strong bias toward FGFR1c. We show that FGF19-7 is equally efficacious as wild type FGF19 in regulating glucose, lipid, and energy metabolism in both diet-induced obesity and leptin-deficient mouse models. These results are the first direct demonstration of the central role of the βKlotho/FGFR1c receptor complex in glucose and lipid regulation, and also strongly suggest that activation of this receptor complex alone might be sufficient to achieve all the metabolic functions of endocrine FGF molecules.

  8. Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism.

    Science.gov (United States)

    Ge, Hongfei; Baribault, Helene; Vonderfecht, Steven; Lemon, Bryan; Weiszmann, Jennifer; Gardner, Jonitha; Lee, Ki Jeong; Gupte, Jamila; Mookherjee, Paramita; Wang, Minghan; Sheng, Jackie; Wu, Xinle; Li, Yang

    2012-01-01

    Diabetes and associated metabolic conditions have reached pandemic proportions worldwide, and there is a clear unmet medical need for new therapies that are both effective and safe. FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Both have potent effects on normalizing glucose, lipid, and energy homeostasis, and therefore, represent attractive potential next generation therapies for combating the growing epidemics of type 2 diabetes and obesity. The mechanism responsible for these impressive metabolic effects remains unknown. While both FGF19 and FGF21 can activate FGFRs 1c, 2c, and 3c in the presence of co-receptor βKlotho in vitro, which receptor is responsible for the metabolic activities observed in vivo remains unknown. Here we have generated a variant of FGF19, FGF19-7, that has altered receptor specificity with a strong bias toward FGFR1c. We show that FGF19-7 is equally efficacious as wild type FGF19 in regulating glucose, lipid, and energy metabolism in both diet-induced obesity and leptin-deficient mouse models. These results are the first direct demonstration of the central role of the βKlotho/FGFR1c receptor complex in glucose and lipid regulation, and also strongly suggest that activation of this receptor complex alone might be sufficient to achieve all the metabolic functions of endocrine FGF molecules.

  9. Expression of aFGF, bFGF, and FGFR1 in ovarian epithelial neoplasm

    Institute of Scientific and Technical Information of China (English)

    张颐; 郭科军; 尚海; 王亚军; 孙黎光

    2004-01-01

    @@ Ovarian epithelial cancer is a common malignant ovarian neoplasm with a high mortality. The factors that regulate the rapid growth of ovarian epithelial cancers are still largely unknown. There are some evidences indicating that oncogene can confer growth factor automatically onto cancer cells. The autocrine secretion hypothesis proposes that, as a result of oncogene activation, neoplastic cells can escape growth-restraining mechanism by independently producing and responding to their own growth factors. In recent years, attention has focused on fibroblast growth factor (FGF), as well as acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF), because it is a polypeptide growth factor with a widespread biological activity. In order to explore the factors responsible for the rapid growth and proliferation of human ovarian cancer, we investigated the possible role of aFGF and bFGF and their receptors (FGFR1).

  10. Decrease of FGF receptor (FGFR) and interstitial fibrosis in the kidney of streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Cheng, M F; Chen, L J; Wang, M C; Hsu, C T; Cheng, J T

    2014-01-01

    Fibrosis is the final disorder of end-stage renal disease. Activation of fibroblast growth factor (FGF) 23-klotho axis could suppress renal fibrosis in mice. Also, a marked decrease of klotho expression was observed in the kidney of streptozotocin-induced diabetic rats (STZ rats). However, relation of FGF in renal fibrosis remained unclear. This study was aimed to screen the effect of hyperglycemia on FGF receptor (FGFR) and fibrosis in kidney of rats with diabetic nephropathy and investigate this potential mechanism in cultured Madin-Darby Canine Kidney (MDCK) epithelial cells. STZ rats were used to treat with insulin or phloridzin at the dose sufficient to correct hyperglycemia for understanding the changes of renal dysfunction. The cultured MDCK cells were also used to treat with high glucose, hydrogen peroxide, or tiron in addition to transfection of siRNA to silence the klotho. Both insulin and phloridzin reversed fibrosis and FGFR expressions in kidney of STZ rats. It was confirmed in high glucose-exposed MDCK cells. However, klotho failed to modify the level of FGFR in MDCK cells. Meanwhile, FGFR was restored by tiron in MDCK cells and in diabetic rats without changing blood glucose. In conclusion, interstitial fibrosis and decreased FGFR expression are observed in the kidney of diabetic rats. This change is reversed by tiron without the correction of blood glucose. Also, klotho has no effect on expression of FGFR. Thus, decrease of oxidative stress is useful for the recovery of FGFR expression and improvement of renal fibrosis in type-1 like diabetic rats.

  11. Combination treatment of prostate cancer with FGF receptor and AKT kinase inhibitors

    Science.gov (United States)

    Feng, Shu; Shao, Longjiang; Castro, Patricia; Coleman, Ilsa; Nelson, Peter S; Smith, Paul D; Davies, Barry R; Ittmann, Michael

    2017-01-01

    Activation of the PI3K/AKT pathway occurs in the vast majority of advanced prostate cancers (PCas). Activation of fibroblast growth factor receptor (FGFR) signaling occurs in a wide variety of malignancies, including PCa. RNA-Seq of castration resistant PCa revealed expression of multiple FGFR signaling components compatible with FGFR signaling in all cases, with multiple FGF ligands expressed in 90% of cases. Immunohistochemistry confirmed FGFR signaling in the majority of xenografts and advanced PCas. AZD5363, an AKT kinase inhibitor and AZD4547, a FGFR kinase inhibitor are under active clinical development. We therefore sought to determine if these two drugs have additive effects in PCa models. The effect of both agents, singly and in combination was evaluated in a variety of PCa cell lines in vitro and in vivo. All cell lines tested responded to both drugs with decreased invasion, soft agar colony formation and growth in vivo, with additive effects seen with combination treatment. Activation of the FGFR, AKT, ERK and STAT3 pathways was examined in treated cells. AZD5363 inhibited AKT signaling and increased FGFR1 signaling, which partially compensated for decreased AKT kinase activity. While AZD4547 could effectively block the ERK pathway, combination treatment was needed to completely block STAT3 activation. Thus combination treatment with AKT and FGFR kinase inhibitors have additive effects on malignant phenotypes in vitro and in vivo by inhibiting multiple signaling pathways and mitigating the compensatory upregulation of FGFR signaling induced by AKT kinase inhibition. Our studies suggest that co-targeting these pathways may be efficacious in advanced PCa. PMID:28008155

  12. Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia.

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    Ai-Luen Wu

    Full Text Available The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23 controls phosphate homeostasis by regulating renal expression of sodium-dependent phosphate co-transporters and cytochrome P450 enzymes involved in vitamin D catabolism. Multiple FGF Receptors (FGFRs can act as receptors for FGF23 when bound by the co-receptor Klotho expressed in the renal tubular epithelium. FGFRs also regulate skeletal FGF23 secretion; ectopic FGFR activation is implicated in genetic conditions associated with FGF23 overproduction and hypophosphatemia. The identity of FGFRs that mediate the activity of FGF23 or that regulate skeletal FGF23 secretion remains ill defined. Here we report that pharmacological activation of FGFR1 with monoclonal anti-FGFR1 antibodies (R1MAb in adult mice is sufficient to cause an elevation in serum FGF23 and mild hypophosphatemia. In cultured rat calvariae osteoblasts, R1MAb induces FGF23 mRNA expression and FGF23 protein secretion into the culture medium. In a cultured kidney epithelial cell line, R1MAb acts as a functional FGF23 mimetic and activates the FGF23 program. siRNA-mediated Fgfr1 knockdown induced the opposite effects. Taken together, our work reveals the central role of FGFR1 in the regulation of FGF23 production and signal transduction, and has implications in the pathogenesis of FGF23-related hypophosphatemic disorders.

  13. Action Mechanism of Fibroblast Growth Factor-2 (FGF-2 in the Promotion of Periodontal Regeneration in Beagle Dogs.

    Directory of Open Access Journals (Sweden)

    Toshie Nagayasu-Tanaka

    Full Text Available Fibroblast growth factor-2 (FGF-2 enhances the formation of new alveolar bone, cementum, and periodontal ligament (PDL in periodontal defect models. However, the mechanism through which FGF-2 acts in periodontal regeneration in vivo has not been fully clarified yet. To reveal the action mechanism, the formation of regenerated tissue and gene expression at the early phase were analyzed in a beagle dog 3-wall periodontal defect model. FGF-2 (0.3% or the vehicle (hydroxypropyl cellulose only were topically applied to the defect in FGF-2 and control groups, respectively. Then, the amount of regenerated tissues and the number of proliferating cells at 3, 7, 14, and 28 days and the number of blood vessels at 7 days were quantitated histologically. Additionally, the expression of osteogenic genes in the regenerated tissue was evaluated by real-time PCR at 7 and 14 days. Compared with the control, cell proliferation around the existing bone and PDL, connective tissue formation on the root surface, and new bone formation in the defect at 7 days were significantly promoted by FGF-2. Additionally, the number of blood vessels at 7 days was increased by FGF-2 treatment. At 28 days, new cementum and PDL were extended by FGF-2. Moreover, FGF-2 increased the expression of bone morphogenetic protein 2 (BMP-2 and osteoblast differentiation markers (osterix, alkaline phosphatase, and osteocalcin in the regenerated tissue. We revealed the facilitatory mechanisms of FGF-2 in periodontal regeneration in vivo. First, the proliferation of fibroblastic cells derived from bone marrow and PDL was accelerated and enhanced by FGF-2. Second, angiogenesis was enhanced by FGF-2 treatment. Finally, osteoblastic differentiation and bone formation, at least in part due to BMP-2 production, were rapidly induced by FGF-2. Therefore, these multifaceted effects of FGF-2 promote new tissue formation at the early regeneration phase, leading to enhanced formation of new bone, cementum

  14. Action Mechanism of Fibroblast Growth Factor-2 (FGF-2) in the Promotion of Periodontal Regeneration in Beagle Dogs.

    Science.gov (United States)

    Nagayasu-Tanaka, Toshie; Anzai, Jun; Takaki, Shu; Shiraishi, Noriko; Terashima, Akio; Asano, Taiji; Nozaki, Takenori; Kitamura, Masahiro; Murakami, Shinya

    2015-01-01

    Fibroblast growth factor-2 (FGF-2) enhances the formation of new alveolar bone, cementum, and periodontal ligament (PDL) in periodontal defect models. However, the mechanism through which FGF-2 acts in periodontal regeneration in vivo has not been fully clarified yet. To reveal the action mechanism, the formation of regenerated tissue and gene expression at the early phase were analyzed in a beagle dog 3-wall periodontal defect model. FGF-2 (0.3%) or the vehicle (hydroxypropyl cellulose) only were topically applied to the defect in FGF-2 and control groups, respectively. Then, the amount of regenerated tissues and the number of proliferating cells at 3, 7, 14, and 28 days and the number of blood vessels at 7 days were quantitated histologically. Additionally, the expression of osteogenic genes in the regenerated tissue was evaluated by real-time PCR at 7 and 14 days. Compared with the control, cell proliferation around the existing bone and PDL, connective tissue formation on the root surface, and new bone formation in the defect at 7 days were significantly promoted by FGF-2. Additionally, the number of blood vessels at 7 days was increased by FGF-2 treatment. At 28 days, new cementum and PDL were extended by FGF-2. Moreover, FGF-2 increased the expression of bone morphogenetic protein 2 (BMP-2) and osteoblast differentiation markers (osterix, alkaline phosphatase, and osteocalcin) in the regenerated tissue. We revealed the facilitatory mechanisms of FGF-2 in periodontal regeneration in vivo. First, the proliferation of fibroblastic cells derived from bone marrow and PDL was accelerated and enhanced by FGF-2. Second, angiogenesis was enhanced by FGF-2 treatment. Finally, osteoblastic differentiation and bone formation, at least in part due to BMP-2 production, were rapidly induced by FGF-2. Therefore, these multifaceted effects of FGF-2 promote new tissue formation at the early regeneration phase, leading to enhanced formation of new bone, cementum, and PDL.

  15. FGF signaling in gastrulation and neural development in Nematostella vectensis, an anthozoan cnidarian.

    Science.gov (United States)

    Matus, David Q; Thomsen, Gerald H; Martindale, Mark Q

    2007-02-01

    The fibroblast growth factor (FGF) signal transduction pathway serves as one of the key regulators of early metazoan development, displaying conserved roles in the specification of endodermal, mesodermal, and neural fates during vertebrate development. FGF signals also regulate gastrulation, in part, by triggering epithelial to mesenchymal transitions in embryos of both vertebrates and invertebrates. Thus, FGF signals coordinate gastrulation movements across many different phyla. To help understand the breadth of FGF signaling deployment across the animal kingdom, we have examined the presence and expression of genes encoding FGF pathway components in the anthozoan cnidarian Nematostella vectensis. We isolated three FGF ligands (NvFGF8A, NvFGF8B, and NvFGF1A), two FGF receptors (NvFGFRa and NvFGFRb), and two orthologs of vertebrate FGF responsive genes, Sprouty (NvSprouty), an inhibitor of FGF signaling, and Churchill (NvChurchill), a Zn finger transcription factor. We found these FGF ligands, receptors, and response gene expressed asymmetrically along the oral/aboral axis during gastrulation and in a developing chemosensory structure of planula stages known as the apical tuft. These results suggest a conserved role for FGF signaling molecules in coordinating both gastrulation and neural induction that predates the Cambrian explosion and the origins of the Bilateria.

  16. Expression of the fibroblast growth factor 4 (FGF-4) gene is regulated by serum in Tera-2 embryonal carcinoma cells.

    Science.gov (United States)

    Lucas, J; Knobloch, T; Lang, J

    1996-02-01

    Expression of the fibroblast growth factor 4 (FGF-4) gene is tightly regulated during mammalian development. Dysregulation of FGF-4 gene expression results in cell transformation and tumorigenesis. It is therefore pertinent to investigate the regulatory mechanisms which control expression of FGF-4. In an initial attempt to identify exogenous factors other than retinoic acid which might control FGF-4 expression, we have investigated the response of endogenous FGF-4 to serum in a number of embryonal carcinoma and embryonic stem cell lines. We have identified a human embryonal carcinoma cell line (Tera-2) in which the FGF-4 gene can be induced by serum. In Tera-2 cells made quiescent by serum deprivation, expression of the FGF-4 gene is repressed. Subsequent addition of serum reactivates FGF-LC expression and further addition of cycloheximide results in superinduction of mRNA suggesting that FGF-4 may be classified as an early response gene. It is suggested that this observation may be explained, at least in part, by the stage of differentiation of the Tera-2 cells.

  17. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.

    Science.gov (United States)

    Desnoyers, L R; Pai, R; Ferrando, R E; Hötzel, K; Le, T; Ross, J; Carano, R; D'Souza, A; Qing, J; Mohtashemi, I; Ashkenazi, A; French, D M

    2008-01-03

    Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice its involvement in human cancer is not well characterized. Here we report that FGF19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and colon tumors and in a subset of human colon cancer cell lines. To test the importance of FGF19 for tumor growth, we developed an anti-FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4. This antibody abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. The efficacy of the antibody in these models was linked to inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.

  18. Genetic insights into the mechanisms of Fgf signaling.

    Science.gov (United States)

    Brewer, J Richard; Mazot, Pierre; Soriano, Philippe

    2016-04-01

    The fibroblast growth factor (Fgf) family of ligands and receptor tyrosine kinases is required throughout embryonic and postnatal development and also regulates multiple homeostatic functions in the adult. Aberrant Fgf signaling causes many congenital disorders and underlies multiple forms of cancer. Understanding the mechanisms that govern Fgf signaling is therefore important to appreciate many aspects of Fgf biology and disease. Here we review the mechanisms of Fgf signaling by focusing on genetic strategies that enable in vivo analysis. These studies support an important role for Erk1/2 as a mediator of Fgf signaling in many biological processes but have also provided strong evidence for additional signaling pathways in transmitting Fgf signaling in vivo.

  19. Therapeutics Targeting FGF Signaling Network in Human Diseases.

    Science.gov (United States)

    Katoh, Masaru

    2016-12-01

    Fibroblast growth factor (FGF) signaling through its receptors, FGFR1, FGFR2, FGFR3, or FGFR4, regulates cell fate, angiogenesis, immunity, and metabolism. Dysregulated FGF signaling causes human diseases, such as breast cancer, chondrodysplasia, gastric cancer, lung cancer, and X-linked hypophosphatemic rickets. Recombinant FGFs are pro-FGF signaling therapeutics for tissue and/or wound repair, whereas FGF analogs and gene therapy are under development for the treatment of cardiovascular disease, diabetes, and osteoarthritis. FGF traps, anti-FGF/FGFR monoclonal antibodies (mAbs), and small-molecule FGFR inhibitors are anti-FGF signaling therapeutics under development for the treatment of cancer, chondrodysplasia, and rickets. Here, I discuss the benefit-risk and cost-effectiveness issues of precision medicine targeting FGFRs, ALK, EGFR, and FLT3. FGFR-targeted therapy should be optimized for cancer treatment, focusing on genomic tests and recurrence.

  20. Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas.

    Science.gov (United States)

    Singhal, Garima; Fisher, Ffolliott Martin; Chee, Melissa J; Tan, Tze Guan; El Ouaamari, Abdelfattah; Adams, Andrew C; Najarian, Robert; Kulkarni, Rohit N; Benoist, Christophe; Flier, Jeffrey S; Maratos-Flier, Eleftheria

    2016-01-01

    Fibroblast growth factor 21 (FGF21) is an important endocrine metabolic regulator expressed in multiple tissues including liver and adipose tissue. Although highest levels of expression are in pancreas, little is known about the function of FGF21 in this tissue. In order to understand the physiology of FGF21 in the pancreas, we analyzed its expression and regulation in both acinar and islet tissues. We found that acinar tissue express 20-fold higher levels than that observed in islets. We also observed that pancreatic FGF21 is nutritionally regulated; a marked reduction in FGF21 expression was noted with fasting while obesity is associated with 3-4 fold higher expression. Acinar and islet cells are targets of FGF21, which when systemically administered, leads to phosphorylation of the downstream target ERK 1/2 in about half of acinar cells and a small subset of islet cells. Chronic, systemic FGF21 infusion down-regulates its own expression in the pancreas. Mice lacking FGF21 develop significant islet hyperplasia and periductal lymphocytic inflammation when fed with a high fat obesogenic diet. Inflammatory infiltrates consist of TCRb+ Thy1+ T lymphocytes with increased levels of Foxp3+ regulatory T cells. Increased levels of inflammatory cells were coupled with elevated expression of cytokines such as TNFα, IFNγ and IL1β. We conclude that FGF21 acts to limit islet hyperplasia and may also prevent pancreatic inflammation.

  1. Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation

    OpenAIRE

    Massafra, Vittoria; Milona, Alexandra; VOS, HARMJAN R.; Burgering, Boudewijn M. T.; van Mil, Saskia W. C.

    2017-01-01

    Fibroblast growth factor 19 (FGF19) is a gut-derived peptide hormone that is produced following activation of Farnesoid X Receptor (FXR). FGF19 is secreted and signals to the liver, where it contributes to the homeostasis of bile acid (BA), lipid and carbohydrate metabolism. FGF19 is a promising therapeutic target for the metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF19-mediated induction of proliferation and hepatocellular carcinoma. To infor...

  2. EXPRESSION AND SIGNIFICANCE OF BASIC FIBROBLAST GWOWTH FACTOR AND FIBROBLAST GROWTH FACTOR RECEPTOR-1 IN OVARIAN EPITHELIAL NEOPLASM

    Institute of Scientific and Technical Information of China (English)

    高尚风; 杨蓉; 高博; 刘惠喜

    2003-01-01

    fibroblast growth factor (bFGF), fibroblast growth factor receptor-1 (FGFR-1) and carcinogenesis and progression of ovarian epithelial neoplasm. Methods Ten cases of normal ovarian tissues and 75 cases of ovarian epithelial neoplasm tissues were detected by immunohistochemical methods: S-P for bFGF, FGFR-1,double immunohistochemistry Lab-SA for Ki-67 antigen and bFGF. Results The expression level of bFGF, FGFR-1in ovarian epithelium and ovarian epithelial neoplasm showed a step-wise increase in the following order:normal〈benign〈borderline〈malignant; The expression level and intensity of bFGF and FGFR-1 were increased with the decrease of differentiation degree and increase of clinical stage in ovarian carcinoma; There was no statistical difference between the expression of bFGF, FGFR-1 in serous cystadenocarcinoma and that of mucinous cystadenocarcinoma; The expression of bFGF was correlated with that of FGFR-1 in neoplastic tissues; There were positive expression rates of bFGF and Ki-67 antigen in ovarian epithelial neoplasm. Conclusion As an important proliferative factor, bFGF plays an important role in carcinogenisis and progression of ovarian epithelial neoplasm.

  3. Isoforms of receptors of fibroblast growth factors.

    Science.gov (United States)

    Gong, Siew-Ging

    2014-12-01

    The breadth and scope of Fibroblast Growth Factor signaling is immense, with documentation of its role in almost every organism and system studied so far. FGF ligands signal through a family of four distinct tyrosine kinase receptors, the FGF receptors (FGFRs). One contribution to the diversity of function and signaling of FGFs and their receptors arises from the numerous alternative splicing variants that have been documented in the FGFR literature. The present review discusses the types and roles of alternatively spliced variants of the FGFR family members and the significant impact of alternative splicing on the physiological functions of five broad classes of FGFR isoforms. Some characterized known regulatory mechanisms of alternative splicing and future directions in studies of FGFR alternative splicing are also discussed. Presence, absence, and/or the combination of specific exons within each FGFR protein impart upon each individual isoform its unique function and expression pattern during normal function and in diseased states (e.g., in cancers and birth defects). A better understanding of the diversity of FGF signaling in different developmental contexts and diseased states can be achieved through increased knowledge of the presence of specific FGFR isoforms and their impact on downstream signaling and functions. Modern high-throughput techniques afford an opportunity to explore the distribution and function of isoforms of FGFR during development and in diseases.

  4. Five Transcription Factors and FGF Pathway Inhibition Efficiently Induce Erythroid Differentiation in the Epiblast

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    Wei Weng

    2014-03-01

    Full Text Available Primitive erythropoiesis follows a stereotypic developmental program of mesoderm ventralization and internalization, hemangioblast formation and migration, and erythroid lineage specification. Induction of erythropoiesis is inefficient in either ES/iPS cells in vitro or nonhemangioblast cell populations in vivo. Using the chick model, we report that epiblast cells can be directly and efficiently differentiated into the erythroid lineage by expressing five hematopoietic transcription regulators (SCL+LMO2+GATA2+LDB1+E2A and inhibiting the FGF pathway. We show that these five genes are expressed with temporal specificity during normal erythropoiesis. Initiation of SCL and LMO2 expression requires FGF activity, whereas erythroid differentiation is enhanced by FGF inhibition. The lag between hematopoiesis and erythropoiesis is attributed to sequential coregulator expression and hemangioblast migration. Globin gene transcription can be ectopically and prematurely induced by manipulating the availability of these factors and the FGF pathway activity. We propose that similar approaches can be taken for efficient erythroid differentiation in vitro.

  5. Immunolocalization of fibroblast growth factor-2 (FGF-2) in the developing root and supporting structures of the murine tooth.

    Science.gov (United States)

    Madan, A K; Kramer, Beverley

    2005-03-01

    Epithelio-mesenchymal interactions are active during the development of the root of the tooth and are regulated by a variety of growth factors, such as fibroblast growth factors. FGF-2, 3, 4, and 8 have all been shown to play a role in the development of the crown of the tooth, but less is known about the factors that govern root formation, particularly FGF-2. The aim of this study was thus to elucidate the spatial and temporal expression of FGF-2 in the root of the developing tooth, as this growth factor is believed to be a mediator of epithelio-mesenchymal interactions. Parasagittal sections of the maxillary and mandibular arches of post-natal mice were utilized and the roots of the molar teeth were studied. Immunocytochemistry utilizing an antibody to FGF-2 was performed on sections of teeth at various stages of development. Intense immunostaining for FGF-2 was observed in differentiating odontoblasts at the apical end of the tooth and in the furcation zone of the developing root at all the stages examined. FGF-2 localization was also observed in cementoblasts on post-natal days 16, 20 and 24. The pattern of localization of FGF-2 in the developing root suggests that this growth factor may participate in the signaling network associated with root development.

  6. Fgf signalling controls diverse aspects of fin regeneration.

    Science.gov (United States)

    Shibata, Eri; Yokota, Yuki; Horita, Natsumi; Kudo, Akira; Abe, Gembu; Kawakami, Koichi; Kawakami, Atsushi

    2016-08-15

    Studies have shown that fibroblast growth factor (Fgf) signalling is necessary for appendage regeneration, but its exact function and the ligands involved during regeneration have not yet been elucidated. Here, we performed comprehensive expression analyses and identified fgf20a and fgf3/10a as major Fgf ligands in the wound epidermis and blastema, respectively. To reveal the target cells and processes of Fgf signalling, we performed a transplantation experiment of mesenchymal cells that express the dominant-negative Fgf receptor 1 (dnfgfr1) under control of the heat-shock promoter. This mosaic knockdown analysis suggested that Fgf signalling is directly required for fin ray mesenchyme to form the blastema at the early pre-blastema stage and to activate the regenerative cell proliferation at a later post-blastema stage. These results raised the possibility that the early epidermal Fgf20a and the later blastemal Fgf3/10a could be responsible for these respective processes. We demonstrated by gain-of-function analyses that Fgf20a induces the expression of distal blastema marker junbl, and that Fgf3 promotes blastema cell proliferation. Our study highlights that Fgfs in the wound epidermis and blastema have distinct functions to regulate fin regeneration cooperatively.

  7. Effects of the binding of a dextran derivative on fibroblast growth factor 2: secondary structure and receptor-binding studies.

    Science.gov (United States)

    Bittoun, P; Bagheri-Yarmand, R; Chaubet, F; Crépin, M; Jozefonvicz, J; Fermandjian, S

    1999-06-15

    CMDB (carboxymethyldextran-benzylamide) are dextrans statistically substituted with carboxymethyl and benzylamide groups which can mimick some of the biological properties of heparin. It has previously been shown that CMDB inhibit autocrine growth of breast tumor cells (Bagheri-Yarmand et al., Biochem. Biophys. Res. Commun. 239: 424-428, 1997) and selectively displace fibroblast growth factor 2 (FGF-2) from its receptor. Here, we used circular dichroism and fluorescence anisotropy measurements to show that the conformation of FGF-2 was significantly altered upon its binding to CMDB and to short CMDB fragments prepared within this study. CMDB and fragments formed a stable 1:1 complex with FGF-2, with affinities being estimated as 20+/-10 nM from fluorescence anisotropy analysis. No such a complex was formed with insulin-like growth factor (IGF-1) or epidermal growth factor (EGF). CMDB competed with the FGF-2 receptor for binding to FGF-2 but did not disturb the binding of IGF-1 and EGF to their receptors. Thus, our results highlight the selectivity of CMDB and their fragments towards FGF-2. Heparin, however, competes with CMDB and their fragments for binding to FGF-2. The carboxymethyl and benzylamide groups of these molecules likely interact directly with a heparin-binding region of FGF-2. The resulting change in conformation disturbs the binding of FGF-2 to its receptor and consecutively its mitogenic activity.

  8. Metabolic actions of FGF21: molecular mechanisms and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Xuan Ge

    2012-08-01

    Full Text Available Fibroblast growth factor 21 (FGF21 is an atypical member of the FGF family that functions as an endocrine factor. In obese animals, elevation of plasma FGF21 levels by either pharmacological or genetic approaches reduces body weight, decreases hyperglycemia and hyperlipidemia, alleviates fatty liver and increases insulin sensitivity. FGF21 exerts its pleiotropic metabolic effects through its actions on multiple targets, including adipose tissue, liver, brain and pancreas. The expression of FGF21 is under the control of both peroxisome proliferator-activated receptor gamma (PPARγ and peroxisome proliferator-activated receptor alpha (PPARα. A growing body of evidence suggests that the metabolic benefits of these two nuclear receptors are mediated in part by induction of FGF21. In humans, plasma levels of FGF21 are elevated in obese subjects and patients with type 2 diabetes, but are reduced in patients with autoimmune diabetes. This review summarizes recent advances in understanding the physiological roles of FGF21 and the molecular pathways underlying its actions, and also discusses the future prospective of developing FGF21 or its agonists as therapeutic agents for obesity-related medical complications.

  9. Relationship of Fibroblast Growth Factor 23 (FGF-23) Serum Levels With Low Bone Mass in Postmenopausal Women.

    Science.gov (United States)

    Shen, Jun; Fu, Shiping; Song, Yuan

    2017-05-02

    The aim of this study was to determine the relationship between serum fibroblast growth factor-23 (FGF-23) level and bone mass in postmenopausal women. A total of 60 premenopausal, 60 early postmenopausal, and 60 late postmenopausal women were investigated by the measurement of bone mineral densities (BMDs) at lumbar spine and proximal femur by DXA, together with serum concentrations of Ca, P, 25 (OH) D3 , OC, iPTH, CTX-I, PINP, and FGF-23. The levels of FGF-23 and PINP in early postmenopausal group were significantly higher than that in the premenopausal or the late postmenopausal groups, their changing patterns were different form 25(OH)D3, iPTH, IGF, CTX-I, and OC. According to the AUCs in the ROC analysis, we found that serum FGF-23 level was associated with the highest validity as compared to the other bone metabolism factors. Further study indicated the significant negative relationships between serum FGF-23 level and lumbar spine/proximal femur BMDs in postmenopausal women. After detection of the sensitivity and specificity of serum FGF- 23 for the low bone mass at different T-score (SD) lumbar spine/proximal femur BMDs, we found that serum FGF-23 level may be a reliable marker for low bone mass in postmenopausal women. The performance of FGF-23 in the differential diagnosis low bone mass from healthy participants indicated that FGF-23 has the capacity to differentiate the women with low bone mass from the normal ones. Our study indicated that serum FGF-23 level could be served as the utility in the early detection of women with low bone mass. J. Cell. Biochem. 9999: 1-6, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  10. Role of FGF19 induced FGFR4 activation in the regulation of glucose homeostasis.

    Science.gov (United States)

    Wu, Xinle; Li, Yang

    2009-12-09

    FGF19, FGF21, and FGF23 form a unique subfamily of fibroblast growth factors. Because they contain intra-molecular disulfide bonds and show reduced affinity toward heparan sulfate located in the extracellular space, it is thought that, in contrast to other FGFs, they function as endocrine hormones. FGF23 and its co-receptor alphaKlotho are involved in the control of aging, but it is not known if the same holds true for FGF19, which can also signal through alphaKlotho. However, considerable evidence supports a role for FGF19 in controlling various aspects of metabolism. We have recently fully characterized FGF19/FGFR/co-factor interactions and signaling, and in the current manuscript discuss the contribution of the FGF19/FGFR4 axis to bile acid and glucose regulation.

  11. Anxiolytic effects of muscarinic acetylcholine receptors agonist oxotremorine in chronically stressed rats and related changes in BDNF and FGF2 levels in the hippocampus and prefrontal cortex.

    Science.gov (United States)

    Di Liberto, Valentina; Frinchi, Monica; Verdi, Vincenzo; Vitale, Angela; Plescia, Fulvio; Cannizzaro, Carla; Massenti, Maria F; Belluardo, Natale; Mudò, Giuseppa

    2017-02-01

    In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation. Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety-depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex. The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2 mg/kg Oxo, and unstressed group treated with Oxo. After 21 days of CRS, the groups were treated for 10 days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p-Erk1/2 levels. Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex CONCLUSIONS: The present study showed that Oxo treatment ameliorates the stress-induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex.

  12. Optimization of acidic fibroblast growth factor (FGF-1) and its delivery through a modified degradable fibrin scaffold

    Science.gov (United States)

    Pandit, Abhay Smashikant

    The aim of this investigation was to develop a degradable fibrin wound dressing that can deliver an optimized dose of acidic fibroblast growth factor (FGF-1). This aim led to three distinct phases of study. In the first phase, a structurally modified fibrin degradable scaffold was developed and tested in a rabbit ear ulcer model. A significant increase in the angiogenic and fibroblastic response with a corresponding decrease in healing time was seen in the modified fibrin-treated ulcers as compared with untreated ulcers and ulcers treated with non-modified fibrin systems. In the second phase of the study, a biochemical factor, FGF-1, was added to this scaffold. An optimal dose of 8 mug of FGF-1 was determined to be required to initiate a desired wound-healing response in a rabbit ear ulcer model, based on an enhanced angiogenic and fibroblastic response and an increased epithelialization rate. The objective of the last phase was to investigate the efficacy of a modified scaffold as a vehicle for FGF-1. In vivo testing was conducted in a full-thickness defect model in a rabbit. Improvements were seen in the angiogenic and fibroblastic responses in the FGF-1/modified fibrin treatment group and, hence, FGF-1/modified fibrin was the preferred treatment. In conclusion, the modified fibrin/FGF-1 matrix served as a suitable vehicle for the growth factor, providing a desired healing response and a desirable release rate and, thus, was determined to be an effective scaffold.

  13. Farnesoid X receptor-dependent and -independent pathways mediate the transcriptional control of human fibroblast growth factor 19 by vitamin A.

    Science.gov (United States)

    Jahn, Daniel; Sutor, Dominic; Dorbath, Donata; Weiß, Johannes; Götze, Oliver; Schmitt, Johannes; Hermanns, Heike M; Geier, Andreas

    2016-02-01

    Fibroblast growth factor 19 (FGF19) is a gut-derived hormone that controls bile acid (BA), carbohydrate and lipid metabolism. Whereas strong evidence supports a key role of BAs and farnesoid X receptor (FXR) for the control of FGF19 expression, information on other regulators is limited. In mice, FGF15 expression (ortholog of human FGF19) is induced by vitamin A (VitA) in an FXR-dependent manner. However, the significance of this finding for human FGF19 is currently unclear. Here, we demonstrate that VitA derivatives induce FGF19 in human intestinal cell lines by a direct transcriptional mechanism. In contrast to mouse FGF15, however, this direct regulation is not dependent on FXR but mediated by retinoic acid receptors (RARs) and their interaction with a novel DR-5 element in the human FGF19 gene. In addition to this direct effect, VitA derivatives impacted on the BA-mediated control of FGF19 by regulation of FXR protein levels. In conclusion, VitA regulates human FGF19 expression through FXR-dependent and -independent pathways. Moreover, we suggest that considerable mechanistic differences exist between humans and mice with regard to the nuclear receptors controlling the VitA-FGF15/19 axis. These findings may implicate a clinical relevance of RAR-activating VitA derivatives for the regulation of FGF19 levels in humans.

  14. Fibroblast growth factor receptor signaling is essential for lens fiber cell differentiation

    OpenAIRE

    Zhao, Haotian; Yang, Tianyu; Madakashira, Bhavani P.; Thiels, Cornelius A.; Bechtle, Chad A.; Garcia, Claudia M.; Zhang, Huiming; Yu, Kai; Ornitz, David M.; Beebe, David C.; Robinson, Michael L.

    2008-01-01

    The vertebrate lens provides an excellent model to study the mechanisms that regulate terminal differentiation. Although fibroblast growth factors (FGFs) are thought to be important for lens cell differentiation, it is unclear which FGF receptors mediate these processes during different stages of lens development. Deletion of three FGF receptors (Fgfr1-3) early in lens development demonstrated that expression of only a single allele of Fgfr2 or Fgfr3 was sufficient for grossly normal lens dev...

  15. Dysregulated FGF signalling in neoplastic disorders.

    Science.gov (United States)

    Tanner, Yasmine; Grose, Richard P

    2016-05-01

    The fibroblast growth factor (FGF) signalling pathway contributes to the regulation of a multitude of cellular functions, impacting on proliferation, survival, differentiation and migration. This biological importance is reflected by its prominent role in carcinogenesis; often being hijacked by cancer cells to offer growth or survival advantage. FGF signalling can contribute a driving force in the malignancy of different cancer types; through alterations in ligands, receptors or regulatory molecules. The dramatic advances in genomics technologies have highlighted how mutation, amplification, translocation or loss of elements in the FGF signalling network can contribute to cancer. Added to this are the stromal influences of FGF signalling. Dissection of the mechanisms that underlie the pro-tumourigenic effects resulting from perturbations to the FGF signalling network will be of utmost importance to the development of therapeutic approaches to treat FGF receptor (FGFR)-driven cancers. In this review, we will focus on the mechanisms of FGF deregulation, the prevalence of aberrations in different cancer types, and how we are progressing in the development of targeted therapies.

  16. 成纤维细胞生长因子与其受体相互作用及其抑制剂的研究进照%Growth Factor Receptor and FGF Inhibitors

    Institute of Scientific and Technical Information of China (English)

    范洪宽; 周慧; 李惟

    2001-01-01

    成纤维细胞生长因子(FGF)有许多重要的生理功能,并与肿瘤的形成有关.为了弄清FGF与成纤维细胞生长因子受体(FGFR)相互作用的机制,人们对FGF和RGFR的各个结合结构域进行了深入、细致的研究,定位了aFGF、bFGF的肝素结合区、bFGF的受体结合区、FGF受体的肝素结合区、配体结合区和FGF受体相互结合区,提出了两个FGF与FGFR相互作用的模型,在此基础上设计了FGF的核酸类、糖类和多肽类抑制剂,为寻找新一代抗癌药物打下了理论基础.

  17. [The influence of fibroblast growth factor (FGF2) on cardiomyocytes differentiation of mesenchymal stem cells of bone marrow ex vivo].

    Science.gov (United States)

    Lobanok, E S; Kvacheva, Z B; Pinchuk, S V; Volk, M V; Mezhevkina, L M; Fesenko, E E; Volotovski, I D

    2014-01-01

    The influence of FGF2 on the efficiency of cardiomyocytes differentiation of mesenchymal stem cells (MSC) of bone marrow induced by 5-azacetidine (5-aza) was studied. The effect of FGF2 developing by the 14th day after the combined action of a differentiating agent and growth factor was manifested in an increase in Mef2A, Mef2D and gene transcription and a rise of ionized Ca2+ concentration in cytoplasm keeping cell viability and proliferation activity. In the presence of FGF2 this approach provided cardiomyogenesis and the increase in the formation of early precursors of cardiomyocytes.

  18. Human fibroblast growth factor 20 (FGF-20; CG53135-05): a novel cytoprotectant with radioprotective potential.

    Science.gov (United States)

    Maclachlan, T; Narayanan, B; Gerlach, V L; Smithson, G; Gerwien, R W; Folkerts, O; Fey, E G; Watkins, B; Seed, T; Alvarez, E

    2005-08-01

    The aim was to evaluate the radioprotective properties of recombinant human fibroblast growth factor 20 (FGF-20; CG53135-05) in vitro and in vivo and to examine its effects on known cellular pathways of radioprotection. Relative transcript levels of the cyclooxygenase 2 (COX2), Mn-super oxide dismutase (SOD), CuZn-SOD, extracellular (EC)-SOD, nuclear respiratory factor 2 (Nrf2), glutathione peroxidase 1 (GPX1) and intestinal trefoil factor 3 (ITF3) genes, which are involved in radiation response pathways, were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) in NIH/3T3, IEC18, CCD-18Co, CCD-1070sk and human umbilical vein endothelial cells (HUVEC) cells exposed to FGF-20. Activation of the radioprotective signal transduction pathways initiating with the serine/threonine Akt kinase and the extracellular regulated kinase (ERK) were analysed. Levels of intracellular hydrogen peroxide and cytosolic redox potential were also measured in irradiated and unirradiated cells in the presence or absence of FGF-20. The effects of FGF-20 on cell survival in vitro following ionizing radiation were evaluated using clonogenic assays. To test the potential activity of FGF-20 as a radioprotectant in vivo, mice were administered a single dose of FGF-20 (4 mg kg(-1), intraperitoneally (i.p.) 1 day before lethal total-body irradiation and evaluated for survival. In vitro exposure to FGF-20 increased expression of the Nrf2 transcription factor and oxygen radical scavenging enzymes such as MnSOD, activated signal transduction pathways (ERK and Akt) and resulted in increased survival of irradiated cells in vitro. FGF-20 treatment also resulted in a concomitant reduction in intracellular levels of injurious reactive oxygen species (ROS) following acute ionizing irradiation. Finally, prophylactic administration of FGF-20 to mice before potentially lethal, whole-body X-irradiation led to significant increases in overall survival. FGF-20 reduced the lethal effects of acute

  19. Characterization of a novel fibroblast growth factor 10 (Fgf10 knock-in mouse line to target mesenchymal progenitors during embryonic development.

    Directory of Open Access Journals (Sweden)

    Elie El Agha

    Full Text Available Fibroblast growth factor 10 (Fgf10 is a key regulator of diverse organogenetic programs during mouse development, particularly branching morphogenesis. Fgf10-null mice suffer from lung and limb agenesis as well as cecal and colonic atresia and are thus not viable. To date, the Mlcv1v-nLacZ-24 transgenic mouse strain (referred to as Fgf10(LacZ, which carries a LacZ insertion 114 kb upstream of exon 1 of Fgf10 gene, has been the only strain to allow transient lineage tracing of Fgf10-positive cells. Here, we describe a novel Fgf10(Cre-ERT2 knock-in line (Fgf10(iCre in which a Cre-ERT2-IRES-YFP cassette has been introduced in frame with the ATG of exon 1 of Fgf10 gene. Our studies show that Cre-ERT2 insertion disrupts Fgf10 function. However, administration of tamoxifen to Fgf10(iCre; Tomato(flox double transgenic embryos or adult mice results in specific labeling of Fgf10-positive cells, which can be lineage-traced temporally and spatially. Moreover, we show that the Fgf10(iCre line can be used for conditional gene inactivation in an inducible fashion during early developmental stages. We also provide evidence that transcription factors located in the first intron of Fgf10 gene are critical for maintaining Fgf10 expression over time. Thus, the Fgf10(iCre line should serve as a powerful tool to explore the functions of Fgf10 in a controlled and stage-specific manner.

  20. FGF-2, TGFβ-1, PDGF-A and respective receptors expression in pleomorphic adenoma myoepithelial cells: an in vivo and in vitro study

    Directory of Open Access Journals (Sweden)

    Lucyene Miguita

    2010-02-01

    Full Text Available Myoepithelial cells have an important role in salivary gland tumor development, contributing to a low grade of aggressiveness of these tumors. Normal myoepithelial cells are known by their suppressor function presenting increased expression of extracellular matrix genes and protease inhibitors. The importance of stromal cells and growth factors during tumor initiation and progression has been highlighted by recent literature. Many tumors result from the alteration of paracrine growth factors pathways. Growth factors mediate a wide variety of biological processes such as development, tissue repair and tumorigenesis, and also contribute to cellular proliferation and transformation in neoplastic cells. OBJECTIVES: This study evaluated the expression of fibroblast growth factor-2 (FGF-2, transforming growth factor β-1 (TGFβ-1, platelet-derived growth factor-A (PDGF-A and their respective receptors (FGFR-1, FGFR-2, TGFβR-II and PDGFR-α in myoepithelial cells from pleomorphic adenomas (PA by in vivo and in vitro experiments. MATERIAL AND METHODS: Serial sections were obtained from paraffin-embedded PA samples obtained from the school's files. Myoepithelial cells were obtained from explants of PA tumors provided by surgery from different donors. Immunohistochemistry, cell culture and immunofluorescence assays were used to evaluate growth factor expression. RESULTS: The present findings demonstrated that myoepithelial cells from PA were mainly positive to FGF-2 and FGFR-1 by immunohistochemistry and immunofluorescence. PDGF-A and PDGFR-α had moderate expression by immunohistochemistry and presented punctated deposits throughout cytoplasm of myoepithelial cells. FGFR-2, TGFβ-1 and TGFβR-II were negative in all samples. CONCLUSIONS: These data suggested that FGF-2 compared to the other studied growth factors has an important role in PA benign myoepithelial cells, probably contributing to proliferation of these cells through the FGFR-1.

  1. Numerous isoforms of Fgf8 reflect its multiple roles in the developing brain.

    Science.gov (United States)

    Sunmonu, N Abimbola; Li, Kairong; Li, James Y H

    2011-07-01

    Soluble growth factors play an important role in the coordination and integration of cell proliferation, differentiation, fate determination, and morphogenesis during development of multicellular organisms. Fibroblast growth factors (FGFs) are a large family of polypeptide growth factors that are present in organisms ranging from nematodes to humans. RNA alternative splicing of FGFs and their receptors further enhances the complexity of this ligand-receptor system. The mouse Fgf8 gene produces eight splice variants, which encode isoform proteins with different N-termini and distinct receptor-binding affinity and biological activity. In this article, we review the roles of Fgf8 in vertebrate development and summarize the recent findings on the in vivo function of different Fgf8 splice variants. We propose that multiple Fgf8 isoform proteins act in concert to regulate the overall function of Fgf8 and account for the diverse and essential role of Fgf8 during vertebrate development.

  2. Cellular signaling by fibroblast growth factor receptors.

    Science.gov (United States)

    Eswarakumar, V P; Lax, I; Schlessinger, J

    2005-04-01

    The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. A variety of human skeletal dysplasias have been linked to specific point mutations in FGFR1, FGFR2 and FGFR3 leading to severe impairment in cranial, digital and skeletal development. Gain of function mutations in FGFRs were also identified in a variety of human cancers such as myeloproliferative syndromes, lymphomas, prostate and breast cancers as well as other malignant diseases. The binding of FGF and HSPG to the extracellular ligand domain of FGFR induces receptor dimerization, activation and autophosphorylation of multiple tyrosine residues in the cytoplasmic domain of the receptor molecule. A variety of signaling proteins are phosphorylated in response to FGF stimulation including Shc, phospholipase-Cgamma, STAT1, Gab1 and FRS2alpha leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape. The docking proteins FRS2alpha and FRS2beta are major mediators of the Ras/MAPK and PI-3 kinase/Akt signaling pathways as well as negative feedback mechanisms that fine-tune the signal that is initiated at the cell surface following FGFR stimulation.

  3. Fgf22 regulated by Fgf3/Fgf8 signaling is required for zebrafish midbrain development

    OpenAIRE

    Ayumi Miyake; Nobuyuki Itoh

    2013-01-01

    Summary Fibroblast growth factor (Fgf) signaling plays important roles in various developmental processes including brain development. Here, we identified zebrafish fgf22 predominantly expressed in the posterior midbrain and anterior midbrain–hindbrain boundary (MHB) primordia during early embryonic brain development. To examine roles of Fgf22 in midbrain development, we analyzed fgf22 knockdown embryos. The fgf22 morphants were defective in proper formation of the MHB constriction and the mi...

  4. Diverse ETS transcription factors mediate FGF signaling in the Ciona anterior neural plate.

    Science.gov (United States)

    Gainous, T Blair; Wagner, Eileen; Levine, Michael

    2015-03-15

    The ascidian Ciona intestinalis is a marine invertebrate belonging to the sister group of the vertebrates, the tunicates. Its compact genome and simple, experimentally tractable embryos make Ciona well-suited for the study of cell-fate specification in chordates. Tunicate larvae possess a characteristic chordate body plan, and many developmental pathways are conserved between tunicates and vertebrates. Previous studies have shown that FGF signals are essential for neural induction and patterning at sequential steps of Ciona embryogenesis. Here we show that two different ETS family transcription factors, Ets1/2 and Elk1/3/4, have partially redundant activities in the anterior neural plate of gastrulating embryos. Whereas Ets1/2 promotes pigment cell formation in lateral lineages, both Ets1/2 and Elk1/3/4 are involved in the activation of Myt1L in medial lineages and the restriction of Six3/6 expression to the anterior-most regions of the neural tube. We also provide evidence that photoreceptor cells arise from posterior regions of the presumptive sensory vesicle, and do not depend on FGF signaling. Cells previously identified as photoreceptor progenitors instead form ependymal cells and neurons of the larval brain. Our results extend recent findings on FGF-dependent patterning of anterior-posterior compartments in the Ciona central nervous system. Copyright © 2015. Published by Elsevier Inc.

  5. Identification of Amino Acid Residues in Fibroblast Growth Factor 14 (FGF14) Required for Structure-Function Interactions with Voltage-gated Sodium Channel Nav1.6.

    Science.gov (United States)

    Ali, Syed R; Singh, Aditya K; Laezza, Fernanda

    2016-05-20

    The voltage-gated Na(+) (Nav) channel provides the basis for electrical excitability in the brain. This channel is regulated by a number of accessory proteins including fibroblast growth factor 14 (FGF14), a member of the intracellular FGF family. In addition to forming homodimers, FGF14 binds directly to the Nav1.6 channel C-tail, regulating channel gating and expression, properties that are required for intrinsic excitability in neurons. Seeking amino acid residues with unique roles at the protein-protein interaction interface (PPI) of FGF14·Nav1.6, we engineered model-guided mutations of FGF14 and validated their impact on the FGF14·Nav1.6 complex and the FGF14:FGF14 dimer formation using a luciferase assay. Divergence was found in the β-9 sheet of FGF14 where an alanine (Ala) mutation of Val-160 impaired binding to Nav1.6 but had no effect on FGF14:FGF14 dimer formation. Additional analysis revealed also a key role of residues Lys-74/Ile-76 at the N-terminal of FGF14 in the FGF14·Nav1.6 complex and FGF14:FGF14 dimer formation. Using whole-cell patch clamp electrophysiology, we demonstrated that either the FGF14(V160A) or the FGF14(K74A/I76A) mutation was sufficient to abolish the FGF14-dependent regulation of peak transient Na(+) currents and the voltage-dependent activation and steady-state inactivation of Nav1.6; but only V160A with a concomitant alanine mutation at Tyr-158 could impede FGF14-dependent modulation of the channel fast inactivation. Intrinsic fluorescence spectroscopy of purified proteins confirmed a stronger binding reduction of FGF14(V160A) to the Nav1.6 C-tail compared with FGF14(K74A/I76A) Altogether these studies indicate that the β-9 sheet and the N terminus of FGF14 are well positioned targets for drug development of PPI-based allosteric modulators of Nav channels.

  6. Decreased expression of fibroblast and keratinocyte growth factor isoforms and receptors during scarless repair.

    Science.gov (United States)

    Dang, Catherine M; Beanes, Steven R; Soo, Chia; Ting, Kang; Benhaim, Prosper; Hedrick, Marc H; Lorenz, H Peter

    2003-05-01

    Fibroblast growth factors (FGFs) are a family of 21 cytokines with a broad spectrum of activities, including regulation of cell proliferation, differentiation, and migration. The various FGFs bind to one or more of four different tyrosine kinase receptor types. FGFs 1, 2, 5, 7, and 10 are up-regulated during adult cutaneous wound healing. However, the expression of FGFs during fetal skin development and scarless wound healing has not been characterized. It was hypothesized that differential expression of FGF isoforms and receptors occurs during fetal skin development and that this differential expression pattern may regulate the transition from scarless repair to healing with scar formation. Excisional wounds (2 mm) were created on fetal rats at gestational days 16.5 (scarless) (one wound per fetus, n = 36 fetuses) and 19.5 (scarring) (one wound per fetus, n = 36 fetuses). Wounds were harvested at 24, 48, and 72 hours. Survival until wound harvest ranged from 66 to 75 percent for the gestational day 16 fetuses, and from 83 to 92 percent for the gestational day 19 fetuses. Nonwounded fetal skin from littermates (n = 12 fetuses per wound harvest time point) was used as the control. Wounds/skins were pooled by harvest time point, and RNA was isolated from pooled wounds/skins. Reduced-cycle, specific-primer reverse transcriptase-polymerase chain reaction was performed to determine the expression of FGF isoforms 2, 5, 7, 9, and 10 and FGF receptors 1, 2, and 4 in wounds relative to unwounded skin.In unwounded fetal skin, FGF isoform 5 expression more than doubled at birth. FGF 10 expression doubled during the transition period. FGF 7 expression increased more than sevenfold at birth. Expression of FGF isoforms 2 and 9 did not change during late fetal skin development. The expression of FGF receptors 1, 2, and 4 increased at birth. After wounding, expression of FGF isoforms 7 and 10 was down-regulated in scarless wounds, whereas FGF receptor 2 expression decreased in

  7. Interleukin-1α Is a Paracrine Inducer of FGF7, a Key Epithelial Growth Factor in Benign Prostatic Hyperplasia

    OpenAIRE

    Giri, Dipak; Ittmann, Michael

    2000-01-01

    Benign prostatic hyperplasia (BPH) is an extremely common disease of older men in which there is benign overgrowth of the prostatic transition zone, leading to obstruction of urine outflow. FGF7, a potent growth factor for prostatic epithelial cells, is increased by threefold in BPH and is correlated with increased epithelial proliferation in this condition. Immunohistochemistry of normal and hyperplastic prostate revealed that FGF7-expressing fibroblastic cells were present in higher numbers...

  8. Role of FGF19 induced FGFR4 activation in the regulation of glucose homeostasis

    OpenAIRE

    Wu, Xinle; Li, Yang

    2009-01-01

    FGF19, FGF21, and FGF23 form a unique subfamily of fibroblast growth factors. Because they contain intra-molecular disulfide bonds and show reduced affinity toward heparan sulfate located in the extracellular space, it is thought that, in contrast to other FGFs, they function as endocrine hormones. FGF23 and its co-receptor αKlotho are involved in the control of aging, but it is not known if the same holds true for FGF19, which can also signal through αKlotho. However, considerable evidence s...

  9. Effects of specific and prolonged expression of zebrafish growth factors, Fgf2 and Lif in primordial germ cells in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wong, Ten-Tsao, E-mail: wong20@purdue.edu [Department of Animal Sciences, Purdue University, 901 W. State Street, West Lafayette, IN 47907 (United States); Collodi, Paul [Department of Animal Sciences, Purdue University, 901 W. State Street, West Lafayette, IN 47907 (United States)

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer We discovered that nanos3 3 Prime UTR prolonged PGC-specific protein expression up to 26 days. Black-Right-Pointing-Pointer Expression of Fgf2 in PGCs significantly increased PGC number at later developmental stages. Black-Right-Pointing-Pointer Expression of Lif in PGCs resulted in a significant disruption of PGC migration. Black-Right-Pointing-Pointer Lif illicited its effect on PGC migration through Lif receptor a. Black-Right-Pointing-Pointer Our approach could be used to achieve prolonged PGC-specific expression of other proteins. -- Abstract: Primordial germ cells (PGCs), specified early in development, proliferate and migrate to the developing gonad before sexual differentiation occurs in the embryo and eventually give rise to spermatogonia or oogonia. In this study, we discovered that nanos3 3 Prime UTR, a common method used to label PGCs, not only directed PGC-specific expression of DsRed but also prolonged this expression up to 26 days post fertilization (dpf) when DsRed-nanos3 3 Prime UTR hybrid mRNAs were introduced into 1- to 2-cell-stage embryos. As such, we employed this knowledge to express zebrafish leukemia inhibitory factor (Lif), basic fibroblast growth factor (Fgf2) and bone morphogenetic protein 4 (Bmp4) in the PGCs and evaluate their effects on PGC development in vivo for over a period of 3 weeks. The results show that expression of Fgf2 significantly increased PGC number at 14- and 21-dpf while Bmp4 resulted in severe ventralization and death of the embryos by 3 days. Expression of Lif resulted in a significant disruption of PGC migration. Mopholino knockdown experiments indicated that Lif illicited its effect on PGC migration through Lif receptor a (Lifra) but not Lifrb. The general approach described in this study could be used to achieve prolonged PGC-specific expression of other proteins to investigate their roles in germ cell and gonad development. The results also indicate that zebrafish PGCs

  10. Liver-specific activities of FGF19 require Klotho beta.

    Science.gov (United States)

    Lin, Benjamin C; Wang, Manping; Blackmore, Craig; Desnoyers, Luc R

    2007-09-14

    Hepatocyte function is regulated by members of the fibroblast growth factor (FGF) family of proteins, but little is known about the specific molecular mechanisms of this endocrine pathway. FGF19 regulates bile acid homeostasis and gall bladder filling; FGF19 binds only to FGF receptor 4 (FGFR4), but its liver-specific activity cannot be explained solely by the distribution of this receptor. Although it has been suggested that Klotho beta (KLB) may have a role in mediating FGF19 activity, we have provided for the first time definitive evidence that KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. We have shown that FGFR4 is widely distributed in mouse, whereas KLB distribution is more restricted. Liver was the only organ in which both genes were abundantly expressed. We show that in mice, FGF19 injection triggers liver-specific induction of c-Fos and repression of CYP7A1. The tissue-specific activity of FGF19 supports the unique intersection of KLB and FGFR4 distribution in liver. These studies define KLB as a novel FGFR4 coreceptor required for FGF19 liver specific functions.

  11. Fibroblast growth factor receptors as therapeutic targets in human melanoma: synergism with BRAF inhibition.

    Science.gov (United States)

    Metzner, Thomas; Bedeir, Alexandra; Held, Gerlinde; Peter-Vörösmarty, Barbara; Ghassemi, Sara; Heinzle, Christine; Spiegl-Kreinecker, Sabine; Marian, Brigitte; Holzmann, Klaus; Grasl-Kraupp, Bettina; Pirker, Christine; Micksche, Michael; Berger, Walter; Heffeter, Petra; Grusch, Michael

    2011-10-01

    Cutaneous melanoma is a tumor with rising incidence and a very poor prognosis at the disseminated stage. Melanomas are characterized by frequent mutations in BRAF and also by overexpression of fibroblast growth factor 2 (FGF2), offering opportunities for therapeutic intervention. We investigated inhibition of FGF signaling and its combination with dacarbazine or BRAF inhibitors as an antitumor strategy in melanoma. The majority of melanoma cell lines displayed overexpression of FGF2 but also FGF5 and FGF18 together with different isoforms of FGF receptors (FGFRs) 1-4. Blockade of FGF signals with dominant-negative receptor constructs (dnFGFR1, 3, or 4) or small-molecule inhibitors (SU5402 and PD166866) reduced melanoma cell proliferation, colony formation, as well as anchorage-independent growth, and increased apoptosis. DnFGFR constructs also significantly inhibited tumor growth in vivo. Combination of FGF inhibitors with dacarbazine showed additive or antagonistic effects, whereas synergistic drug interaction was observed when combining FGFR inhibition with the multikinase/BRAF inhibitor sorafenib or the V600E mutant-specific BRAF inhibitor RG7204. In conclusion, FGFR inhibition has antitumor effects against melanoma cells in vitro and in vivo. Combination with BRAF inhibition offers a potential for synergistic antimelanoma effects and represents a promising therapeutic strategy against advanced melanoma.

  12. REGULATION OF NONCLASSICAL FGF1 RELEASE AND FGF-DEPENDENT CELL TRANSFORMATION BY CBF1-MEDIATED NOTCH SIGNALING

    Science.gov (United States)

    Kacer, Doreen; McIntire, Christian; Kirov, Alek; Kany, Erin; Roth, Jennifer; Liaw, Lucy; Small, Deena; Friesel, Robert; Basilico, Claudio; Tarantini, Francesca; Verdi, Joseph; Prudovsky, Igor

    2011-01-01

    FGF1, a widely expressed proangiogenic factor involved in tissue repair and carcinogenesis, is released from cells through a nonclassical pathway independent of endoplasmic reticulum and Golgi. Although several proteins participating in FGF1 export were identified, genetic mechanisms regulating this process remained obscure. We found that FGF1 export and expression are regulated through Notch signaling mediated by transcription factor CBF1and its partner MAML. The expression of a dominant negative (dn) form of CBF1 in 3T3 cells induces transcription of FGF1 and sphingosine kinase 1 (SphK1), which is a component of FGF1 export pathway. dnCBF1 expression stimulates the stress-independent release of transduced FGF1 from NIH 3T3 cells and endogenous FGF1 from A375 melanoma cells. NIH 3T3 cells transfected with dnCBF1 form colonies in soft agar and produce rapidly growing highly angiogenic tumors in nude mice. The transformed phenotype of dnCBF1 transfected cells is efficiently blocked by dn forms of FGF receptor 1 and S100A13, which is a component of FGF1 export pathway. FGF1 export and acceleration of cell growth induced by dnCBF1 depend on SphK1. Similar to dnCBF1, dnMAML transfection induces FGF1 expression and release, and accelerates cell proliferation. The latter effect is strongly decreased in FGF1 null cells. We suggest that the regulation of FGF1 expression and release by CBF1-mediated Notch signaling can play an important role in tumor formation. PMID:21302306

  13. Deregulation of Flk-1/vascular endothelial growth factor receptor-2 in fibroblast growth factor receptor-1-deficient vascular stem cell development.

    Science.gov (United States)

    Magnusson, Peetra; Rolny, Charlotte; Jakobsson, Lars; Wikner, Charlotte; Wu, Yan; Hicklin, Daniel J; Claesson-Welsh, Lena

    2004-03-15

    We have employed embryoid bodies derived from murine embryonal stem cells to study effects on vascular development induced by fibroblast growth factor (FGF)-2 and FGF receptor-1, in comparison to the established angiogenic factor vascular endothelial growth factor (VEGF)-A and its receptor VEGF receptor-2. Exogenous FGF-2 promoted formation of morphologically distinct, long slender vessels in the embryoid bodies, whereas VEGF-A-treated bodies displayed a compact plexus of capillaries. FGF-2 stimulation of embryonal stem cells under conditions where VEGF-A/VEGFR-2 function was blocked, led to formation of endothelial cell clusters, which failed to develop into vessels. FGFR-1(-/-) embryoid bodies responded to VEGF-A by establishment of the characteristic vascular plexus, but FGF-2 had no effect on vascular development in the absence of FGFR-1. The FGFR-1(-/-) embryoid bodies displayed considerably increased basal level of vessel formation, detected by immunohistochemical staining for platelet-endothelial cell adhesion molecule (PECAM)/CD31. This basal vascularization was blocked by neutralizing antibodies against VEGFR-2 or VEGF-A and biochemical analyses indicated changes in regulation of VEGFR-2 in the absence of FGFR-1 expression. We conclude that VEGF-A/VEGFR-2-dependent vessel formation occurs in the absence of FGF-2/FGFR-1, which, however, serve to modulate vascular development.

  14. Stimulation of chondrocytes in vitro by gene transfer with plasmids coding for epidermal growth factor (hEGF) and basic fibroblast growth factor (bFGF)

    DEFF Research Database (Denmark)

    Schmal, H; Mehlhorn, A T; Zwingmann, J

    2005-01-01

    Human epidermal growth factor (hEGF) and basic fibroblast growth factor (bFGF) influence critical characteristics of chondrocytes. The effects on metabolism and differentiation were evaluated following transfection using specific plasmids coding for both cytokines. Chondrocytes were isolated from...... of recombinant hEGF and bFGF resulted in a significant increase in cell proliferation and glucosaminoglycan production. Chondrocytes were transfected with vectors coding for either hEGF or bFGF and the production of these proteins was measured in supernatants by ELISA. Expression kinetics showed different...... patterns: hEGF was detectable 2.5 days following transfection and peaked at day 5.5, whereas bFGF-production reached its maximum 1.5 days after transfection, declining thereafter. Chondrocytes endogenously produced significant amounts of bFGF within 5 days following isolation. Proliferation of h...

  15. Expression pattern of fibroblast growth factors (FGFs), their receptors and antagonists in primary endothelial cells and vascular smooth muscle cells.

    Science.gov (United States)

    Antoine, M; Wirz, W; Tag, C G; Mavituna, M; Emans, N; Korff, T; Stoldt, V; Gressner, A M; Kiefer, P

    2005-06-01

    Fibroblast growth factors (FGFs) are important angiogenic growth factors. While basic FGF (FGF2) is well established as a potent inducer of angiogenesis much less is known about other FGFs possibly expressed by EC. We investigated the expression of all known FGFs, their main tyrosine kinase receptors and antagonists by RT-PCR analysis in human umbilical vascular endothelial cells (HUVECs) to obtain a complete expression profile of this important growth factor system in model endothelial cells (EC). In addition to FGFR1IIIc, which is considered as the major FGF receptor in EC, HUVECs express similar levels of FGFR3IIIc, detectable amounts of FGFR2IIIc and a new FGF receptor without an intracellular kinase domain (FGFR5). HUVECs express several secreted FGFs, including FGF5, 7, 8, 16 and 18 and two members of the fibroblast growth factor homologous factors (FHFs), not yet reported to be expressed in EC. The expression panel was compared with that obtained from human vascular smooth muscle cells (VSMCs) and human aortic tissue. Human umbilical artery smooth muscle cells (HUASMCs) and HUVECs express the identical FGF receptor and ligand panel implicating that both cell types act, according the FGF signals more as an entity than as individual cell types. Expression of Fgf1, 2, 7, 16 and 18 and the antagonists Sprouty 2,3 and 4 was demonstrated for all analysed cDNAs. The IIIc isoforms of FGFR1 and 2 and the novel FGFR5 were expressed in the aorta, but expression of the FGF receptor 3 was not detected in cDNAs derived from aortic tissue. In the VSMC of rat aortic tissue and in HUASM cultured cells we could demonstrate FGF18 immunoreactivity in the nucleus of the cells. The expression of several secreted FGFs by EC may focus the view more on their paracrine effects on neighbouring cells during tissue regeneration or tumor formation.

  16. High molecular weight FGF2 isoforms demonstrate canonical receptor-mediated activity and support human embryonic stem cell self-renewal

    Directory of Open Access Journals (Sweden)

    Denis Kole

    2017-05-01

    Full Text Available Basic fibroblast growth factor (FGF2 is a highly pleiotropic member of a large family of growth factors with a broad range of activities, including mitogenesis and angiogenesis (Ornitz et al., 1996; Zhang et al., 2006, and it is known to be essential for maintenance of balance between survival, proliferation, and self-renewal in human pluripotent stem cells (Eiselleova et al., 2009; Zoumaro-Djayoon et al., 2011. A single FGF2 transcript can be translated into five FGF2 protein isoforms, an 18 kDa low molecular weight (LMW isoform and four larger high molecular weight (HMW isoforms (Arese et al., 1999; Arnaud et al., 1999. As they are not generally secreted, high molecular weight (HMW FGF2 isoforms have predominantly been investigated intracellularly; only a very limited number of studies have investigated their activity as extracellular factors. Here we report over-expression, isolation, and biological activity of all recombinant human FGF2 isoforms. We show that HMW FGF2 isoforms can support self-renewal of human embryonic stem cells (hESCs in vitro. Exogenous supplementation with HMW FGF2 isoforms also activates the canonical FGFR/MAPK pathway and induces mitogenic activity in a manner similar to that of the 18 kDa FGF2 isoform. Though all HMW isoforms, when supplemented exogenously, are able to recapitulate LMW FGF2 activity to some degree, it appears that certain isoforms tend to do so more poorly, demonstrating a lesser functional response by several measures. A better understanding of isoform-specific FGF2 effects will lead to a better understanding of developmental and pathological FGF2 signaling.

  17. Identification of fibroblast growth factor 1 (FGF-1) in a black market product.

    Science.gov (United States)

    Walpurgis, Katja; Thomas, Andreas; Laussmann, Tim; Horta, Luis; Metzger, Sabine; Schänzer, Wilhelm; Thevis, Mario

    2011-01-01

    The use of growth factors for accelerated healing of sports injuries is restricted under the terms of the World Anti-Doping Agency (WADA) anti-doping code. Cheating athletes have used the black market as a source of performance-enhancing substances. Drugs that currently undergo clinical trials are frequently offered--despite the unknown health risks associated with the administration of unapproved pharmaceuticals. Recently, a new growth factor (referred to as fibroblast growth factor 1/FGF-1) with known effects on the repair and regeneration of damaged tissue was detected in an unlabelled black market product confiscated by the German customs. The identification of the protein was achieved by one- and two-dimensional polyacrylamide gel electrophoresis (SDS-PAGE and 2D-PAGE), different proteolytic digestions, immunological methods and nano-liquid chromatography high-resolution/high-accuracy Orbitrap mass spectrometry. The SDS-PAGE analysis revealed slight differences concerning the molecular weight of recombinant human and black market FGF-1. Using in-gel proteolysis, a truncation or modification located at the N-terminus of the protein was suggested. These findings demonstrate that drug candidates without clinical approval can be readily obtained from the black market, regardless of potential dangerous consequences for the consumer, which corroborates the necessity of proactive and preventive doping control approaches. In that regard, physiological concentrations of blood and urine specimens collected from healthy individuals were analyzed and were found to range below 28 pg/ml in urine, while there was no detectable FGF-1 in plasma.

  18. Effect of growth factors (BMP-4/7 & bFGF on proliferation & osteogenic differentiation of bone marrow stromal cells

    Directory of Open Access Journals (Sweden)

    Shaohui Yuan

    2013-01-01

    Full Text Available Background & objectives: BMP (bone morphogenetic protein-4/7 and bFGF (basic fibroblast growth factor significantly promote the osteogenic activity and the proliferation of rabbit BMSCs (bone marrow stromal cells, respectively. However, their synergistic effects on the proliferation and the differentiation of BMSCs remain unclear. In the present study, the effects of bFGF and BMP-4/7 were investigated on the proliferation and the differentiation of rat BMSCs in vitro. Methods: BMSCs were isolated from New Zealand white rabbits and cultured to the third passage. The samples were divided into five groups according to the material implanted: (A 80 ng/ml BMP-4/7; (B 80 ng/ml bFGF; (C 30 ng/ml BMP-4/7 and 30 ng/ml bFGF; (D 50 ng/ml BMP-4/7 and 50 ng/ml bFGF; and (E 80 ng/ml BMP-4/7 and 80 ng/ml bFGF. Cell proliferation was analyzed using methyl thiazolyl tetrazolium (MTT assay. Alkaline phosphatase activity and osteocalcin (OC dynamics were also measured. Results: BMP-4/7 alone significantly (P<0.05 promoted the proliferation of BMSCs. At the same time, it also promoted or inhibited the osteogenic differentiation of BMSCs. The synergistic effects of BMP-4/7 and bFGF significantly promoted both the proliferation and the osteogenic differentiation of BMSCs. The treatment of the synergistic effects was dose and time dependent. Interpretation & conclusions: A rational combination of BMP-4/7 and bFGF can promote the proliferation and the osteogenic differentiation of BMSCs. In addition, the synergistic functions are effective.

  19. Differential regulation of potassium currents by FGF-1 and FGF-2 in embryonic Xenopus laevis myocytes.

    Science.gov (United States)

    Chauhan-Patel, R; Spruce, A E

    1998-10-01

    1. Fibroblast growth factors (FGFs) are involved in the regulation of many aspects of muscle development. This study investigated their role in regulating voltage-dependent K+ currents in differentiating Xenopus laevis myocytes. Both FGF-1 and FGF-2 are expressed by developing muscle cells, so their actions were compared. Experiments were performed on cultured myocytes isolated from stage 15 embryos. 2. Long-term exposure of the embryonic myocytes to FGF-1 downregulated inward rectifier K+ current (IK(IR)) density as well as both sustained and inactivating voltage-dependent outward K+ currents (IK,S and IK,I, respectively) and their densities. In contrast, FGF-2 upregulated these currents, although, because of an increase in capacitance caused by FGF-2, current density did not change with this factor. 3. The regulation of IK(IR) by FGF-1 was prevented by the cytoplasmic tyrosine kinase inhibitor herbimycin A, but that of IK,S and IK,I was unaffected, indicating that FGF-1 achieves its regulatory effects on electrical development via separate signalling pathways. The receptor tyrosine kinase inhibitor genistein in isolation suppressed K+ currents, but this may have occurred through a channel-blocking mechanism. 4. In many cells, IK, S was found to be composed of two components with differing voltage dependencies of activation. The FGFs brought about an alteration in the amount of total IK,S by equal effects on each component. Conversely, herbimycin A increased the proportion of low voltage-activated current without affecting total current amplitude. Therefore, we suggest that a single species of channel whose voltage dependence is shifted by tyrosine phosphorylation generates IK,S. 5. In summary, FGF-1 and FGF-2 exert opposite effects on voltage-dependent K+ currents in embryonic myocytes and, furthermore, FGF-1 achieves its effects on different K+ currents via separate second messenger pathways.

  20. The participation of fibroblast growth factor 23 (FGF23)in the progression of osteoporosis via JAK/STAT pathway.

    Science.gov (United States)

    Xu, Lijun; Zhang, Lixia; Zhang, Huijuan; Yang, Zaigang; Qi, Lei; Wang, Yurong; Ren, Shuxin

    2017-08-07

    Osteoporosis (OP) is a major skeletal disorder for the old man. The fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by osteoblasts and osteocytes. However, the regulatory mechanisms of FGF23 in the progression of osteoporosis remain poorly understood. This study aims to explore the downstream regulating pathway of FGF23 in postmenopausal osteoporosis. The rat model of osteoporosis was established through ovariectomy (OVX). The investigation demonstrated that the serum levels of FGF23 and the phosphorylation levels of JAK2, STAT1 and STAT3 were up-regulated in the OVX + NVP-BGJ398 group while were down-regulated in the OVX + Anti-FGF23 group than that in the OVX group. Moreover, the JAK2/ STAT1/3 inhibitor, AG490 promoted the OVX-induced increase in the osteocalcin, ALP, BALP, TRAP and CTX-I levels. Besides, AG490 enhanced cartilage lesions and increased TUNEL-positive chondrocytes in the OVX group. In addition, higher protein expression of MMP-1 and MMP-13 and lower expression of COX-II were observed in the OVX + AG490 group than that in the OVX group. Our findings suggested that FGF23 was involved in the progression of osteoporosis via the JAK/STAT signaling pathway. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  1. The molecular basis of the cooperation between EGF, FGF and eCB receptors in the regulation of neural stem cell function.

    Science.gov (United States)

    Sütterlin, Philipp; Williams, Emma J; Chambers, David; Saraf, Kathryn; von Schack, David; Reisenberg, Melina; Doherty, Patrick; Williams, Gareth

    2013-01-01

    Adult neurogenesis relies on EGF and FGF receptor (EGFR/FGFR) function and endocannabinoid (eCB) signalling. Here we have used a neural stem cell (NSC) line to determine how these systems cooperate to regulate neurogenesis. The results show the EGFR to be solely responsible for maintaining PI3K activation explaining its dominant role in promoting NSC survival. The EGFR and FGFR synergistically regulate the ERK/MAPK pathway, and this explains the requirement for both for optimal cell proliferation. The eCB receptors did not contribute to activation of the PI3K or ERK/MAPK pathways, highlighting the importance of another major proliferation pathway. The EGFR plays the dominant role in maintaining the transcriptome, with significant changes in the expression of over 3500 transcripts seen within hours of inhibition or activation of this receptor. The FGFR has a more modest effect on transcription with evidence for nodal integration with EGFR signalling at the level of the ERK/MAPK pathway. A common set of transcripts are regulated by the CB1 and CB2 receptors, with cooperation between these receptors and the EGFR apparent in the regulation of a pool of transcripts, most likely representing signal integration downstream from an as yet to be identified node. Finally, a first level molecular analysis of the transcriptional response shows regulation of a number of key growth factors, growth factor receptors and GPCRs to be under the control of the EGFR. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Homodimerization Controls the Fibroblast Growth Factor 9 Subfamily's Receptor Binding and Heparan Sulfate-Dependent Diffusion in the Extracellular Matrix

    Energy Technology Data Exchange (ETDEWEB)

    Kalinina, J.; Byron, S; Makarenkova, H; Olsen, S; Eliseenkova, A; Larochelle, W; Dhanabal, M; Blais, S; Mohammadi, M; et. al.

    2009-01-01

    Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its activity in check. Herein, we demonstrate that FGF9 and FGF20 ligands undergo a reversible homodimerization, occluding their key receptor binding sites. To test the role of dimerization in ligand autoinhibition, we introduced structure-based mutations into the dimer interfaces of FGF9 and FGF20. The mutations weakened the ability of the ligands to dimerize, effectively increasing the concentrations of monomeric ligands capable of binding and activating their cognate FGF receptor in vitro and in living cells. Interestingly, the monomeric ligands exhibit reduced heparin binding, resulting in their increased radii of heparan sulfate-dependent diffusion and biologic action, as evidenced by the wider dilation area of ex vivo lung cultures in response to implanted mutant FGF9-loaded beads. Hence, our data demonstrate that homodimerization autoregulates FGF9 and FGF20's receptor binding and concentration gradients in the extracellular matrix. Our study is the first to implicate ligand dimerization as an autoregulatory mechanism for growth factor bioactivity and sets the stage for engineering modified FGF9 subfamily ligands, with desired activity for use in both basic and translational research.

  3. Suramin blocks interaction between human FGF1 and FGFR2 D2 domain and reduces downstream signaling activity

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Zong-Sian, E-mail: gary810426@hotmail.com [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China); Liu, Che Fu, E-mail: s9823002@m98.nthu.edu.tw [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China); Fu, Brian, E-mail: brianfu9@gmail.com [Northwood High School, Irvine, CA (United States); Chou, Ruey-Hwang, E-mail: rhchou@mail.cmu.edu.tw [Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan (China); Department of Biotechnology, Asia University, Taiwan (China); Yu, Chin, E-mail: cyu.nthu@gmail.com [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China)

    2016-09-02

    The extracellular portion of the human fibroblast growth factor receptor2 D2 domain (FGFR2 D2) interacts with human fibroblast growth factor 1 (hFGF1) to activate a downstream signaling cascade that ultimately affects mitosis and differentiation. Suramin is an antiparasiticdrug and a potent inhibitor of FGF-induced angiogenesis. Suramin has been shown to bind to hFGF1, and might block the interaction between hFGF1 and FGFR2 D2. Here, we titrated hFGF1 with FGFR2 D2 and suramin to elucidate their interactions using the detection of NMR. The docking results of both hFGF1-FGFR2 D2 domain and hFGF1-suramin complex were superimposed. The results indicate that suramin blocks the interaction between hFGF1 and FGFR2 D2. We used the PyMOL software to show the hydrophobic interaction of hFGF1-suramin. In addition, we used a Water-soluble Tetrazolium salts assay (WST1) to assess hFGF1 bioactivity. The results will be useful for the development of new antimitogenic activity drugs. - Highlights: • The interfacial residues on hFGF1-FGFR2 D2 and hFGF1-Suramin contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • hFGF1-FGFR2 D2 and hFGF1-Suramin complex models were generated from NMR restraints by using HADDOCK program. • We analyzed hFGF1-Suramin complex models and found the interaction between hFGF1-Suramin is hydrophobic. • The bioactivity of the hFGF1-FGFR2 D2 and hFGF1-Suramin complex was studied by using WST1 assay.

  4. PLAP-1/Asporin Positively Regulates FGF-2 Activity.

    Science.gov (United States)

    Awata, T; Yamada, S; Tsushima, K; Sakashita, H; Yamaba, S; Kajikawa, T; Yamashita, M; Takedachi, M; Yanagita, M; Kitamura, M; Murakami, S

    2015-10-01

    PLAP-1 is an extracellular matrix protein that is predominantly expressed in the periodontal ligament within periodontal tissue. It was previously revealed that PLAP-1 negatively regulates bone morphogenetic protein 2 and transforming growth factor β activity through direct interactions. However, the interaction between PLAP-1 and other growth factors has not been defined. Here, we revealed that PLAP-1 positively regulates the activity of fibroblast growth factor 2 (FGF-2), a critical growth factor in tissue homeostasis and repair. In this study, we isolated mouse embryonic fibroblasts (MEFs) from Plap-1(-/-) mice generated in our laboratory. Interestingly, Plap-1(-/-) MEFs exhibited enhanced responses to bone morphogenetic protein 2 but defective responses to FGF-2, and Plap-1 transfection into Plap-1(-/-) MEFs rescued these defective responses. In addition, binding assays revealed that PLAP-1 promotes FGF-2-FGF receptor 1 (FGFR1) complex formation by direct binding to FGF-2. Immunocytochemistry analyses revealed colocalization of PLAP-1 and FGF-2 in wild-type MEFs and reduced colocalization of FGF-2 and FGFR1 in Plap-1(-/-) MEFs compared with wild-type MEFs. Taken together, PLAP-1 positively regulates FGF-2 activity through a direct interaction. Extracellular matrix-growth factor interactions have considerable effects; thus, this approach may be useful in several regenerative medicine applications.

  5. Fibroblast Growth Factor Type 1 (FGF1)-Overexpressed Adipose-Derived Mesenchaymal Stem Cells (AD-MSC(FGF1)) Induce Neuroprotection and Functional Recovery in a Rat Stroke Model.

    Science.gov (United States)

    Ghazavi, Hamed; Hoseini, Seyed Javad; Ebrahimzadeh-Bideskan, Alireza; Mashkani, Baratali; Mehri, Soghra; Ghorbani, Ahmad; Sadri, Kayvan; Mahdipour, Elahe; Ghasemi, Faezeh; Forouzanfar, Fatemeh; Hoseini, Azar; Pasdar, Ali Reza; Sadeghnia, Hamid Reza; Ghayour-Mobarhan, Majid

    2017-08-09

    Stroke, as the second most common cause of death, imposes a great financial burden on both the individual and society. Mesenchymal stem cells from rodents have demonstrated efficacy in experimental animal models of stroke due to enhanced neurological recovery. Since FGF1 (fibroblast growth factor 1) displays neuroprotective properties, for the first time, we investigated the effect of acute intravenous administration of FGF1 gene transfected adipose-derived mesenchymal stem cell (AD-MSC(FGF1)) on transient experimental ischemic stroke in rats. Stroke induction was made by transient middle cerebral artery occlusion (tMCAO). 2 × 10(6) AD-MSC(FGF1) was administrated intravenously 30 min after carotid reperfusion. The ability of technetium(99m)-hexamethyl propylene amine oxime ((99m)Tc-HMPAO)-labeled AD-MSC(FGF1) to enter into ischemic brain was evaluated 2 h post injection. 24 h post operation, the neurological recovery (rotarod and Roger's tests), the infarct volume (2, 3, 5-triphenyltetrazolium chloride, TTC assay), apoptosis rate (TUNEL assay), and the expression of FGF1 protein (western blotting) in the ischemic hemisphere were assessed. The (99m)Tc-HMPAO-labeled AD-MSC(FGF1) could enter into the ischemic brain. Ischemic hemisphere activity was significantly higher than that observed in the contralateral hemisphere (p = 0.002). The administration of AD-MSC(FGF1) resulted in significant improvement of neurological function tests and increased density of FGF1 protein in the peri-infarct area, while the infarct volume and the apoptotic index were significantly decreased, in comparison to the other treated groups. In conclusion, acute intravenous administration of AD-MSC(FGF1) can be a novel and promising candidate approach for the treatment of ischemic stroke.

  6. IL-1β inhibits β-Klotho expression and FGF19 signaling in hepatocytes.

    Science.gov (United States)

    Zhao, Yueshui; Meng, Chenling; Wang, Yang; Huang, Huihui; Liu, Wenjing; Zhang, Jin-Fang; Zhao, Hui; Feng, Bo; Leung, Po Sing; Xia, Yin

    2016-02-15

    Fibroblast growth factor (FGF) 19 is a member of the FGF15/19 subfamily of FGFs that includes FGF15/19, FGF21, and FGF23. FGF19 has been shown to have profound effects on liver metabolism and regeneration. FGF19 binds to FGFR4 and its coreceptor β-Klotho to activate intracellular kinases, including Erk1/2. Studies have shown that proinflammatory cytokines such as TNFα impair FGF21 signaling in adipose cells by repressing β-Klotho expression. However, little is known about the effects of inflammation on the FGF19 pathway in the liver. In the present study, we found that lipopolysaccharide (LPS) inhibited β-Klotho and Fgfr4 expression in livers in mice, whereas LPS had no effects on the two FGF19 receptors in Huh-7 and HepG2 cells. Of the three inflammatory cytokines TNFα, IL-1β, and IL-6, IL-1β drastically inhibited β-Klotho expression, whereas TNFα and IL-6 had no or minor effects. None of the three cytokines had any effects on FGFR4 expression. IL-1β directly inhibited β-Klotho transcription, and this inhibition required both the JNK and NF-κB pathways. In addition, IL-1β inhibited FGF19-induced Erk1/2 activation and cell proliferation. These results suggest that inflammation and IL-1β play an important role in regulating FGF19 signaling and function in the liver.

  7. Detection of isoform-specific fibroblast growth factor receptors by whole-mount in situ hybridization in early chick embryos.

    Science.gov (United States)

    Nishita, Junko; Ohta, Sho; Bleyl, Steven B; Schoenwolf, Gary C

    2011-06-01

    We have developed "b" and "c" isoform-specific chicken fibroblast growth factor (FGF) receptor 1-3 probes for in situ hybridization. We rigorously demonstrate the specificity of these probes by using both dot blot hybridization and whole-mount in situ hybridization during neurulation and early postneurulation stages, and we compare expression patterns of each of the three isoform-specific probes to one another and to generic probes to each of the three (non-isoform-specific) FGF receptors. We show that the expression pattern of each receptor is represented by the collective expression of each of its two isoforms, with the expression of each FGF receptor being most similar to that of its "c" isoform at two of the three stages studied, and that tissue and stage differences exist in the patterns of expression of the six isoforms. We demonstrate the usefulness of these probes for defining the differential tissue expression of FGF receptor 1-3 isoforms.

  8. FGF23 and the parathyroid glands.

    Science.gov (United States)

    Silver, Justin; Naveh-Many, Tally

    2010-11-01

    Fibroblast growth factor 23 (FGF23) is a phosphatonin that is secreted by osteocytes and osteoblasts in response to hyperphosphatemia and 1,25-dihydroxyvitamin D (1,25D). It acts on its receptor complex, Klotho-FGFR1c (fibroblast growth factor receptor 1 c-splicing form), in the distal convoluted tubule to repress renal phosphorus reabsorption in the proximal tubule and suppress the renal synthesis of 1,25D. Klotho-FGFR1c is also expressed in the parathyroid glands. FGF23 acts on the receptor complex in the parathyroid glands to decrease parathyroid hormone (PTH) gene expression and PTH secretion through activation of the MAPK pathway. In chronic kidney disease (CKD), both FGF23 and PTH are increased, implying resistance of the parathyroid glands to FGF23. There is a decrease in the Klotho-FGFR1c complex in the parathyroid glands in both experimental CKD and in patients with end-stage renal disease. In addition, in advanced experimental CKD, FGF23 has a decreased ability to inhibit PTH expression.

  9. Influence of heparin mimetics on assembly of the FGF.FGFR4 signaling complex.

    Science.gov (United States)

    Saxena, Krishna; Schieborr, Ulrich; Anderka, Oliver; Duchardt-Ferner, Elke; Elshorst, Bettina; Gande, Santosh Lakshmi; Janzon, Julia; Kudlinzki, Denis; Sreeramulu, Sridhar; Dreyer, Matthias K; Wendt, K Ulrich; Herbert, Corentin; Duchaussoy, Philippe; Bianciotto, Marc; Driguez, Pierre-Alexandre; Lassalle, Gilbert; Savi, Pierre; Mohammadi, Moosa; Bono, Françoise; Schwalbe, Harald

    2010-08-20

    Fibroblast growth factor (FGF) signaling regulates mammalian development and metabolism, and its dysregulation is implicated in many inherited and acquired diseases, including cancer. Heparan sulfate glycosaminoglycans (HSGAGs) are essential for FGF signaling as they promote FGF.FGF receptor (FGFR) binding and dimerization. Using novel organic synthesis protocols to prepare homogeneously sulfated heparin mimetics (HM), including hexasaccharide (HM(6)), octasaccharide (HM(8)), and decasaccharide (HM(10)), we tested the ability of these HM to support FGF1 and FGF2 signaling through FGFR4. Biological assays show that both HM(8) and HM(10) are significantly more potent than HM(6) in promoting FGF2-mediated FGFR4 signaling. In contrast, all three HM have comparable activity in promoting FGF1.FGFR4 signaling. To understand the molecular basis for these differential activities in FGF1/2.FGFR4 signaling, we used NMR spectroscopy, isothermal titration calorimetry, and size-exclusion chromatography to characterize binding interactions of FGF1/2 with the isolated Ig-domain 2 (D2) of FGFR4 in the presence of HM, and binary interactions of FGFs and D2 with HM. Our data confirm the existence of both a secondary FGF1.FGFR4 interaction site and a direct FGFR4.FGFR4 interaction site thus supporting the formation of the symmetric mode of FGF.FGFR dimerization in solution. Moreover, our results show that the observed higher activity of HM(8) relative to HM(6) in stimulating FGF2.FGFR4 signaling correlates with the higher affinity of HM(8) to bind and dimerize FGF2. Notably FGF2.HM(8) exhibits pronounced positive binding cooperativity. Based on our findings we propose a refined symmetric FGF.FGFR dimerization model, which incorporates the differential ability of HM to dimerize FGFs.

  10. Mifepristone inhibits MPA-and FGF2-induced mammary tumor growth but not FGF2-induced mammary hyperplasia

    Directory of Open Access Journals (Sweden)

    Juan P. Cerliani

    2010-12-01

    Full Text Available We have previously demonstrated a crosstalk between fibroblast growth factor 2 (FGF2 and progestins inducing experimental breast cancer growth. The aim of the present study was to compare the effects of FGF2 and of medroxyprogesterone acetate (MPA on the mouse mammary glands and to investigate whether the antiprogestin RU486 was able to reverse the MPA- or FGF2-induced effects on both, mammary gland and tumor growth. We demonstrate that FGF2 administered locally induced an intraductal hyperplasia that was not reverted by RU486, suggesting that FGF2-induced effects are progesterone receptor (PR-independent. However, MPA-induced paraductal hyperplasia was reverted by RU486 and a partial agonistic effect was observed in RU486-treated glands. Using C4-HD tumors which only grow in the presence of MPA, we showed that FGF2 administered intratumorally was able to stimulate tumor growth as MPA. The histology of FGF2-treated tumors showed different degrees of gland differentiation. RU486 inhibited both, MPA or FGF2 induced tumor growth. However, only complete regression was observed in MPA-treated tumors. Our results support the hypothesis that stromal FGF2 activates PR inducing hormone independent tumor growth.

  11. Expression of the Cardiac Maintenance and Survival Factor FGF-16 Gene Is Regulated by Csx/Nkx2.5 and Is an Early Target of Doxorubicin Cardiotoxicity.

    Science.gov (United States)

    Wang, Jie; Jin, Yan; Cattini, Peter A

    2017-02-01

    The fibroblast growth factor (FGF) 16 gene (Fgf-16) is preferentially expressed by neonatal cardiomyocytes after birth, with levels increasing into adulthood. Null mice and isolated heart studies suggest a role for FGF-16 in cardiac maintenance and survival, including increased resistance to doxorubicin (DOX)-induced injury. However, the effect of DOX on endogenous FGF-16 synthesis and specifically regulation of cardiac Fgf-16 expression has not been reported. Here we assess the effect of DOX on FGF-16 RNA levels and stability as well as promoter activity and use sequence analysis, knockdown, and overexpression to investigate the role of cardiac transcription factor(s) implicated in the response. Endogenous FGF-16 RNA levels were reduced >70% in 8-week-old rats treated with 15 mg DOX/kg for 6 h. This was modeled in neonatal rat cardiomyocyte cultures, where an equivalent decrease was also seen within 6 h of 1 μM DOX treatment. Six kilobases of mouse Fgf-16 upstream flanking and promoter DNA was also assessed for DOX responsiveness in transfected cardiomyocytes. A decrease in FGF-16 promoter activity was seen with only 747 base pairs containing the Fgf-16 TATA box that includes a putative and highly conserved binding site for the cardiac transcription factor Csx/Nkx2.5. There was also no effect of DOX on FGF-16 RNA stability, consistent with transcriptional control. Levels and binding of Csx/Nkx2.5 to the FGF-16 promoter were reduced with DOX treatment. Knockdown of Csx/Nkx2.5 specifically decreased endogenous FGF-16 RNA and protein levels, whereas Csx/Nkx2.5 overexpression stimulated levels, and increased resistance to the rapid DOX-induced depletion of FGF-16. These observations indicate that Fgf-16 expression is directly regulated by Csx/Nkx2.5 in neonatal cardiomyocytes, and a negative effect of DOX on Csx/Nkx2.5 and, thus, endogenous FGF-16 synthesis may contribute indirectly to its cardiotoxic effects. Targeting FGF-16 levels could, however, offer

  12. Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning.

    OpenAIRE

    Celli, G; LaRochelle, W J; Mackem, S; Sharp, R.; Merlino, G.

    1998-01-01

    Despite a wealth of experimental data implicating fibroblast growth factor (FGF) signaling in various developmental processes, genetic inactivation of individual genes encoding specific FGFs or their receptors (FGFRs) has generally failed to demonstrate their role in vertebrate organogenesis due to early embryonic lethality or functional redundancy. Here we show that broad mid-gestational expression of a novel secreted kinase-deficient receptor, specific for a defined subset of the FGF superf...

  13. Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice

    NARCIS (Netherlands)

    Stroeve, Johanna H. M.; Brufau, Gemma; Stellaard, Frans; Gonzalez, Frank J.; Staels, Bart; Kuipers, Folkert

    2010-01-01

    Hepatic bile acid synthesis is subject to complex modes of transcriptional control, in which the bile acid-activated nuclear receptor farnesoid X receptor (FXR) in liver and intestine-derived, FXR-controlled fibroblast growth factor 15 (Fgf15) are involved. The Fgf15 pathway is assumed to contribute

  14. FGF19 Regulates Cell Proliferation, Glucose and Bile Acid Metabolism via FGFR4-Dependent and Independent Pathways

    OpenAIRE

    Ai-Luen Wu; Sally Coulter; Christopher Liddle; Anne Wong; Jeffrey Eastham-Anderson; French, Dorothy M.; Peterson, Andrew S.; Junichiro Sonoda

    2011-01-01

    Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB). In this report, we investigate the role of FGFR4...

  15. The heparan sulfate co-receptor and the concentration of fibroblast growth factor-2 independently elicit different signalling patterns from the fibroblast growth factor receptor

    Directory of Open Access Journals (Sweden)

    Duchesne Laurence

    2010-06-01

    Full Text Available Abstract Background The fibroblast growth factor receptor (FGFR interprets concentration gradients of FGF ligands and structural changes in the heparan sulfate (HS co-receptor to generate different cellular responses. However, whether the FGFR generates different signals is not known. Results We have previously shown in rat mammary fibroblasts that in cells deficient in sulfation, and so in HS co-receptor, FGF-2 can only stimulate a transient phosphorylation of p42/44 MAPK and so cannot stimulate DNA synthesis. Here we demonstrate that this is because in the absence of HS, FGF-2 fails to stimulate the phosphorylation of the adaptor FGFR substrate 2 (FRS2. In cells possessing the HS co-receptor, FGF-2 elicits a bell-shaped dose response: optimal concentrations stimulate DNA synthesis, but supramaximal concentrations (≥ 100 ng/mL have little effect. At optimal concentrations (300 pg/mL FGF-2 stimulates a sustained dual phosphorylation of p42/44 MAPK and tyrosine phosphorylation of FRS2. In contrast, 100 ng/mL FGF-2 only stimulates a transient early peak of p42/44 MAPK phosphorylation and fails to stimulate appreciably the phosphorylation of FRS2 on tyrosine. Conclusions These results suggest that the nature of the FGFR signal produced is determined by a combination of the HS co-receptor and the concentration of FGF ligand. Both the phosphorylation of the adaptor FRS2, the kinetics (sustained or transient of phosphorylation of p42/44(MAPK are varied, and so differing cellular responses are produced.

  16. Epac1 increases migration of endothelial cells and melanoma cells via FGF2-mediated paracrine signaling

    DEFF Research Database (Denmark)

    Baljinnyam, Erdene; Umemura, Masanari; Chuang, Christine

    2014-01-01

    Fibroblast growth factor (FGF2) regulates endothelial and melanoma cell migration. The binding of FGF2 to its receptor requires N-sulfated heparan sulfate (HS) glycosamine. We have previously reported that Epac1, an exchange protein activated by cAMP, increases N-sulfation of HS in melanoma....... Therefore, we examined whether Epac1 regulates FGF2-mediated cell-cell communication. Conditioned medium (CM) of melanoma cells with abundant expression of Epac1 increased migration of human umbilical endothelial cells (HUVEC) and melanoma cells with poor expression of Epac1. CM-induced increase...... in migration was inhibited by antagonizing FGF2, by the removal of HS and by the knockdown of Epac1. In addition, knockdown of Epac1 suppressed the binding of FGF2 to FGF receptor in HUVEC, and in vivo angiogenesis in melanoma. Furthermore, knockdown of Epac1 reduced N-sulfation of HS chains attached...

  17. Homology modeling and virtual screening studies of FGF-7 protein-a structure-based approach to design new molecules against tumor angiogenesis.

    Science.gov (United States)

    Vadija, Rajender; Mustyala, Kiran Kumar; Nambigari, Navaneetha; Dulapalli, Ramasree; Dumpati, Rama Krishna; Ramatenki, Vishwanath; Vellanki, Santhi Prada; Vuruputuri, Uma

    2016-07-01

    Keratinocyte growth factor (KGF) protein is a member of the fibroblast growth factor (FGF) family, which is also known as FGF-7. The FGF-7 plays an important role in tumor angiogenesis. In the present work, FGF-7 is treated as a potential therapeutic target to prevent angiogenesis in cancerous tissue. Computational techniques are applied to evaluate and validate the 3D structure of FGF-7 protein. The active site region of the FGF-7 protein is identified based on hydrophobicity calculations using CASTp and Q-site Finder active site prediction tools. The protein-protein docking study of FGF-7 with its natural receptor FGFR2b is carried out to confirm the active site region in FGF-7. The amino acid residues Asp34, Arg67, Glu116, and Thr194 in FGF-7 interact with the receptor protein (FGFR2b). A grid is generated at the active site region of FGF-7 using Glide module of Schrödinger suite. Subsequently, a virtual screening study is carried out at the active site using small molecular structural databases to identify the ligand molecules. The binding interactions of the ligand molecules, with piperazine moiety as a pharmacophore, are observed at Arg67 and Glu149 residues of the FGF-7 protein. The identified ligand molecules against the FGF-7 protein show permissible pharmacokinetic properties (ADME). The ligand molecules with good docking scores and satisfactory pharmacokinetic properties are prioritized and identified as novel ligands for the FGF-7 protein in cancer therapy.

  18. Formation of the embryonic organizer is restricted by the competitive influences of Fgf signaling and the SoxB1 transcription factors.

    Directory of Open Access Journals (Sweden)

    Cheng-Liang Kuo

    Full Text Available The organizer is one of the earliest structures to be established during vertebrate development and is crucial to subsequent patterning of the embryo. We have previously shown that the SoxB1 transcription factor, Sox3, plays a central role as a transcriptional repressor of zebrafish organizer gene expression. Recent data suggest that Fgf signaling has a positive influence on organizer formation, but its role remains to be fully elucidated. In order to better understand how Fgf signaling fits into the complex regulatory network that determines when and where the organizer forms, the relationship between the positive effects of Fgf signaling and the repressive effects of the SoxB1 factors must be resolved. This study demonstrates that both fgf3 and fgf8 are required for expression of the organizer genes, gsc and chd, and that SoxB1 factors (Sox3, and the zebrafish specific factors, Sox19a and Sox19b can repress the expression of both fgf3 and fgf8. However, we also find that these SoxB1 factors inhibit the expression of gsc and chd independently of their repression of fgf expression. We show that ectopic expression of organizer genes induced solely by the inhibition of SoxB1 function is dependent upon the activation of fgf expression. These data allow us to describe a comprehensive signaling network in which the SoxB1 factors restrict organizer formation by inhibiting Fgf, Nodal and Wnt signaling, as well as independently repressing the targets of that signaling. The organizer therefore forms only where Nodal-induced Fgf signaling overlaps with Wnt signaling and the SoxB1 proteins are absent.

  19. Neuroprotective and memory enhancing properties of a dual agonist of the FGF receptor and NCAM

    DEFF Research Database (Denmark)

    Enevoldsen, Maj N; Kochoyan, Artur; Jurgenson, Monika

    2012-01-01

    The fibroblast growth factor receptor (FGFR) plays a vital role in the development of the nervous system regulating a multitude of cellular processes. One of the interaction partners of the FGFR is the neural cell adhesion molecule (NCAM), which is known to play an important role in neuronal deve...

  20. Glucagon stimulates hepatic FGF21 secretion through a PKA- and EPAC-dependent posttranscriptional mechanism.

    Directory of Open Access Journals (Sweden)

    Holly A Cyphert

    Full Text Available Previous studies have shown that whole body deletion of the glucagon receptor suppresses the ability of starvation to increase hepatic fibroblast growth factor 21 (FGF21 expression and plasma FGF21 concentration. Here, we investigate the mechanism by which glucagon receptor activation increases hepatic FGF21 production. Incubating primary rat hepatocyte cultures with glucagon, dibutyryl cAMP or forskolin stimulated a 3-4-fold increase in FGF21 secretion. The effect of these agents on FGF21 secretion was not associated with an increase in FGF21 mRNA abundance. Glucagon induction of FGF21 secretion was additive with the stimulatory effect of a PPARα activator (GW7647 on FGF21 secretion. Inhibition of protein kinase A (PKA and downstream components of the PKA pathway [i.e. AMP-activated protein kinase and p38 MAPK] suppressed glucagon activation of FGF21 secretion. Incubating hepatocytes with an exchange protein directly activated by cAMP (EPAC-selective cAMP analog [i.e. 8-(4-chlorophenylthio-2'-O-methyladenosine-3', 5'-cyclic monophosphate (cpTOME], stimulated a 3.9-fold increase FGF21 secretion, whereas inhibition of the EPAC effector, Rap1, suppressed glucagon activation of FGF21 secretion. Treatment of hepatocytes with insulin also increased FGF21 secretion. In contrast to glucagon, insulin activation of FGF21 secretion was associated with an increase in FGF21 mRNA abundance. Glucagon synergistically interacted with insulin to stimulate a further increase in FGF21 secretion and FGF21 mRNA abundance. These results demonstrate that glucagon increases hepatic FGF21 secretion via a posttranscriptional mechanism and provide evidence that both the PKA branch and EPAC branch of the cAMP pathway play a role in mediating this effect. These results also identify a novel synergistic interaction between glucagon and insulin in the regulation of FGF21 secretion and FGF21 mRNA abundance. We propose that this insulin/glucagon synergism plays a role in

  1. Polyguluronate sulfate and its oligosaccharides but not heparin promotes FGF19/FGFR1c signaling

    Science.gov (United States)

    Lan, Ying; Zeng, Xuan; Guo, Zhihua; Zeng, Pengjiao; Hao, Cui; Zhao, Xia; Yu, Guangli; Zhang, Lijuan

    2017-06-01

    Fibroblast growth factor 19(FGF19) functions as a hormone by affecting glucose metabolism. FGF19 improves glucose tolerance when overexpressed in mice with impaired glucose tolerance or diabetes. A functional cellular FGF19 receptor consists of FGF receptor (FGFR) and glycosaminoglycan complexed with either α Klotho or β Klotho. Interestingly, in mice with diet-induced diabetes, a single injection of FGF1 is enough to restore blood sugar levels to a healthy range. FGF1 binds heparin with high affinity whereas FGF19 does not, indicating that polysaccharides other than heparin might enhance FGF19/FGFR signaling. Using a FGFs/FGFR1c signaling-dependent BaF3 cell proliferation assay, we discovered that polyguluronate sulfate (PGS) and its oligosaccharides, PGS12 and PGS25, but not polyguluronate (PG), a natural marine polysaccharide, enhanced FGF19/FGFR1c signaling better than that of heparin based on 3H-thymidine incorporation. Interestingly, PGS6, PGS8, PGS10, PGS12, PGS25, and PGS, but not PG, had comparable FGF1/FGFR1c signal-stimulating activity compared to that of heparin. These results indicated that PGS and its oligosaccharides were excellent FGF1/FGFR1c and FGF19/FGFR1c signaling enhancers at cellular level. Since the inexpensive PGS and PGS oligosaccharides can be absorbed through oral route, these seaweed-derived compounds merit further investigation as novel agents for the treatment of type 2 diabetes through enhancing FGF1/FGFR1c and FGF19/FGFR1c signaling in future.

  2. Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR

    OpenAIRE

    Wistuba, Wolfgang; Gnewuch, Carsten; Liebisch, Gerhard; Schmitz, Gerd; Langmann, Thomas

    2007-01-01

    AIM: To study the effect of the toxic secondary bile acid lithocholic acid (LCA) on the expression of fibroblast growth factor 19 (FGF19) in intestinal cells and to characterize the pregnane-X-receptor (PXR) response of the FGF19 promoter region.

  3. Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis.

    Science.gov (United States)

    Barnard, Joanna C; Williams, Allan J; Rabier, Bénédicte; Chassande, Olivier; Samarut, Jacques; Cheng, Sheue-Yann; Bassett, J H Duncan; Williams, Graham R

    2005-12-01

    Childhood hypothyroidism causes growth arrest with delayed ossification and growth-plate dysgenesis, whereas thyrotoxicosis accelerates ossification and growth. Thyroid hormone (T(3)) regulates chondrocyte proliferation and is essential for hypertrophic differentiation. Fibroblast growth factors (FGFs) are also important regulators of chondrocyte proliferation and differentiation, and activating mutations of FGF receptor-3 (FGFR3) cause achondroplasia. We investigated the hypothesis that T(3) regulates chondrogenesis via FGFR3 in ATDC5 cells, which undergo a defined program of chondrogenesis. ATDC5 cells expressed two FGFR1, four FGFR2, and one FGFR3 mRNA splice variants throughout chondrogenesis, and expression of each isoform was stimulated by T(3) during the first 6-12 d of culture, when T(3) inhibited proliferation by 50%. FGFR3 expression was also increased in cells treated with T(3) for 21 d, when T(3) induced an earlier onset of hypertrophic differentiation and collagen X expression. FGFR3 expression was reduced in growth plates from T(3) receptor alpha-null mice, which exhibit skeletal hypothyroidism, but was increased in T(3) receptor beta(PV/PV) mice, which display skeletal thyrotoxicosis. These findings indicate that FGFR3 is a T(3)-target gene in chondrocytes. In further experiments, T(3) enhanced FGF2 and FGF18 activation of the MAPK-signaling pathway but inhibited their activation of signal transducer and activator of transcription-1. FGF9 did not activate MAPK or signal transducer and activator of transcription-1 pathways in the absence or presence of T(3). Thus, T(3) exerted differing effects on FGFR activation during chondrogenesis depending on which FGF ligand stimulated the FGFR and which downstream signaling pathway was activated. These studies identify novel interactions between T(3) and FGFs that regulate chondrocyte proliferation and differentiation during chondrogenesis.

  4. Comparison of human dermal fibroblasts (HDFs) growth rate in culture media supplemented with or without basic fibroblast growth factor (bFGF).

    Science.gov (United States)

    Abdian, Narges; Ghasemi-Dehkordi, Payam; Hashemzadeh-Chaleshtori, Morteza; Ganji-Arjenaki, Mahbobe; Doosti, Abbas; Amiri, Beheshteh

    2015-12-01

    Basic fibroblast growth factor (bFGF or FGF-2) is a member of the FGF family secreted by different kinds of cells like HDFs and it is an important nutritional factor for cell growth and differentiation. The HDFs release bFGF in culture media at very low. The present study aims to investigate the HDFs growth rate in culture media supplemented either with or without bFGF. In brief, HDFs were isolated from human foreskin sample and were cultured in vitro in media containing bFGF and lack of this factor. The cells growth rate was calculated by trypan blue. The karyotyping was performed using G-banding to investigate the chromosomal abnormality of HDFs in both groups. Total RNA of each groups were extracted and cDNA samples were synthesized then, real-time Q-PCR was used to measure the expression level of p27kip1 and cyclin D1 genes normalized to internal control gene (GAPDH). The karyotype analysis showed that HDFs cultured in media or without bFGF had normal karyotype (46 chromosomes, XY) and chromosomal abnormalities were not observed. The cell growth rates in both groups were normal with proliferated exponentially but the slope of growth curve in HDFs cultured in media containing bFGF was increased. Karyotyp test showed that bFGF does not affect on cytogenetic stability of cells. The survey of p27kip1 and cyclin D1 genes by real-time Q-PCR showed that the expression level of these genes were up-regulated when adding bFGF in culture media (p media with growth factor like bFGF could enhance the proliferation and differentiation capacity of cells and improve cells growth rate. Similarly, fibroblast growth factors did not induce any chromosomal abnormality in cells. Furthermore, in HDFs cultured in bFGF supplemented media, the p27kip1 and cyclin D1 genes were up-regulated and suggesting an important role for bFGF in cell-cycle regulation and progression and fibroblast division stimulation. It also suggests that the effects of bFGF on different cell types with

  5. FGF21 as a hepatokine, adipokine, and myokine in metabolism and diseases

    Directory of Open Access Journals (Sweden)

    Nobuyuki eItoh

    2014-07-01

    Full Text Available Fibroblast growth factor (FGF family members are mostly secreted as signaling proteins with diverse functions in development and metabolism. FGF21 is a unique FGF with metabolic, but not proliferative activities. FGF21 is mostly induced by different kinds of stress and acts though FGF receptor 1c with β−Klotho as a cofactor in an endocrine or, in parts, autocirne/paracrine manner. Hepatic FGF21 directly acts on white adipocytes to inhibit lipolysis and acts through the brain to increase systemic glucocorticoid levels and suppress physical activity in response to starvation. It also protects against dioxin toxicity. Adipocytic FGF21 induces the browning of white adipose tissue (WAT and activates brown adipocytes in response to cold exposure. It also acts as an upstream effector of adiponectin in white adipocytes. Myocytic FGF21 protects against diet-induced obesity and insulin resistance, induces the browning of WAT, and protects against cardiac hypertrophy. In addition, Fgf21 polymorphisms are possibly related with metabolic diseases and FGF21 are biomarker of metabolic diseases. These findings indicate that FGF21 plays roles as a hepatokine, adipokine, and myokine in metabolism, injury protection, and diseases.

  6. Characterization of the expression profiles of adipogenesis-related factors, ZNF423, KLFs and FGF10, during preadipocyte differentiation and abdominal adipose tissue development in chickens.

    Science.gov (United States)

    Matsubara, Yusuke; Aoki, Michiru; Endo, Tonami; Sato, Kan

    2013-07-01

    Adipogenesis is controlled by a complicated process involving certain transcriptional events. In chicken adipogenesis, peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of preadipocyte differentiation and abdominal fat accumulation. However, in a recent study in mammals, some novel factors related to regulation of adipogenesis, including preadipocyte differentiation, were identified in mammals. Therefore, in this study, we aimed to determine the expression profiles of these mammalian adipogenesis-related factors, such as zinc-finger protein 423 (ZNF423), Krüppel-like factor -2, -5, and -15 (KLF-2, -5, -15), and FGF10, in the chicken (Gallus gallus). Specifically, we analyzed their expression in primary preadipocyte differentiation in vitro and also analyzed their tissue distribution and their temporal expression in adipose tissue development in vivo. During chicken adipocyte differentiation, the gene expression of ZNF423, KLF-2, KLF-5 and FGF10 was found to rapidly decrease in the early stage of preadipocyte differentiation. Expression of ZNF423 then increased in the late stage of differentiation. KLF-15 expression increased in a time-dependent manner for 48 h. Protein expressions of these factors were reflected by Western blot analysis. High levels of aP2, PPARγ and FGF10 mRNA were found in adipose tissue. In addition, aP2, PPARγ and ZNF423 mRNA levels in the adipose tissue were elevated at days 10 and 20. These expression profiles of the adipogenesis-related factors in chicken are, in part, different from mammalian adipogenesis but this seems to reflect the differences in the regulation of adipogenesis and in adipose tissue functions between avians and mammals.

  7. A Network Map of FGF-1/FGFR Signaling System

    Directory of Open Access Journals (Sweden)

    Rajesh Raju

    2014-01-01

    Full Text Available Fibroblast growth factor-1 (FGF-1 is a well characterized growth factor among the 22 members of the FGF superfamily in humans. It binds to all the four known FGF receptors and regulates a plethora of functions including cell growth, proliferation, migration, differentiation, and survival in different cell types. FGF-1 is involved in the regulation of diverse physiological processes such as development, angiogenesis, wound healing, adipogenesis, and neurogenesis. Deregulation of FGF-1 signaling is not only implicated in tumorigenesis but also is associated with tumor invasion and metastasis. Given the biomedical significance of FGFs and the fact that individual FGFs have different roles in diverse physiological processes, the analysis of signaling pathways induced by the binding of specific FGFs to their cognate receptors demands more focused efforts. Currently, there are no resources in the public domain that facilitate the analysis of signaling pathways induced by individual FGFs in the FGF/FGFR signaling system. Towards this, we have developed a resource of signaling reactions triggered by FGF-1/FGFR system in various cell types/tissues. The pathway data and the reaction map are made available for download in different community standard data exchange formats through NetPath and NetSlim signaling pathway resources.

  8. FGF signaling facilitates postinjury recovery of mouse hematopoietic system.

    Science.gov (United States)

    Zhao, Meng; Ross, Jason T; Itkin, Tomer; Perry, John M; Venkatraman, Aparna; Haug, Jeffrey S; Hembree, Mark J; Deng, Chu-Xia; Lapidot, Tsvee; He, Xi C; Li, Linheng

    2012-08-30

    Previous studies have shown that fibroblast growth factor (FGF) signaling promotes hematopoietic stem and progenitor cell (HSPC) expansion in vitro. However, it is unknown whether FGF promotes HSPC expansion in vivo. Here we examined FGF receptor 1 (FGFR1) expression and investigated its in vivo function in HSPCs. Conditional knockout (CKO) of Fgfr1 did not affect phenotypical number of HSPCs and homeostatic hematopoiesis, but led to a reduced engraftment only in the secondary transplantation. When treated with 5-fluorouracil (5FU), the Fgfr1 CKO mice showed defects in both proliferation and subsequent mobilization of HSPCs. We identified megakaryocytes (Mks) as a major resource for FGF production, and further discovered a novel mechanism by which Mks underwent FGF-FGFR signaling dependent expansion to accelerate rapid FGF production under stress. Within HSPCs, we observed an up-regulation of nuclear factor κB and CXCR4, a receptor for the chemoattractant SDF-1, in response to bone marrow damage only in control but not in Fgfr1 CKO model, accounting for the corresponding defects in proliferation and migration of HSPCs. This study provides the first in vivo evidence that FGF signaling facilitates postinjury recovery of the mouse hematopoietic system by promoting proliferation and facilitating mobilization of HSPCs.

  9. Roles of FGF19 in liver metabolism.

    Science.gov (United States)

    Kir, S; Kliewer, S A; Mangelsdorf, D J

    2011-01-01

    Fibroblast growth factor 19 (FGF19) is an ileum-derived postprandial enterokine that governs bile acid and nutrient metabolism. Synthesis of FGF19 is up-regulated by bile acids and, conversely, bile acid synthesis is down-regulated by FGF19. FGF19 also controls gallbladder volume. FGF19 has been shown to have profound effects on glucose and lipid metabolism. Recent studies have described FGF19 as a postprandial regulator of hepatic glucose and protein metabolism. Like insulin, FGF19 induces protein and glycogen synthesis and suppresses gluconeogenesis in liver. However, unlike insulin, FGF19 does not stimulate lipogenesis. A key difference between FGF19 and insulin lies in their use of different cellular signaling pathways. The beneficial effects of FGF19 on liver metabolism raise the question of whether FGF19 and its variants can be used as therapeutic agents in the treatment of diabetes.

  10. FGF23 regulates renal sodium handling and blood pressure

    OpenAIRE

    Andrukhova, Olena; Slavic, Svetlana; Smorodchenko, Alina; Zeitz, Ute; Shalhoub, Victoria; Lanske, Beate; Pohl, Elena E.; Erben, Reinhold G.

    2014-01-01

    Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regulates the membrane abundance of the Na+:Cl− co-transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/αKlotho complex, extracellular signal-regulated kinase 1/2 (ERK1/2), serum/glucocorticoid-regulated kinase 1 (SGK1), and with-no lysine kinase-4 (WNK4). Renal sodium (...

  11. Elevated Fibroblast growth factor 21 (FGF21) in obese, insulin resistant states is normalised by the synthetic retinoid Fenretinide in mice

    Science.gov (United States)

    Morrice, Nicola; Mcilroy, George D.; Tammireddy, Seshu R.; Reekie, Jennifer; Shearer, Kirsty D.; Doherty, Mary K.; Delibegović, Mirela; Whitfield, Phillip D.; Mody, Nimesh

    2017-01-01

    Fibroblast growth factor 21 (FGF21) has emerged as an important beneficial regulator of glucose and lipid homeostasis but its levels are also abnormally increased in insulin-resistant states in rodents and humans. The synthetic retinoid Fenretinide inhibits obesity and improves glucose homeostasis in mice and has pleotropic effects on cellular pathways. To identify Fenretinide target genes, we performed unbiased RNA-seq analysis in liver from mice fed high-fat diet ± Fenretinide. Strikingly, Fgf21 was the most downregulated hepatic gene. Fenretinide normalised elevated levels of FGF21 in both high-fat diet-induced obese mice and in genetically obese-diabetic Leprdbmice. Moreover, Fenretinide-mediated suppression of FGF21 was independent of body weight loss or improved hepatic insulin sensitivity and importantly does not induce unhealthy metabolic complications. In mice which have substantially decreased endogenous retinoic acid biosynthesis, Fgf21 expression was increased, whereas acute pharmacological retinoid treatment decreased FGF21 levels. The repression of FGF21 levels by Fenretinide occurs by reduced binding of RARα and Pol-II at the Fgf21 promoter. We therefore establish Fgf21 as a novel gene target of Fenretinide signalling via a retinoid-dependent mechanism. These results may be of nutritional and therapeutic importance for the treatment of obesity and type-2 diabetes. PMID:28256636

  12. Transcriptional repressor E4-binding protein 4 (E4BP4) regulates metabolic hormone fibroblast growth factor 21 (FGF21) during circadian cycles and feeding.

    Science.gov (United States)

    Tong, Xin; Muchnik, Marina; Chen, Zheng; Patel, Manish; Wu, Nan; Joshi, Shree; Rui, Liangyou; Lazar, Mitchell A; Yin, Lei

    2010-11-19

    Fibroblast growth factor 21 (FGF21) is a potent antidiabetic and triglyceride-lowering hormone whose hepatic expression is highly responsive to food intake. FGF21 induction in the adaptive response to fasting has been well studied, but the molecular mechanism responsible for feeding-induced repression remains unknown. In this study, we demonstrate a novel link between FGF21 and a key circadian output protein, E4BP4. Expression of Fgf21 displays a circadian rhythm, which peaks during the fasting phase and is anti-phase to E4bp4, which is elevated during feeding periods. E4BP4 strongly suppresses Fgf21 transcription by binding to a D-box element in the distal promoter region. Depletion of E4BP4 in synchronized Hepa1c1c-7 liver cells augments the amplitude of Fgf21 expression, and overexpression of E4BP4 represses FGF21 secretion from primary mouse hepatocytes. Mimicking feeding effects, insulin significantly increases E4BP4 expression and binding to the Fgf21 promoter through AKT activation. Thus, E4BP4 is a novel insulin-responsive repressor of FGF21 expression during circadian cycles and feeding.

  13. Ecto-5' -Nucleotidase CD73 (NT5E), vitamin D receptor and FGF23 gene polymorphisms may play a role in the development of calcific uremic arteriolopathy in dialysis patients – Data from the German Calciphylaxis Registry

    Science.gov (United States)

    Brandenburg, Vincent; Haun, Margot; Kollerits, Barbara; Kronenberg, Florian; Ketteler, Markus; Wanner, Christoph

    2017-01-01

    Introduction Calciphylaxis/calcific uremic arteriolopathy affects mainly end-stage kidney disease patients but is also associated with malignant disorders such as myeloma, melanoma and breast cancer. Genetic risk factors of calciphylaxis have never been studied before. Methods We investigated 10 target genes using a tagging SNP approach: the genes encoding CD73/ ecto-5'-nucleotidase (purinergic pathway), Matrix Gla protein, Fetuin A, Bone Gla protein, VKORC1 (all related to intrinsic calcification inhibition), calcium-sensing receptor, FGF23, Klotho, vitamin D receptor, stanniocalcin 1 (all related to CKD-MBD). 144 dialysis patients from the German calciphylaxis registry were compared with 370 dialysis patients without history of CUA. Genotyping was performed using iPLEX Gold MassARRAY(Sequenom, San Diego, USA), KASP genotyping chemistry (LGC, Teddington, Middlesex, UK) or sequencing. Statistical analysis comprised logistic regression analysis with adjustment for age and sex. Results 165 SNPs were finally analyzed and 6 SNPs were associated with higher probability for calciphylaxis (OR>1) in our cohort. Nine SNPs of three genes (CD73, FGF23 and Vitamin D receptor) reached nominal significance (p< 0.05), but did not reach statistical significance after correction for multiple testing. Of the CD73 gene, rs4431401 (OR = 1.71, 95%CI 1.08–2.17, p = 0.023) and rs9444348 (OR = 1.48, 95% CI 1.11–1.97, p = 0.008) were associated with a higher probability for CUA. Of the FGF23 and VDR genes, rs7310492, rs11063118, rs13312747 and rs17882106 were associated with a higher probability for CUA. Conclusion Polymorphisms in the genes encoding CD73, vitamin D receptor and FGF23 may play a role in calciphylaxis development. Although our study is the largest genetic study on calciphylaxis, it is limited by the low sample sizes. It therefore requires replication in other cohorts if available. PMID:28212442

  14. Enhanced Expression of Integrin αvβ3 Induced by TGF-β Is Required for the Enhancing Effect of Fibroblast Growth Factor 1 (FGF1 in TGF-β-Induced Epithelial-Mesenchymal Transition (EMT in Mammary Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Seiji Mori

    Full Text Available Epithelial-to-mesenchymal transition (EMT plays a critical role in cancer metastasis, and is regulated by growth factors such as transforming growth factor β (TGF-β and fibroblast growth factors (FGF secreted from the stromal and tumor cells. However, the role of growth factors in EMT has not been fully established. Several integrins are upregulated by TGF-β1 during EMT. Integrins are involved in growth factor signaling through integrin-growth factor receptor crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and the interaction was required for FGF1 functions such as cell proliferation and migration. We studied the role of αvβ3 induced by TGF-β on TGF-β-induced EMT. Here, we describe that FGF1 augmented EMT induced by TGF-β1 in MCF10A and MCF12A mammary epithelial cells. TGF-β1 markedly amplified integrin αvβ3 and FGFR1 (but not FGFR2. We studied if the enhancing effect of FGF1 on TGF-β1-induced EMT requires enhanced levels of both integrin αvβ3 expression and FGFR1. Knockdown of β3 suppressed the enhancement by FGF1 of TGF-β1-induced EMT in MCF10A cells. Antagonists to FGFR suppressed the enhancing effect of FGF1 on EMT. Integrin-binding defective FGF1 mutant did not augment TGF-β1-induced EMT in MCF10A cells. These findings suggest that enhanced integrin αvβ3 expression in addition to enhanced FGFR1 expression is critical for FGF1 to augment TGF-β1-induced EMT in mammary epithelial cells.

  15. Activation of AP-1 Transcription Factors Differentiates FGF2 and Vascular Endothelial Growth Factor Regulation of Endothelial Nitric-oxide Synthase Expression in Placental Artery Endothelial Cells*

    Science.gov (United States)

    Mata-Greenwood, Eugenia; Liao, Wu-xiang; Wang, Wen; Zheng, Jing; Chen, Dong-bao

    2010-01-01

    FGF2 (fibroblast growth factor 2), but not vascular endothelial growth factor (VEGF), stimulates sustained activation of ERK2/1 for endothelial NOS3 (nitric-oxide synthase 3) protein expression in ovine fetoplacental artery endothelial cells (oFPAEC). We deciphered herein the downstream signaling of ERK2/1 responsible for NOS3 expression by FGF2 in oFPAEC. FGF2, but not VEGF, increased NOS3 mRNA levels without altering its degradation. FGF2, but not VEGF, trans-activated sheep NOS3 promoter, and this was dependent on ERK2/1 activation. FGF2 did not trans-activate NOS3 promoters with deletions upstream of the consensus AP-1 site (TGAGTC A, −678 to −685). Trans-activation of wild-type NOS3 promoter by FGF2 was significantly inhibited when either the AP-1 or the cAMP-response element (CRE)-like sequence (TGCGTCA, −752 to −758) was mutated and was completely blocked when both were mutated. EMSA analyses showed that FGF2, but not VEGF, stimulated AP-1 and CRE DNA-protein complexes primarily composed of JunB and Fra1. Chromatin immunoprecipitation assays confirmed JunB/Fra1 binding to NOS3 promoter AP-1 and CRE elements in intact cells. FGF2, but not VEGF, stimulated JunB and Fra1 expressions; all preceded NOS3 up-regulation and were inhibited by PD98059. Down-regulation of JunB or Fra-1, but not c-Jun, blocked FGF2 stimulation of NOS3 expression and NO production. AP-1 inhibition suppressed FGF2 stimulation of NOS3 expression in human umbilical vein EC and uterine artery endothelial cells. Thus, FGF2 induction of NOS3 expression is mainly mediated by AP-1-dependent transcription involving JunB and Fra1 up-regulation via sustained ERK2/1 activation in endothelial cells. PMID:20371606

  16. Targeting Nuclear FGF Receptor to Improve Chemotherapy Response in Triple-Negative Breast Cancer

    Science.gov (United States)

    2015-10-01

    in FGF-mediated bevacizumab-resistant head and neck squamous cell carcinoma. Mol Cancer Res. 2013;11(12):1585–96. 12. Marek L, Ware KE, Fritzsche A...TK, Kleczko E, Singleton KR, Marek LA, Helfrich BA, et al. A mechanism of resistance to gefitinib mediated by cellular reprogramming and the...Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS, et al. Molecular profiling of the residual disease of triple-negative breast cancers after

  17. Fibroblast growth factor 19 entry into brain

    OpenAIRE

    Hsuchou, Hung; Pan, Weihong; Kastin, Abba J.

    2013-01-01

    Background Fibroblast growth factor (FGF)-19, an endocrine FGF protein mainly produced by the ileum, stimulates metabolic activity and alleviates obesity. FGF19 modulates metabolism after either intravenous or intracerebroventricular injection, and its receptor FGFR4 is present in the hypothalamus. This led to the question whether blood-borne FGF19 crosses the blood-brain barrier (BBB) to exert its metabolic effects. Methods We determined the pharmacokinetics of FGF19 permeation from blood to...

  18. Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9.

    Science.gov (United States)

    Lindner, Maren; Thümmler, Katja; Arthur, Ariel; Brunner, Sarah; Elliott, Christina; McElroy, Daniel; Mohan, Hema; Williams, Anna; Edgar, Julia M; Schuh, Cornelia; Stadelmann, Christine; Barnett, Susan C; Lassmann, Hans; Mücklisch, Steve; Mudaliar, Manikhandan; Schaeren-Wiemers, Nicole; Meinl, Edgar; Linington, Christopher

    2015-07-01

    Remyelination failure plays an important role in the pathophysiology of multiple sclerosis, but the underlying cellular and molecular mechanisms remain poorly understood. We now report actively demyelinating lesions in patients with multiple sclerosis are associated with increased glial expression of fibroblast growth factor 9 (FGF9), which we demonstrate inhibits myelination and remyelination in vitro. This inhibitory activity is associated with the appearance of multi-branched 'pre-myelinating' MBP+ / PLP+ oligodendrocytes that interact with axons but fail to assemble myelin sheaths; an oligodendrocyte phenotype described previously in chronically demyelinated multiple sclerosis lesions. This inhibitory activity is not due to a direct effect of FGF9 on cells of the oligodendrocyte lineage but is mediated by factors secreted by astrocytes. Transcriptional profiling and functional validation studies demonstrate that these include effects dependent on increased expression of tissue inhibitor of metalloproteinase-sensitive proteases, enzymes more commonly associated with extracellular matrix remodelling. Further, we found that FGF9 induces expression of Ccl2 and Ccl7, two pro-inflammatory chemokines that contribute to recruitment of microglia and macrophages into multiple sclerosis lesions. These data indicate glial expression of FGF9 can initiate a complex astrocyte-dependent response that contributes to two distinct pathogenic pathways involved in the development of multiple sclerosis lesions. Namely, induction of a pro-inflammatory environment and failure of remyelination; a combination of effects predicted to exacerbate axonal injury and loss in patients.

  19. 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.

  20. Fgf regulates dedifferentiation during skeletal muscle regeneration in adult zebrafish.

    Science.gov (United States)

    Saera-Vila, Alfonso; Kish, Phillip E; Kahana, Alon

    2016-09-01

    Fibroblast growth factors (Fgfs) regulate critical biological processes such as embryonic development, tissue homeostasis, wound healing, and tissue regeneration. In zebrafish, Fgf signaling plays an important role in the regeneration of the spinal cord, liver, heart, fin, and photoreceptors, although its exact mechanism of action is not fully understood. Utilizing an adult zebrafish extraocular muscle (EOM) regeneration model, we demonstrate that blocking Fgf receptor function using either a chemical inhibitor (SU5402) or a dominant-negative transgenic construct (dnFGFR1a:EGFP) impairs muscle regeneration. Adult zebrafish EOMs regenerate through a myocyte dedifferentiation process, which involves a muscle-to-mesenchyme transition and cell cycle reentry by differentiated myocytes. Blocking Fgf signaling reduced cell proliferation and active caspase 3 levels in the regenerating muscle with no detectable levels of apoptosis, supporting the hypothesis that Fgf signaling is involved in the early steps of dedifferentiation. Fgf signaling in regenerating myocytes involves the MAPK/ERK pathway: inhibition of MEK activity with U0126 mimicked the phenotype of the Fgf receptor inhibition on both muscle regeneration and cell proliferation, and activated ERK (p-ERK) was detected in injured muscles by immunofluorescence and western blot. Interestingly, following injury, ERK2 expression is specifically induced and activated by phosphorylation, suggesting a key role in muscle regeneration. We conclude that the critical early steps of myocyte dedifferentiation in EOM regeneration are dependent on Fgf signaling.

  1. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways.

    Directory of Open Access Journals (Sweden)

    Ai-Luen Wu

    Full Text Available Fibroblast growth factor 19 (FGF19 is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4, although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB. In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation.

  2. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways.

    Science.gov (United States)

    Wu, Ai-Luen; Coulter, Sally; Liddle, Christopher; Wong, Anne; Eastham-Anderson, Jeffrey; French, Dorothy M; Peterson, Andrew S; Sonoda, Junichiro

    2011-03-18

    Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB). In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v) which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation.

  3. Mechanisms of FGF gradient formation during embryogenesis.

    Science.gov (United States)

    Balasubramanian, Revathi; Zhang, Xin

    2016-05-01

    Fibroblast growth factors (FGFs) have long been attributed to influence morphogenesis in embryonic development. Signaling by FGF morphogen encodes positional identity of tissues by creating a concentration gradient over the developing embryo. Various mechanisms that influence the development of such gradient have been elucidated in the recent past. These mechanisms of FGF gradient formation present either as an extracellular control over FGF ligand diffusion or as a subcellular control of FGF propagation and signaling. In this review, we describe our current understanding of FGF as a morphogen, the extracellular control of FGF gradient formation by heparan sulfate proteoglycans (HSPGs) and mechanisms of intracellular regulation of FGF signaling that influence gradient formation.

  4. Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR

    Institute of Scientific and Technical Information of China (English)

    Wolfgang Wistuba; Carsten Gnewuch; Gerhard Liebisch; Gerd Schmitz; Thomas Langmann

    2007-01-01

    AIM: To study the effect of the toxic secondary bile acid lithocholic acid (LCA) on the expression of fibroblast growth factor 19 (FGF19) in intestinal cells and to characterize the pregnane-X-receptor (PXR) response of the FGF19 promoter region.METHODS: The intestinal cell line LS174T was stimulated with various concentrations of chenodeoxycholic acid and lithocholic acid for several time points.FGF19 mRNA levels were determined with quantitative realtime RT-PCR. FGF19 deletion promoter constructs were generated and the LCA response was analzyed in reporter assays. Co-transfections with PXR and RXR were carried out to study FGF19 regulation by these factors.RESULTS: LCA and CDCA strongly up-regulate FGF19 mRNA expression in LS174T cells in a time and dose dependent manner. Using reporter gene assays with several deletion constructs we found that the LCA responsive element in the human FGF19 promoter maps to the proximal regulatory region containing two potential binding sites for PXR. Overexpression of PXR and its dimerization partner retinoid X receptor (RXR) and stimulation with LCA or the potent PXR ligand rifampicin leads to a significant induction of FGF19 promoter activity in intestinal cells.CONCLUSION: LCA induced feedback inhibition of bile acid synthesis in the liver is likely to be regulated by PXR inducing intestinal FGF19 expression.

  5. Phosphorylation of the growth factors bFGF, NGF and BDNF: a prerequisite for their biological activity.

    Science.gov (United States)

    Klumpp, Susanne; Kriha, Dorothee; Bechmann, Gunther; Maassen, Alexander; Maier, Sandra; Pallast, Stefanie; Hoell, Patrick; Krieglstein, Josef

    2006-01-01

    The aim of this work was to test whether growth factors such as basic fibroblast growth factor (bFGF), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) undergo autophosphorylation and whether this affects their biological activity. Incubation of those growth factors with [gamma-(32)P]ATP resulted in phosphorylation in vitro. The phosphate bond was resistant to alkaline pH, yet acid-labile. Addition of alkaline phosphatase resulted in time and protein dependent dephosphorylation. Concomitantly, alkaline phosphatase abolished the neuroprotective effect of those growth factors upon oxygen and glucose deprivation and upon staurosporine-induced cell death. For those studies, we were using primary cultures of cortical and hippocampal neurons from embryonic and neonatal rats. Incubation of bFGF with non-hydrolyzable ATP-gammaS resulted in phosphorylation and in neuroprotection resistant to alkaline phosphatase. We conclude that bFGF, NGF and BDNF undergo autophosphorylation on site(s) other than serine, threonine, tyrosine and/or ATP-binding, and that this binding of phosphate is essential for neuroprotection in vivo.

  6. Differential role of FGF9 on epithelium and mesenchyme in mouse embryonic lung.

    Science.gov (United States)

    del Moral, Pierre-Marie; De Langhe, Stijn P; Sala, Frédéric G; Veltmaat, Jacqueline M; Tefft, Denise; Wang, Kasper; Warburton, David; Bellusci, Savério

    2006-05-01

    Mesothelial Fibroblast Growth Factor 9 (Fgf9) has been demonstrated by inactivation studies in mouse to be critical for the proliferation of the mesenchyme. We now show that Fgf9 is also expressed at significant levels in the distal epithelium from the mid-pseudoglandular stages. Using mesenchymal-free lung endoderm culture, we show that FGF9 triggers the proliferation of the distal epithelium leading to the formation of a cyst-like structure. On embryonic Fgfr2b-/- lungs, FGF9 induces proliferation of the mesenchyme but fails to trigger a similar effect on the epithelium, therefore involving the FGFR2b receptor in the proliferative response of the epithelium to FGF9. While FGF9 inhibits the differentiation of the mesenchyme, the epithelium appears to differentiate normally. At the molecular level, FGF9 up-regulates Fgf10 expression in the mesenchyme likely via increased expression of Tbx4 and 5 and controls the transcription of Hedgehog targets Ptc and Gli-1 in a Hedgehog-independent manner. We also show that FGF9 inhibits the activation of the canonical Wnt pathway in the epithelium by increasing Dkk1 expression, a canonical Wnt antagonist. Our work shows for the first time that FGF9 acts on the epithelium involving FGFR2b to control its proliferation but not its differentiation and contributes to the regulation of canonical Wnt signaling in the epithelium.

  7. Roles of FGF20 in dopaminergic neurons and Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Nobuyuki eItoh

    2013-05-01

    Full Text Available The fibroblast growth factor (FGF family comprises 22 members with diverse functions in development and metabolism. Fgf20 was originally identified as a new Fgf preferentially expressed in the substantia nigra pars compacta. Fgf20, which acts on proximal cells, significantly enhanced the survival of cultured dopaminergic neurons by activating the MAPK pathway through Fgf receptor 1c. In the rat model of Parkinson's disease, Fgf20 afforded significant protection against the loss of dopaminergic neurons. The significant correlation of Parkinson’s disease with single-nucleotide polymorphisms in FGF20 indicates that the genetic variability of FGF20 can be a Parkinson’s disease risk. Neural and embryonic stem cells have been considered as cell resources for restorative transplantation strategies in Parkinson's disease. Fgf20 promoted the differentiation of these stem cells into dopaminergic neurons, which attenuated neurological symptoms in animal models of Parkinson's disease. These findings indicate the importance of FGF20 for the differentiation and survival of dopaminergic neurons and the etiology and therapy of Parkinson’s disease.

  8. Research progress on the association of fibroblast growth factor 19 (FGF19) with lipid metabolism%成纤维细胞生长因子19(FGF19)与脂代谢的研究进展

    Institute of Scientific and Technical Information of China (English)

    郝亚平

    2014-01-01

    成纤维细胞生长因子19(fibroblast growth factor 19,FGF19)是在回肠末端特异性合成并分泌的细胞因子,属于FGFs的特殊成员之一.近年来自动物及细胞学的研究发现,FGF19不仅在胆汁酸代谢的调节中发挥重要作用,而且与多种心血管疾病危险因素密切相关.流行病学研究显示,2型糖尿病、代谢综合征及肥胖者FGF19水平降低.深入研究FGF19的生物学意义可能为肥胖及血脂紊乱的防治提供新的靶点.本文将介绍FGF19与脂代谢相关性的研究进展.

  9. Effects of concomitant use of fibroblast growth factor (FGF)-2 with beta-tricalcium phosphate ({beta}-TCP) on the beagle dog 1-wall periodontal defect model

    Energy Technology Data Exchange (ETDEWEB)

    Anzai, Jun, E-mail: anzai_jun@kaken.co.jp [Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., 14, Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042 (Japan); Department of Periodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871 (Japan); Kitamura, Masahiro, E-mail: kitamura@dent.osaka-u.ac.jp [Department of Periodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871 (Japan); Nozaki, Takenori, E-mail: tnozaki@dent.osaka-u.ac.jp [Department of Periodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871 (Japan); Nagayasu, Toshie, E-mail: nagayasu_toshie@kaken.co.jp [Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., 14, Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042 (Japan); Terashima, Akio, E-mail: terashima_akio@kaken.co.jp [Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., 14, Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042 (Japan); Asano, Taiji, E-mail: asano_taiji@kaken.co.jp [Pharmacology Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., 14, Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042 (Japan); Murakami, Shinya, E-mail: ipshinya@dent.osaka-u.ac.jp [Department of Periodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871 (Japan)

    2010-12-17

    Research highlights: {yields} Concomitant use of FGF-2 and {beta}-TCP (an osteo-conductive scaffold) significantly promotes periodontal regeneration in the severe periodontitis model (1-wall defect model) of beagle dog. {yields} FGF-2 enhanced new bone formation via {beta}-TCP at the defects. {yields} In particular, FGF-2 dramatically regenerated new periodontal ligament and cementum formations at the defects, that is one of the most important healing outcomes during the process of periodontal regeneration. {yields} Epithelial downgrowth (undesirable wound healing) was decreased by administration of FGF-2. {yields} This manuscript indicates for the first time that concomitant use of FGF-2 and {beta}-TCP is efficacious in regenerating periodontal tissue following severe destruction of the tissue by progression of periodontitis. -- Abstract: The effects of concomitant use of fibroblast growth factor-2 (FGF-2) and beta-tricalcium phosphate ({beta}-TCP) on periodontal regeneration were investigated in the beagle dog 1-wall periodontal defect model. One-wall periodontal defects were created in the mesial portion of both sides of the mandibular first molars, and 0.3% FGF-2 plus {beta}-TCP or {beta}-TCP alone was administered. Radiographic evaluation was performed at 0, 3, and 6 weeks. At 6 weeks, the periodontium with the defect site was removed and histologically analyzed. Radiographic findings showed that co-administration of FGF-2 significantly increased bone mineral contents of the defect sites compared with {beta}-TCP alone. Histologic analysis revealed that the length of the regenerated periodontal ligament, the cementum, distance to the junctional epithelium, new bone height, and area of newly formed bone were significantly increased in the FGF-2 group. No abnormal inflammatory response or ankylosis was observed in either group. These findings indicate the efficacy of concomitant use of FGF-2 and {beta}-TCP as an osteoconductive material for periodontal

  10. Single-domain antibodies that compete with the natural ligand fibroblast growth factor block the internalization of the fibroblast growth factor receptor 1

    Energy Technology Data Exchange (ETDEWEB)

    Veggiani, Gianluca; Ossolengo, Giuseppe; Aliprandi, Marisa; Cavallaro, Ugo [IFOM-IEO Campus, Via Adamello 16, 20139 Milano (Italy); Marco, Ario de, E-mail: ario.demarco@ung.si [IFOM-IEO Campus, Via Adamello 16, 20139 Milano (Italy); Dept. Environmental Sciences, University of Nova Gorica (UNG), Vipavska 13, P.O. Box 301-SI-5000, Rozna Dolina, Nova Gorica (Slovenia)

    2011-05-20

    Highlights: {yields} Recombinant antibodies for FGFR1 were isolated from a llama naive library in VHH format. {yields} These antibodies compete with the natural ligand FGF-2 for the same epitope on FGFR1. {yields} The antibody competition inhibits the FGF-2-dependent internalization of FGFR1. -- Abstract: Single-domain antibodies in VHH format specific for fibroblast growth factor receptor 1 (FGFR1) were isolated from a phage-display llama naive library. In particular, phage elution in the presence of the natural receptor ligand fibroblast growth factor (FGF) allowed for the identification of recombinant antibodies that compete with FGF for the same region on the receptor surface. These antibodies posses a relatively low affinity for FGFR1 and were never identified when unspecific elution conditions favoring highly affine binders were applied to panning procedures. Two populations of competitive antibodies were identified that labeled specifically the receptor-expressing cells in immunofluorescence and recognize distinct epitopes. Antibodies from both populations effectively prevented FGF-dependent internalization and nuclear accumulation of the receptor in cultured cells. This achievement indicates that these antibodies have a capacity to modulate the receptor physiology and, therefore, constitute powerful reagents for basic research and a potential lead for therapeutic applications.

  11. Fibroblast growth factor receptors, developmental corruption and malignant disease.

    Science.gov (United States)

    Kelleher, Fergal C; O'Sullivan, Hazel; Smyth, Elizabeth; McDermott, Ray; Viterbo, Antonella

    2013-10-01

    Fibroblast growth factors (FGF) are a family of ligands that bind to four different types of cell surface receptor entitled, FGFR1, FGFR2, FGFR3 and FGFR4. These receptors differ in their ligand binding affinity and tissue distribution. The prototypical receptor structure is that of an extracellular region comprising three immunoglobulin (Ig)-like domains, a hydrophobic transmembrane segment and a split intracellular tyrosine kinase domain. Alternative gene splicing affecting the extracellular third Ig loop also creates different receptor isoforms entitled FGFRIIIb and FGFRIIIc. Somatic fibroblast growth factor receptor (FGFR) mutations are implicated in different types of cancer and germline FGFR mutations occur in developmental syndromes particularly those in which craniosynostosis is a feature. The mutations found in both conditions are often identical. Many somatic FGFR mutations in cancer are gain-of-function mutations of established preclinical oncogenic potential. Gene amplification can also occur with 19-22% of squamous cell lung cancers for example having amplification of FGFR1. Ontologic comparators can be informative such as aberrant spermatogenesis being implicated in both spermatocytic seminomas and Apert syndrome. The former arises from somatic FGFR3 mutations and Apert syndrome arises from germline FGFR2 mutations. Finally, therapeutics directed at inhibiting the FGF/FGFR interaction are a promising subject for clinical trials.

  12. Multivalent proteoglycan modulation of FGF mitogenic responses in perivascular cells.

    Science.gov (United States)

    Cattaruzza, Sabrina; Ozerdem, Ugur; Denzel, Martin; Ranscht, Barbara; Bulian, Pietro; Cavallaro, Ugo; Zanocco, Daniela; Colombatti, Alfonso; Stallcup, William B; Perris, Roberto

    2013-04-01

    Sprouting of angiogenic perivascular cells is thought to be highly dependent upon autocrine and paracrine growth factor stimulation. Accordingly, we report that corneal angiogenesis induced by ectopic FGF implantation is strongly impaired in NG2/CSPG4 proteoglycan (PG) null mice known to harbour a putative deficit in pericyte proliferation/mobilization. Conversely, no significant differences were seen between wild type and knockout corneas when VEGF was used as an angiocrine factor. Perturbed responsiveness of NG2-deficient pericytes to paracrine and autocrine stimulation by several FGFs could be confirmed in cells isolated from NG2 null mice, while proliferation induced by other growth factors was equivalent in wild type and knockout cells. Identical results were obtained after siRNA-mediated knock-down of NG2 in human smooth muscle-like cell lines, as also demonstrated by the decreased levels of FGF receptor phosphorylation detected in these NG2 deprived cells. Binding assays with recombinant proteins and molecular interactions examined on live cells asserted that FGF-2 bound to NG2 in a glycosaminoglycan-independent, core protein-mediated manner and that the PG was alone capable of retaining FGF-2 on the cell membrane for subsequent receptor presentation. The use of dominant-negative mutant cells, engineered by combined transduction of NG2 deletion constructs and siRNA knock-down of the endogenous PG, allowed us to establish that the FGF co-receptor activity of NG2 is entirely mediated by its extracellular portion. In fact, forced overexpression of the NG2 ectodomain in human smooth muscle-like cells increased their FGF-2-induced mitosis and compensated for low levels of FGF receptor surface expression, in a manner equivalent to that produced by overexpression of the full-length NG2. Upon FGF binding, the cytoplasmic domain of NG2 is phosphorylated, but there is no evidence that this event elicits signal transductions that could bypass the FGFR-mediated ones

  13. Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation

    Science.gov (United States)

    Vos, Harmjan R.; Burgering, Boudewijn M. T.; van Mil, Saskia W. C.

    2017-01-01

    Fibroblast growth factor 19 (FGF19) is a gut-derived peptide hormone that is produced following activation of Farnesoid X Receptor (FXR). FGF19 is secreted and signals to the liver, where it contributes to the homeostasis of bile acid (BA), lipid and carbohydrate metabolism. FGF19 is a promising therapeutic target for the metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF19-mediated induction of proliferation and hepatocellular carcinoma. To inform future rational design of FGF19-variants, we have conducted temporal quantitative proteomic and gene expression analyses to identify FGF19-targets related to metabolism and proliferation. Mice were fasted for 16 hours, and injected with human FGF19 (1 mg/kg body weight) or vehicle. Liver protein extracts (containing “light” lysine) were mixed 1:1 with a spike-in protein extract from 13C6-lysine metabolically labelled mouse liver (containing “heavy” lysine) and analysed by LC-MS/MS. Our analyses provide a resource of FGF19 target proteins in the liver. 189 proteins were upregulated (≥ 1.5 folds) and 73 proteins were downregulated (≤ -1.5 folds) by FGF19. FGF19 treatment decreased the expression of proteins involved in fatty acid (FA) synthesis, i.e., Fabp5, Scd1, and Acsl3 and increased the expression of Acox1, involved in FA oxidation. As expected, FGF19 increased the expression of proteins known to drive proliferation (i.e., Tgfbi, Vcam1, Anxa2 and Hdlbp). Importantly, many of the FGF19 targets (i.e., Pdk4, Apoa4, Fas and Stat3) have a dual function in both metabolism and cell proliferation. Therefore, our findings challenge the development of FGF19-variants that fully uncouple metabolic benefit from mitogenic potential. PMID:28178326

  14. Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation.

    Science.gov (United States)

    Massafra, Vittoria; Milona, Alexandra; Vos, Harmjan R; Burgering, Boudewijn M T; van Mil, Saskia W C

    2017-01-01

    Fibroblast growth factor 19 (FGF19) is a gut-derived peptide hormone that is produced following activation of Farnesoid X Receptor (FXR). FGF19 is secreted and signals to the liver, where it contributes to the homeostasis of bile acid (BA), lipid and carbohydrate metabolism. FGF19 is a promising therapeutic target for the metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF19-mediated induction of proliferation and hepatocellular carcinoma. To inform future rational design of FGF19-variants, we have conducted temporal quantitative proteomic and gene expression analyses to identify FGF19-targets related to metabolism and proliferation. Mice were fasted for 16 hours, and injected with human FGF19 (1 mg/kg body weight) or vehicle. Liver protein extracts (containing "light" lysine) were mixed 1:1 with a spike-in protein extract from 13C6-lysine metabolically labelled mouse liver (containing "heavy" lysine) and analysed by LC-MS/MS. Our analyses provide a resource of FGF19 target proteins in the liver. 189 proteins were upregulated (≥ 1.5 folds) and 73 proteins were downregulated (≤ -1.5 folds) by FGF19. FGF19 treatment decreased the expression of proteins involved in fatty acid (FA) synthesis, i.e., Fabp5, Scd1, and Acsl3 and increased the expression of Acox1, involved in FA oxidation. As expected, FGF19 increased the expression of proteins known to drive proliferation (i.e., Tgfbi, Vcam1, Anxa2 and Hdlbp). Importantly, many of the FGF19 targets (i.e., Pdk4, Apoa4, Fas and Stat3) have a dual function in both metabolism and cell proliferation. Therefore, our findings challenge the development of FGF19-variants that fully uncouple metabolic benefit from mitogenic potential.

  15. Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment.

    Science.gov (United States)

    Kaibori, Masaki; Sakai, Kazuko; Ishizaki, Morihiko; Matsushima, Hideyuki; De Velasco, Marco A; Matsui, Kosuke; Iida, Hiroya; Kitade, Hiroaki; Kwon, A-Hon; Nagano, Hiroaki; Wada, Hiroshi; Haji, Seiji; Tsukamoto, Tadashi; Kanazawa, Akishige; Takeda, Yutaka; Takemura, Shigekazu; Kubo, Shoji; Nishio, Kazuto

    2016-08-02

    The multi-kinase inhibitor sorafenib is clinically approved for the treatment of patients with advanced hepatocellular carcinoma (HCC). We previously reported that fibroblast growth factor 3 and 4 (FGF3/FGF4) amplification is a predictor of a response to sorafenib. This study aims to analyze the relationship between FGF-FGF receptor (FGFR) genetic alterations and the response to sorafenib. Formalin-fixed, paraffin-embedded tissue specimens from HCC patients who had achieved a complete response (CR, N=6) or non-CR (N=39) to sorafenib were collected and were examined for FGF-FGFR gene alterations using next generation sequencing and copy number assay. FGFR mutations were detected in 5 of 45 (11.1%) cases. There was no significant association between FGFR mutation status and the response to sorafenib. We detected no increase in the FGF3/FGF4 copy number in CR cases. An FGF19 copy number gain was detected more frequently among CR cases (2/6, 33.3%) than among non-CR cases (2/39, 5.1%) (P = 0.024, Chi-squared test). In conclusion, a copy number gain for FGF19 may be a predictor of a response to sorafenib, in addition to FGF3/FGF4 amplification.

  16. FGF23 Regulates Bone Mineralization in a 1,25(OH)2 D3 and Klotho-Independent Manner.

    Science.gov (United States)

    Murali, Sathish Kumar; Roschger, Paul; Zeitz, Ute; Klaushofer, Klaus; Andrukhova, Olena; Erben, Reinhold G

    2016-01-01

    Fibroblast growth factor-23 (Fgf23) is a bone-derived hormone, suppressing phosphate reabsorption and vitamin D hormone (1,25(OH)2 D3 ) production in the kidney. It has long been an enigma why lack of Fgf23 or of Klotho, the coreceptor for Fgf23, leads to severe impairment in bone mineralization despite the presence of hypercalcemia and hyperphosphatemia. Using Fgf23(-/-) or Klotho(-/-) mice together with compound mutant mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor, we show that in Klotho(-/-) mice the mineralization defect is solely driven by 1,25(OH)2 D3 -induced upregulation of the mineralization-inhibiting molecules osteopontin and pyrophosphate in bone. In Fgf23(-/-) mice, the mineralization defect has two components, a 1,25(OH)2 D3 -driven component similar to Klotho(-/-) mice and a component driven by lack of Fgf23, causing additional accumulation of osteopontin. We found that FGF23 regulates osteopontin secretion indirectly by suppressing alkaline phosphatase transcription and phosphate production in osteoblastic cells, acting through FGF receptor-3 in a Klotho-independent manner. Hence, FGF23 secreted from osteocytes may form an autocrine/paracrine feedback loop for the local fine-tuning of bone mineralization.

  17. Analysis of the fibroblast growth factor receptor (FGFR) signalling network with heparin as coreceptor: evidence for the expansion of the core FGFR signalling network.

    Science.gov (United States)

    Xu, Ruoyan; Rudd, Timothy R; Hughes, Ashley J; Siligardi, Giuliano; Fernig, David G; Yates, Edwin A

    2013-05-01

    The evolution of the fibroblast growth factor (FGF)-FGF receptor (FGFR) signalling system has closely followed that of multicellular organisms. The abilities of nine FGFs (FGF-1 to FGF-9; examples of FGF subfamilies 1, 4, 7, 8, and 9) and seven FGFRs or isoforms (FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4) to support signalling in the presence of heparin, a proxy for the cellular heparan sulfate coreceptor, were assembled into a network. A connection between two FGFRs was defined as their mutual ability to signal with a particular FGF. The network contained a core of four receptors (FGFR1c, FGFR2c, FGFR3c, and FGFR4) with complete connectivity and high redundancy. Analysis of the wider network indicated that neither FGF-3 nor FGF-7 was well connected to this core of four receptors, and that divergence of a precursor of FGF subgroups 1, 4 and 9 from FGF subgroup 8 may have allowed expansion from a three-member FGFR core signalling system to the four-member core network. This increases by four-fold the number of possible signalling combinations. Synchrotron radiation CD spectra of the FGFs with heparin revealed no overall common structural change, suggesting the existence of distinct heparin-binding sites throughout the FGFs. The approach provides a potential method of identifying agents capable of influencing particular FGF-FGFR combinations, or areas of the signalling network, for experimental or therapeutic purposes.

  18. Cheiradone: a vascular endothelial cell growth factor receptor antagonist

    Directory of Open Access Journals (Sweden)

    Ahmed Nessar

    2008-01-01

    Full Text Available Abstract Background Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with physiological (for example wound healing and pathological conditions (tumour development. Vascular endothelial growth factor (VEGF, fibroblast growth factor-2 (FGF-2 and epidermal growth factor (EGF are the major angiogenic regulators. We have identified a natural product (cheiradone isolated from a Euphorbia species which inhibited in vivo and in vitro VEGF- stimulated angiogenesis but had no effect on FGF-2 or EGF activity. Two primary cultures, bovine aortic and human dermal endothelial cells were used in in vitro (proliferation, wound healing, invasion in Matrigel and tube formation and in vivo (the chick chorioallantoic membrane models of angiogenesis in the presence of growth factors and cheiradone. In all cases, the concentration of cheiradone which caused 50% inhibition (IC50 was determined. The effect of cheiradone on the binding of growth factors to their receptors was also investigated. Results Cheiradone inhibited all stages of VEGF-induced angiogenesis with IC50 values in the range 5.20–7.50 μM but did not inhibit FGF-2 or EGF-induced angiogenesis. It also inhibited VEGF binding to VEGF receptor-1 and 2 with IC50 values of 2.9 and 0.61 μM respectively. Conclusion Cheiradone inhibited VEGF-induced angiogenesis by binding to VEGF receptors -1 and -2 and may be a useful investigative tool to study the specific contribution of VEGF to angiogenesis and may have therapeutic potential.

  19. Modulation of the NMDA Receptor Through Secreted Soluble Factors.

    Science.gov (United States)

    Cerpa, Waldo; Ramos-Fernández, Eva; Inestrosa, Nibaldo C

    2016-01-01

    Synaptic activity is a critical determinant in the formation and development of excitatory synapses in the central nervous system (CNS). The excitatory current is produced and regulated by several ionotropic receptors, including those that respond to glutamate. These channels are in turn regulated through several secreted factors that function as synaptic organizers. Specifically, Wnt, brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF), and transforming growth factor (TGF) particularly regulate the N-methyl-D-aspartate receptor (NMDAR) glutamatergic channel. These factors likely regulate early embryonic development and directly control key proteins in the function of important glutamatergic channels. Here, we review the secreted molecules that participate in synaptic organization and discuss the cell signaling behind of this fine regulation. Additionally, we discuss how these factors are dysregulated in some neuropathologies associated with glutamatergic synaptic transmission in the CNS.

  20. Pathophysiological roles of Fgf signaling in the heart

    Directory of Open Access Journals (Sweden)

    Nobuyuki eItoh

    2013-09-01

    Full Text Available Cardiac remodeling progresses to heart failure, which represents a major cause of morbidity and mortality. Cardiomyokines, cardiac secreted proteins, may play roles in cardiac remodeling. Fibroblast growth factors (FGFs are secreted proteins with diverse functions, mainly in development and metabolism. However, some FGFs play pathophysiological roles in cardiac remodelling as cardiomyokines. FGF2 promotes cardiac hypertrophy and fibrosis by activating MAPK signaling through the activation of FGF receptor (FGFR 1c. In contrast, FGF16 may prevent these by competing with FGF2 for the binding site of FGFR1c. FGF21 prevents cardiac hypertrophy by activating MAPK signaling through the activation of FGFR1c with β-Klotho as a co-receptor. In contrast, FGF23 induces cardiac hypertrophy by activating calcineurin/NFAT signaling without αKlotho. These FGFs play crucial roles in cardiac remodeling via distinct action mechanisms. These findings provide new insights into the pathophysiological roles of FGFs in the heart and may provide potential therapeutic strategies for heart failure.

  1. Biological Effects of bFGF on Murine Endometrium in the Process of Blastocyst Implantation

    Institute of Scientific and Technical Information of China (English)

    赤晶; 高英茂; 刘凯; 李少玲; 张保华; 邴鲁军

    2001-01-01

    Objective To study the biological effects of basic fibroblast growth factor (bFGF) in the process of embryo implantation in mouse Materials & Methods The transcription and translocation of bFGF and its receptor (Flg) in endometrium of 60 Kunming mice were detected with the methods of im munohistochemistry and hybridization in situ. Endometrial tissue was obtained on the day 4 from pregnancy mice. The cells were cultured and attached in 1 : 1 F12/DMEM (vol/vol) supplemented with 10% FBS for 24 h The medium supplemented with 1% FBS and bFGF (50 ng/mL), anti-bFGF antibody (250 ng/mL) or anti-Flg antibody (250 ng/mL) was added in different culture wells. At different culture stages, the biological effect of bFGF on cell survival and expression of LN, FN and c-myc was detected by using MTT analysis, immunohistochemistry and hybridization in situ.Results bFGF and Flg was located in luminal and glandual cells on day 4 and 5 of pregnancy. Embryonic implantation was accompanied by increased bFGF and its recep tor in decidual cell around implantation site, in which low level of bFGF and its recep tor was apparent on day 7 and 8 of pregnancy. In vitro, the OD value in culture wells containing bFGF was significantly higher than that in control group. Exogenous bFGF promoted the expression of LN, FN and c-myc.Conclusion Changes in the cell-specific distribution of bFGF and the effects of bFGF on cultured endometrial cells imply a multifunctional role of the growth factor in uterine cell proliferation, differentiation and embryonic implantation.

  2. Involvement of intracellular expression of FGF12 in radiation-induced apoptosis in mast cells.

    Science.gov (United States)

    Nakayama, Fumiaki; Müller, Kerstin; Hagiwara, Akiko; Ridi, Roland; Akashi, Makoto; Meineke, Viktor

    2008-09-01

    Several fibroblast growth factors (FGFs) are able to reduce and improve radiation-induced tissue damage through the activation of surface fibroblast growth factor receptors (FGFRs). In contrast, some FGFs lack classical signal sequences, which play roles in the release of FGFs, and the intracellular function of these FGFs is not well clarified. In this study, we evaluated the transcript levels of 22 FGFs in a human mast cell line, HMC-1, using quantitative RT-PCR and found that FGF2 and FGF12 were expressed in HMC-1 cells. FGF12 not only lacks classical signal sequences but also fails to activate FGFRs. HMC-1 cells were transfected with an expression vector of FGF12 to clarify the intracellular function of FGF12 after irradiation. The overexpression of FGF12 in HMC-1 cells decreased ionizing radiation-induced apoptosis, and siRNA-mediated repression of FGF12 expression augmented apoptosis in HMC-1 cells. The overexpression of FGF12 strongly suppressed the marked augmentation of apoptosis induced by inhibition of the MEK/ERK pathway with PD98059. In contrast, the mitogen-activated protein kinase (MAPK) scaffold protein islet brain 2 (IB2), which was reported to bind to FGF12, did not interfere with the anti-apoptotic effect of FGF12. The expression of FGF12 transcripts was also detected in murine cultured mast cells derived from bone marrow or fetal skin. These findings suggest that FGF12 intracellularly suppresses radiation-induced apoptosis in mast cells independently of IB2.

  3. A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia.

    Science.gov (United States)

    Xiao, Zhousheng; Riccardi, Demian; Velazquez, Hector A; Chin, Ai L; Yates, Charles R; Carrick, Jesse D; Smith, Jeremy C; Baudry, Jerome; Quarles, L Darryl

    2016-11-22

    Fibroblast growth factor-23 (FGF-23) interacts with a binary receptor complex composed of α-Klotho (α-KL) and FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism in the kidney. Excess FGF-23 production, which causes hypophosphatemia, is genetically inherited or occurs with chronic kidney disease. Among other symptoms, hypophosphatemia causes vitamin D deficiency and the bone-softening disorder rickets. Current therapeutics that target the receptor complex have limited utility clinically. Using a computationally driven, structure-based, ensemble docking and virtual high-throughput screening approach, we identified four novel compounds predicted to selectively inhibit FGF-23-induced activation of the FGFR/α-KL complex. Additional modeling and functional analysis found that Zinc13407541 bound to FGF-23 and disrupted its interaction with the FGFR1/α-KL complex; experiments in a heterologous cell expression system showed that Zinc13407541 selectivity inhibited α-KL-dependent FGF-23 signaling. Zinc13407541 also inhibited FGF-23 signaling in isolated renal tubules ex vivo and partially reversed the hypophosphatemic effects of excess FGF-23 in a mouse model. These chemical probes provide a platform to develop lead compounds to treat disorders caused by excess FGF-23.

  4. Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma

    Science.gov (United States)

    Doughtie, Anne; Cui, Guozhen; Li, Xuanyi; Pandit, Harshul; Yang, Yingbin; Li, Suping; Martin, Robert

    2016-01-01

    Background Human fibroblast growth factor 19 (FGF19), its receptor (FGFR4) and EpCAM play an important role in cell proliferation, differentiation, motility, and overexpression have been linked to hepatocellular carcinoma (HCC). The aim of this study was to evaluate the FGF19 signals responsible for the progression of HCC arising from fatty liver. Results FGF19 level was significantly increased in the HCC patients' serum compared to non-HCC controls. The IHC results demonstrated significant increases of protein expressions of FGF19, FGFR4 and EpCAM in specimens with fatty liver, NASH, cirrhosis, and HCC compared to healthy liver tissue. There was a significant positive correlation between the protein expressions (FGF19, FGFR4, and EpCAM) and histopathologic changes from FL to HCC. Furthermore, FGF19 was positively correlated with FGFR4 and with EpCAM. Materials and Methods FGF19 protein levels in serum and tissues were determined by ELISA assay. The FGFR4, and EpCAM expression and tissue distribution were further evaluated by immunohistochemical staining in tissue array samples. FGF19, FGFR4 and EpCAM expressions between the different histologic stages of fatty liver steatohepatitis-cirrhosis-HCC carcinogenesis sequence were compared to healthy hepatic tissue. Conclusions Overexpression of FGF19/FGFR4 significantly correlated with EpCAM as a marker of hepatic cancer stem cells within the fatty liver-steatosis-cirrhosis-HCC sequence. Impact This is the first study to elucidate FGF19/FGFR4 signaling in favor of HCC cells developing as indicated by increased EpCAM within the carcinogenesis sequence from fatty liver to hepatocellular carcinoma. Our study has the potential to yield novel and cost effective screening strategies for HCC patients. PMID:27447573

  5. 幽门螺杆菌与胃黏膜bFGF,FGFR-2表达的关系及意义%Correlations of Helicobacter pylori infection with the expression of basic fibroblast growth factor and fibroblast growth factor receptor-2 in gastric mucosa and their significances

    Institute of Scientific and Technical Information of China (English)

    李信; 姜海行; 陈罡; 雷琳; 覃山羽

    2007-01-01

    目的:探讨幽门螺杆菌(H pylori)感染的胃黏膜上皮细胞碱性成纤维细胞生长因子(bFGF)、成纤维细胞生长因子受体-2(FGFR-2)的表达及其在胃黏膜癌变过程中的意义.方法:选择慢性浅表性胃炎(CSG)30例、胃黏膜肠上皮化生(IM)29例、不典型增生(Dys)31例及胃癌(GC)55例.采用免疫组化SP法检测胃黏膜上皮细胞bFGF,FGFR-2表达状况,用快速尿素酶试验和组织学Warthin-Starry嗜银染色法联合检测胃黏膜Hpylori感染情况.结果:CSG组bFGF,FGFR-2的表达显著低于其余三组(IM组:χ2=4.002,P<0.05;χ2=4.163,P<0.05;Dys组:χ2=15.779,P=0.000;χ2=15.949,P=0.000;GC组:χ2=24.110,P=0.000;χ2=18.736,P=0.000),IM组的表达低于Dys组及GC组(Dys组:χ2=4.258,P<0.05;χ2=4.212,P<0.05;GC组:χ2=7.786,P<0.01;χ2=4.687,P<0.05),而Dys组与GC组间无显著性差异.Hpylori阳性IM及Dys组bFGF, FGFR-2的表达均显著高于阴性组(IM组:χ2=10.076,P<0.01;χ2=7.535,P<0.01;Dys组:χ2=11.501,P<0.01;χ2=8.330,P<0.01).Hpylori阳性Dys组bFGF, FGFR-2表达显著高于GC组(χ2=4.201,P<0.05;χ2=3.982,P<0.05),H pylori阳性IM组则与G C组的表达无显著性差异;Hpylori阴性Dys组及IM组bFGF的表达均显著低于GG组(χ2=5.736,P<0.05;χ2=17.113,P=0.000),H pylori阴性Dys组FGFR-2表达与GC组无显著性差异而IM组的FGFR-2的表达显著低于GC组(χ2=11.091,P<0.05).结论:H pylori感染引起胃黏膜上皮细胞bFGF及FGFR-2的过度表达可能与H pylori感染致胃黏膜上皮细胞的癌变有关.

  6. [Expression of TGFbeta family factors and FGF2 in mouse and human embryonic stem cells maintained in different culture systems].

    Science.gov (United States)

    Lifantseva, N V; Kol'tsova, A M; Polianskaia, G G; Gordeeva, O F

    2013-01-01

    Mouse and human embryonic stem cells are in different states of pluripotency (naive/ground and primed states). Mechanisms of signaling regulation in cells with ground and primed states of pluripotency are considerably different. In order to understand the contribution of endogenous and exogenous factors in the maintenance of a metastable state of the cells in different phases ofpluripotency, we examined the expression of TGFbeta family factors (ActivinA, Nodal, Leftyl, TGFbeta1, GDF3, BMP4) and FGF2 initiating the appropriate signaling pathways in mouse and human embryonic stem cells (mESCs, hESCs) and supporting feeder cells. Quantitative real-time PCR analysis of gene expression showed that the expression patterns of endogenous factors studied were considerably different in mESCs and hESCs. The most significant differences were found in the levels of endogenous expression of TGFbeta1, BMP4 and ActivinA. The sources of exogenous factors ActivnA, TGFbeta1, and FGF2 for hESCs are feeder cells (mouse and human embryonic fibroblasts) expressing high levels of these factors, as well as low levels of BMP4. Thus, our data demonstrated that the in vitro maintenance of metastable state of undifferentiated pluripotent cells is achieved in mESCs and hESCs using different schemes of the regulations of ActivinA/Nodal/Lefty/Smad2/3BMP/Smad1/5/8 endogenous branches of TGFbeta signaling. The requirement for exogenous stimulation or inhibition of these signaling pathways is due to different patterns of endogenous expression of TGFbeta family factors and FGF2 in the mESCs and hESCs. For the hESCs, enhanced activity of ActivinA/Nodal/Lefty/Smad2/3 signaling by exogenous factor stimulation is necessary to mitigate the effects of BMP/Smadl/5/8 signaling pathways that promote cell differentiation into the extraembryonic structures. Significant differences in endogenous FGF2 expression in the cells in the ground and primary states of pluripotency demonstrate diverse involvement of this

  7. The physical basis of FGFR3 response to fgf1 and fgf2

    OpenAIRE

    Chen, Fenghao; Hristova, Kalina

    2011-01-01

    Fibroblast growth factors (fgfs) play important roles in embryonic development and in adult life, by controlling cell proliferation, differentiation, and migration. There are 18 known fgfs which activate four fibroblast growth factor receptors (FGFRs), with different isoforms due to alternative splicing. The physical basis behind the specificity of the biological responses mediated by different fgf-FGFR pairs is currently unknown. To gain insight into the specificity of FGFR3c, a membrane rec...

  8. Fgf and Sdf-1 pathways interact during zebrafish fin regeneration.

    Science.gov (United States)

    Bouzaffour, Mohamed; Dufourcq, Pascale; Lecaudey, Virginie; Haas, Petra; Vriz, Sophie

    2009-06-08

    The chemokine stromal cell-derived factor-1 (SDF1) was originally identified as a pre-B cell stimulatory factor but has been recently implicated in several other key steps in differentiation and morphogenesis. In addition, SDF1 as well as FGF signalling pathways have recently been shown to be involved in the control of epimorphic regeneration. In this report, we address the question of a possible interaction between the two signalling pathways during adult fin regeneration in zebrafish. Using a combination of pharmaceutical and genetic tools, we show that during epimorphic regeneration, expression of sdf1, as well as of its cognate receptors, cxcr4a, cxcr4b and cxcr7 are controlled by FGF signalling. We further show that, Sdf1a negatively regulates the expression of fgf20a. Together, these results lead us to propose that: 1) the function of Fgf in blastema formation is, at least in part, relayed by the chemokine Sdf1a, and that 2) Sdf1 exerts negative feedback on the Fgf pathway, which contributes to a transient expression of Fgf20a downstream genes at the beginning of regeneration. However this feedback control can be bypassed since the Sdf1 null mutants regenerate their fin, though slower. Very few mutants for the regeneration process were isolated so far, illustrating the difficulty in identifying genes that are indispensable for regeneration. This observation supports the idea that the regeneration process involves a delicate balance between multiple pathways.

  9. Fgf and Sdf-1 pathways interact during zebrafish fin regeneration.

    Directory of Open Access Journals (Sweden)

    Mohamed Bouzaffour

    Full Text Available The chemokine stromal cell-derived factor-1 (SDF1 was originally identified as a pre-B cell stimulatory factor but has been recently implicated in several other key steps in differentiation and morphogenesis. In addition, SDF1 as well as FGF signalling pathways have recently been shown to be involved in the control of epimorphic regeneration. In this report, we address the question of a possible interaction between the two signalling pathways during adult fin regeneration in zebrafish. Using a combination of pharmaceutical and genetic tools, we show that during epimorphic regeneration, expression of sdf1, as well as of its cognate receptors, cxcr4a, cxcr4b and cxcr7 are controlled by FGF signalling. We further show that, Sdf1a negatively regulates the expression of fgf20a. Together, these results lead us to propose that: 1 the function of Fgf in blastema formation is, at least in part, relayed by the chemokine Sdf1a, and that 2 Sdf1 exerts negative feedback on the Fgf pathway, which contributes to a transient expression of Fgf20a downstream genes at the beginning of regeneration. However this feedback control can be bypassed since the Sdf1 null mutants regenerate their fin, though slower. Very few mutants for the regeneration process were isolated so far, illustrating the difficulty in identifying genes that are indispensable for regeneration. This observation supports the idea that the regeneration process involves a delicate balance between multiple pathways.

  10. FGF-2 induces neuronal death through upregulation of system xc-.

    Science.gov (United States)

    Liu, Xiaoqian; Albano, Rebecca; Lobner, Doug

    2014-02-14

    The cystine/glutamate antiporter (system xc-) transports cystine into cell in exchange for glutamate. Fibroblast growth factor-2 (FGF-2) upregulates system xc- selectively on astrocytes, which leads to increased cystine uptake, the substrate for glutathione production, and increased glutamate release. While increased intracellular glutathione can limit oxidative stress, the increased glutamate release can potentially lead to excitotoxicity to neurons. To test this hypothesis, mixed neuronal and glial cortical cultures were treated with FGF-2. Treatment with FGF-2 for 48 h caused a significant neuronal death in these cultures. Cell death was not observed in neuronal-enriched cultures, or astrocyte-enriched cultures, suggesting the toxicity was the result of neuron-glia interaction. Blocking system xc- eliminated the neuronal death as did the AMPA/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX), but not the NMDA receptor antagonist memantine. When cultures were exposed directly to glutamate, both NBQX and memantine blocked the neuronal toxicity. The mechanism of this altered profile of glutamate receptor mediated toxicity by FGF-2 is unclear. The selective calcium permeable AMPA receptor antagonist 1-naphthyl acetyl spermine (NASPM) failed to offer protection. The most likely explanation for the results is that 48 h FGF-2 treatment induces AMPA/kainate receptor toxicity through increased system xc- function resulting in increased release of glutamate. At the same time, FGF-2 alters the sensitivity of the neurons to glutamate toxicity in a manner that promotes selective AMPA/kainate receptor mediated toxicity.

  11. Fibroblast growth factor receptor signaling is essential for lens fiber cell differentiation.

    Science.gov (United States)

    Zhao, Haotian; Yang, Tianyu; Madakashira, Bhavani P; Thiels, Cornelius A; Bechtle, Chad A; Garcia, Claudia M; Zhang, Huiming; Yu, Kai; Ornitz, David M; Beebe, David C; Robinson, Michael L

    2008-06-15

    The vertebrate lens provides an excellent model to study the mechanisms that regulate terminal differentiation. Although fibroblast growth factors (FGFs) are thought to be important for lens cell differentiation, it is unclear which FGF receptors mediate these processes during different stages of lens development. Deletion of three FGF receptors (Fgfr1-3) early in lens development demonstrated that expression of only a single allele of Fgfr2 or Fgfr3 was sufficient for grossly normal lens development, while mice possessing only a single Fgfr1 allele developed cataracts and microphthalmia. Profound defects were observed in lenses lacking all three Fgfrs. These included lack of fiber cell elongation, abnormal proliferation in prospective lens fiber cells, reduced expression of the cell cycle inhibitors p27(kip1) and p57(kip2), increased apoptosis and aberrant or reduced expression of Prox1, Pax6, c-Maf, E-cadherin and alpha-, beta- and gamma-crystallins. Therefore, while signaling by FGF receptors is essential for lens fiber differentiation, different FGF receptors function redundantly.

  12. Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy

    Directory of Open Access Journals (Sweden)

    Szlachcic A

    2016-08-01

    Full Text Available Anna Szlachcic, Malgorzata Zakrzewska, Michal Lobocki, Piotr Jakimowicz, Jacek Otlewski Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland Abstract: Fibroblast growth factor receptors (FGFRs are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V, was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE, and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody–drug conjugates. The FGF1V–valine–citrulline–MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V–vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality. Keywords: fibroblast growth factor 1, FGF receptor, targeted cancer therapy, cytotoxic conjugates, FGFR-dependent cancer, MMAE, auristatin

  13. FGF9-Pitx2-FGF10 signaling controls cecal formation in mice.

    Science.gov (United States)

    Al Alam, Denise; Sala, Frederic G; Baptista, Sheryl; Galzote, Rosanna; Danopoulos, Soula; Tiozzo, Caterina; Gage, Philip; Grikscheit, Tracy; Warburton, David; Frey, Mark R; Bellusci, Saverio

    2012-09-15

    Fibroblast growth factor (FGF) signaling to the epithelium and mesenchyme mediated by FGF10 and FGF9, respectively, controls cecal formation during embryonic development. In particular, mesenchymal FGF10 signals to the epithelium via FGFR2b to induce epithelial cecal progenitor cell proliferation. Yet the precise upstream mechanisms controlling mesenchymal FGF10 signaling are unknown. Complete deletion of Fgf9 as well as of Pitx2, a gene encoding a homeobox transcription factor, both lead to cecal agenesis. Herein, we used mouse genetic approaches to determine the precise contribution of the epithelium and/or mesenchyme tissue compartments in this process. Using tissue compartment specific Fgf9 versus Pitx2 loss of function approaches in the gut epithelium and/or mesenchyme, we determined that FGF9 signals to the mesenchyme via Pitx2 to induce mesenchymal Fgf10 expression, which in turn leads to epithelial cecal bud formation.

  14. Expression of chick Fgf19 and mouse Fgf15 orthologs is regulated in the developing brain by Fgf8 and Shh.

    Science.gov (United States)

    Gimeno, L; Martinez, S

    2007-08-01

    Fibroblast growth factors (Fgfs) constitute a family of signaling molecules that play essential roles in development. We have studied the expression pattern of mouse Fgf15 in the developing brain. Fgf19 is another member of the FGF family that has been suggested as the chick and human ortholog of mouse and rat Fgf15. Here, we compare the expression pattern during neural development of chick Fgf19 with mouse Fgf15. Unlike Fgf15, Fgf19 presents an expression in the isthmic alar plate, diencephalic and mesencephalic parabasal plates, hindbrain basal plate, as well as in the zona limitans intrathalamica (zli). Moreover, we explored the regulation between Fgf19 and the signaling molecules of the isthmic and zli organizers: Fgf8 and Shh, respectively. Considering the possibility that Fgf19 plays a similar role in humans and chicks, this finding could explain the significant diencephalic phenotypic differences between humans and mice in models and diseases where the Shh pathway is affected.

  15. Expression and potential role of fibroblast growth factor 2 and its receptors in human embryonic stem cells.

    Science.gov (United States)

    Dvorak, Petr; Dvorakova, Dana; Koskova, Stanislava; Vodinska, Martina; Najvirtova, Miroslava; Krekac, Daniel; Hampl, Ales

    2005-09-01

    Although the detection of several components of the fibroblast growth factor (FGF) signaling pathway in human embryonic stem cells (hESCs) has been reported, the functionality of that pathway and effects on cell fate decisions are yet to be established. In this study we characterized expression of FGF-2, the prototypic member of the FGF family, and its receptors (FGFRs) in undifferentiated and differentiating hESCs; subsequently, we analyzed the effects of FGF-2 on hESCs, acting as both exogenous and endogenous factors. We have determined that undifferentiated hESCs are abundant in several molecular-mass isoforms of FGF-2 and that expression pattern of these isoforms remains unchanged under conditions that induce hESC differentiation. Significantly, FGF-2 is released by hESCs into the medium, suggesting an autocrine activity. Expression of FGFRs in undifferentiated hESCs follows a specific pattern, with FGFR1 being the most abundant species and other receptors showing lower expression in the following order: FGFR1 --> FGFR3 --> FGFR4 --> FGFR2. Initiation of differentiation is accompanied by profound changes in FGFR expression, particularly the upregulation of FGFR1. When hESCs are exposed to exogenous FGF-2, extracellular signal-regulated kinases are phosphorylated and thereby activated. However, the presence or absence of exogenous FGF-2 does not significantly affect the proliferation of hESCs. Instead, increased concentration of exogenous FGF-2 leads to reduced outgrowth of hESC colonies with time in culture. Finally, the inhibitor of FGFRs, SU5402, was used to ascertain whether FGF-2 that is released by hESCs exerts its activities via autocrine pathways. Strikingly, the resultant inhibition of FGFR suppresses activation of downstream protein kinases and causes rapid cell differentiation, suggesting an involvement of autocrine FGF signals in the maintenance of proliferating hESCs in the undifferentiated state. In conclusion from our data, we propose that this

  16. FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Ishino, Ruri; Minami, Kaori; Tanaka, Satowa [Laboratory of Hematology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142 (Japan); Nagai, Mami [Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 159-8555 (Japan); Matsui, Keiji; Hasegawa, Natsumi [Laboratory of Hematology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142 (Japan); Roeder, Robert G. [Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065 (United States); Asano, Shigetaka [Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 159-8555 (Japan); Ito, Mitsuhiro, E-mail: itomi@med.kobe-u.ac.jp [Laboratory of Hematology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142 (Japan); Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065 (United States); Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 159-8555 (Japan); Department of Family and Community Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 654-0142 (Japan)

    2013-10-11

    Highlights: •FGF7 is downregulated in MED1-deficient mesenchymal cells. •FGF7 produced by mesenchymal stromal cells is a novel hematopoietic niche molecule. •FGF7 supports hematopoietic progenitor cells and niche-dependent leukemia cells. •FGF7 activates FGFR2IIIb of bone marrow stromal cells in an autocrine manner. •FGF7 indirectly acts on hematopoietic cells lacking FGFR2IIIb via stromal cells. -- Abstract: FGF1 and FGF2 support hematopoietic stem and progenitor cells (HSPCs) under stress conditions. In this study, we show that fibroblast growth factor (FGF7) may be a novel niche factor for HSPC support and leukemic growth. FGF7 expression was attenuated in mouse embryonic fibroblasts (MEFs) deficient for the MED1 subunit of the Mediator transcriptional coregulator complex. When normal mouse bone marrow (BM) cells were cocultured with Med1{sup +/+} MEFs or BM stromal cells in the presence of anti-FGF7 antibody, the growth of BM cells and the number of long-time culture-initiating cells (LTC-ICs) decreased significantly. Anti-FGF7 antibody also attenuated the proliferation and cobblestone formation of MB1 stromal cell-dependent myeloblastoma cells. The addition of recombinant FGF7 to the coculture of BM cells and Med1{sup −/−} MEFs increased BM cells and LTC-ICs. FGF7 and its cognate receptor, FGFR2IIIb, were undetectable in BM cells, but MEFs and BM stromal cells expressed both. FGF7 activated downstream targets of FGFR2IIIb in Med1{sup +/+} and Med1{sup −/−} MEFs and BM stromal cells. Taken together, we propose that FGF7 supports HSPCs and leukemia-initiating cells indirectly via FGFR2IIIb expressed on stromal cells.

  17. Association of serum fibroblast growth factor 23 (FGF23) and incident fractures in older men: the Osteoporotic Fractures in Men (MrOS) study.

    Science.gov (United States)

    Lane, Nancy E; Parimi, Neeta; Corr, Maripat; Yao, Wei; Cauley, Jane A; Nielson, Carrie M; Ix, Joseph H; Kado, Deborah; Orwoll, Eric

    2013-11-01

    Normal mineral metabolism is critical for skeletal integrity, and recently serum fibroblast growth factor 23 (FGF23) levels were found to be directly related to overall fracture risk in elderly Swedish men. To confirm this association, we performed a prospective case-cohort study to understand the relation of FGF23 and fracture risk in older white men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men attending the baseline MrOS examination, we evaluated a subgroup of 387 men with incident nonvertebral fracture including 73 hip fractures and a sample of 1385 men randomly selected from the cohort with baseline mineral and calcium hormone measurements. FGF23 was measured in baseline serum samples by ELISA (Millipore, Billerica, MA, USA). Modified Cox proportional hazards models that account for case-cohort study design were used to estimate the relative hazards (RH) of fracture in men across quartiles of FGF23. Subjects were also stratified by renal function, and RH per strata was estimated in men with the highest quartile of FGF23 compared with quartiles 3, 2, and 1. Overall, there was no difference in risk of nonspine or hip fracture by baseline FGF23. However, associations differed by strata of eGFRCrCy . Among men with eGFRCrCys 60 mL/min/1.73 m2 (304/1370 fractures) the RH was 0.91 (95% CI 0.66-1.25) after adjustment for age, clinic site, body mass index, race, total hip bone mineral density, vitamin D, parathyroid hormone, alcohol use, physical activity, fracture history, and serum phosphorus. Serum FGF23 levels are not associated with incident fractures in elderly men overall. However, higher levels of serum FGF23 are associated with fracture risk in those with poor renal function.

  18. Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of cancer.

    Science.gov (United States)

    Harding, Thomas C; Long, Li; Palencia, Servando; Zhang, Hongbing; Sadra, Ali; Hestir, Kevin; Patil, Namrata; Levin, Anita; Hsu, Amy W; Charych, Deborah; Brennan, Thomas; Zanghi, James; Halenbeck, Robert; Marshall, Shannon A; Qin, Minmin; Doberstein, Stephen K; Hollenbaugh, Diane; Kavanaugh, W Michael; Williams, Lewis T; Baker, Kevin P

    2013-03-27

    The fibroblast growth factor (FGF) pathway promotes tumor growth and angiogenesis in many solid tumors. Although there has long been interest in FGF pathway inhibitors, development has been complicated: An effective FGF inhibitor must block the activity of multiple mitogenic FGF ligands but must spare the metabolic hormone FGFs (FGF-19, FGF-21, and FGF-23) to avoid unacceptable toxicity. To achieve these design requirements, we engineered a soluble FGF receptor 1 Fc fusion protein, FP-1039. FP-1039 binds tightly to all of the mitogenic FGF ligands, inhibits FGF-stimulated cell proliferation in vitro, blocks FGF- and vascular endothelial growth factor (VEGF)-induced angiogenesis in vivo, and inhibits in vivo growth of a broad range of tumor types. FP-1039 antitumor response is positively correlated with RNA levels of FGF2, FGF18, FGFR1c, FGFR3c, and ETV4; models with genetic aberrations in the FGF pathway, including FGFR1-amplified lung cancer and FGFR2-mutated endometrial cancer, are particularly sensitive to FP-1039-mediated tumor inhibition. FP-1039 does not appreciably bind the hormonal FGFs, because these ligands require a cell surface co-receptor, klotho or β-klotho, for high-affinity binding and signaling. Serum calcium and phosphate levels, which are regulated by FGF-23, are not altered by administration of FP-1039. By selectively blocking nonhormonal FGFs, FP-1039 treatment confers antitumor efficacy without the toxicities associated with other FGF pathway inhibitors.

  19. Smooth muscle FGF/TGFβ cross talk regulates atherosclerosis progression.

    Science.gov (United States)

    Chen, Pei-Yu; Qin, Lingfeng; Li, Guangxin; Tellides, George; Simons, Michael

    2016-07-01

    The conversion of vascular smooth muscle cells (SMCs) from contractile to proliferative phenotype is thought to play an important role in atherosclerosis. However, the contribution of this process to plaque growth has never been fully defined. In this study, we show that activation of SMC TGFβ signaling, achieved by suppression of SMC fibroblast growth factor (FGF) signaling input, induces their conversion to a contractile phenotype and dramatically reduces atherosclerotic plaque size. The FGF/TGFβ signaling cross talk was observed in vitro and in vivo In vitro, inhibition of FGF signaling increased TGFβ activity, thereby promoting smooth muscle differentiation and decreasing proliferation. In vivo, smooth muscle-specific knockout of an FGF receptor adaptor Frs2α led to a profound inhibition of atherosclerotic plaque growth when these animals were crossed on Apoe(-/-) background and subjected to a high-fat diet. In particular, there was a significant reduction in plaque cellularity, increase in fibrous cap area, and decrease in necrotic core size. In agreement with these findings, examination of human coronary arteries with various degrees of atherosclerosis revealed a strong correlation between the activation of FGF signaling, loss of TGFβ activity, and increased disease severity. These results identify SMC FGF/TGFβ signaling cross talk as an important regulator of SMC phenotype switch and document a major contribution of medial SMC proliferation to atherosclerotic plaque growth.

  20. The impact of hyperbaric oxygen therapy on serological values of vascular endothelial growth factor (VEGF and basic fibroblast growth factor (bFGF

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    Ziebura Thomas

    2010-12-01

    Full Text Available Abstract Background Hyperbaric oxygen (HBO therapy is an effective adjunct treatment for ischemic disorders such as chronic infection or chronic wounds. It combines hyperoxic effects with the stimulating potential of post-therapeutic reactive hypoxia. As its crucial effects, stimulation of fibroblast growth, induction of collagen synthesis and the initiation of angiogenesis are discussed. Angiogenesis is a multistage process resulting in the growth of blood vessels. It includes degradation of extracellular matrix, proliferation and migration of different cell populations and finally formation of new vessel structures. This complex chain of procedures is orchestrated by different cytokines and growth factors. Crucial mediators of angiogenesis are basic fibroblast growth factor (bFGF and vascular endothelial growth factor (VEGF; their in-vivo function is still not fully understood. Methods Forty-three patients suffering from sudden sensorineural hearing loss or tinnitus were treated with HBO. The therapy included 10 sessions of 90 minutes each, one session a day. Serological levels of bFGF and VEGF were assessed by enzyme-linked immunosorbent assays performed according to the manufacturer's instructions on day 1, 2, 5 and 10 of HBO therapy and were compared to mean values of the control group, related to the patient's age and sex, and their development observed over the ten days of HBO. Results There was no sex- or age dependency of bFGF observed in the present study, whereas under HBO our results showed a significant mitigation of the bFGF concentration. In the present data, there was no connection between the VEGF concentration and the patients' ages. Women showed significantly higher levels of VEGF. There was no significant change of VEGF concentration or the VEGF/bFGF ratio during HBO. All scored results varied within the range of standard values as described in the current literature. Conclusions A significant effect of HBO on serum

  1. Prostaglandin E2 regulates angiogenesis via activation of fibroblast growth factor receptor-1.

    Science.gov (United States)

    Finetti, Federica; Solito, Raffaella; Morbidelli, Lucia; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra

    2008-01-25

    Prostaglandin E(2) (PGE(2)) behaves as a mitogen in epithelial tumor cells as well as in many other cell types. We investigated the actions of PGE(2) on microvascular endothelial cells (capillary venular endothelial cells) with the purpose of delineating the signaling pathway leading to the acquisition of the angiogenic phenotype and to new vessel formation. PGE(2) (100 nM) produced activation of the fibroblast growth factor receptor 1 (FGFR-1), as measured by its phosphorylation, but not of vascular endothelial growth factor receptor 2. PGE(2) stimulated the EP3 subtype receptor, as deduced by abrogation of EP3 Galpha(i) subunit activity through pertussis toxin. Consistent with this result, in human umbilical venular endothelial cells missing the EP3 receptor, PGE(2) did not phosphorylate FGFR-1. Upon binding to its receptor, PGE(2) initiated an autocrine/paracrine signaling cascade involving the intracellular activation of c-Src, activation of matrix metalloproteinase (predominantly MMP2), which in turn caused the mobilization of membrane-anchored fibroblast growth factor-2 (FGF-2). In fact, in cells unable to release FGF-2 the transfection with both FGFR-1 and EP3 did not result in FGFR-1 phosphorylation in response to PGE(2). Relevance for the FGF2-FGFR-1 system was highlighted by confocal analysis, showing receptor internalization after cell exposure to the prostanoid. ERK1/2 appeared to be the distal signal involved, its phosphorylation being sensitive to either cSrc inhibitor or FGFR-1 blocker. Finally, PGE(2) stimulated cell migration and capillary formation in aortic rings, which were severely reduced by inhibitors of signaling molecules or by receptor antagonist. In conclusion, this study provides evidence for the involvement of FGFR-1 through FGF2 in eliciting PGE(2) angiogenic responses. This signaling pattern is similar to the autocrine-paracrine mechanism which operates in endothelial cells to support neovascular growth.

  2. Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes

    DEFF Research Database (Denmark)

    Sonne, David P; van Nierop, F Samuel; Kulik, Willem

    2016-01-01

    CONTEXT: Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may be implic......CONTEXT: Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may...... be implicated in postprandial glucose metabolism. OBJECTIVE: To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls. DESIGN AND SETTING: Descriptive study, performed at the Center for Diabetes Research, Gentofte Hospital...... and FGF-19 concentrations. RESULTS: Postprandial total bile acid concentrations increased with increasing meal fat content (P

  3. Porphyrin analogues as novel antagonists of fibroblast growth factor and vascular endothelial growth factor receptor binding that inhibit endothelial cell proliferation, tumor progression, and metastasis.

    Science.gov (United States)

    Aviezer, D; Cotton, S; David, M; Segev, A; Khaselev, N; Galili, N; Gross, Z; Yayon, A

    2000-06-01

    Fibroblast growth factors (FGFs) and vascular endothelial growth factor (VEGF) play a pivotal role in the multistep pathway of tumor progression, metastasis, and angiogenesis. We have identified a porphyrin analogue, 5,10,15,20-tetrakis(methyl-4-pyridyl)-21H,23H-porphine-tetra -p-tosylate salt (TMPP), as a potent inhibitor of FGF2 and VEGF receptor binding and activation. TMPP demonstrated potent inhibition of binding of soluble FGF receptor 1 (FGFR1) to FGF2 immobilized on heparin at submicromolar concentrations. TMPP inhibits binding of radiolabeled FGF2 to FGFR in a cell-free system as well as to cells genetically engineered to express FGFR1. Furthermore, TMPP also inhibits the binding of VEGF to its tyrosine kinase receptor in a dose-dependent manner. In an in vitro angiogenic assay measuring the extent of endothelial cell growth, tube formation, and sprouting, TMPP dramatically reduced the extent of the FGF2-induced endothelial cell outgrowth and differentiation. In a Lewis lung carcinoma model, mice receiving TMPP showed a marked inhibition of both primary tumor progression and lung metastases development, with nearly total inhibition of the metastatic phenotype upon alternate daily injections of TMPP at 25 microg/g of body mass. Finally, novel meso-pyridylium-substituted, nonsymmetric porphyrins, as well as a novel corrole-based derivative, with >50-fold increase in activity in vitro, had a significantly improved efficacy in blocking tumor progression and metastasis in vivo.

  4. Fibroblast Growth Factor 21 (FGF21, Free Fatty Acid (FFA, High Sensitivity C-reactive Protein (hsCRP and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR Among Indonesian Obese Non-Diabetic Males

    Directory of Open Access Journals (Sweden)

    Yani Lina

    2009-12-01

    Full Text Available BACKGROUND: Fibroblast growth factor-21 (FGF21 is known as an important endocrine and paracrine regulator of metabolic homeostasis. Recent studies have shown that FGF21 attenuates lipolysis in human adipocytes, which is suggested as a FGF21's mechanism as anti-hyperlipidemia, anti-hyperglycemia and anti-obesity. The aim of this study was to measure the correlation between FGF21, FFA, hsCRP and HOMA-IR among Indonesian obese non diabetic males. METHODS: The study was observational with cross sectional design. The analysis was done in 137 subjects aged 30-60 years with non diabetic abdominal obesity. We measured the biochemical markers FGF21, FFA, hsCRP, fasting insulin and fasting glucose. We also measured weight, height, waist circumrefence (WC, creatinine, serum glutamin oxaloacetic transaminase (SGOT, and serum glutamic pyruvic transaminase (SGPT, systolic blood pressure (SBP and diastolic blood pressure (DBP. Correlation between markers was measured using Pearson and Spearman's analysis. RESULTS: There were significant positive correlations between FGF21-HOMA-IR (r=0.314, p=0.000; FGF21-WC (r=0.173, p=0.043; FFA=hsCRP r=0.270, p=0.001; and WC-HOMA-IR (r=0.279, p=0.001. There was significant negative correlation between FGF21-FFA (r=-0.038, p=0.657 and FGF21-hsCRP (r=-0.061, p=0.482. CONCLUSIONS: In this study we found that although there was no significant correlation, FGF21 might act as an anti-lipolytic and anti-inflammation agent among Indonesian obese non-diabetic males. Our findings agree with results of previous studies that the positive correlation between FGF21-WC and FGF21-HOMA-IR might occur as a compensatory mechanism or resistance to FGF21 in obesity. KEYWORDS: obesity, FGF21, FFA, hsCRP, HOMA-IR.

  5. Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB.

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    Chaofeng Yang

    Full Text Available BACKGROUND: Recent studies suggest that betaKlotho (KLB and endocrine FGF19 and FGF21 redirect FGFR signaling to regulation of metabolic homeostasis and suppression of obesity and diabetes. However, the identity of the predominant metabolic tissue in which a major FGFR-KLB resides that critically mediates the differential actions and metabolism effects of FGF19 and FGF21 remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: We determined the receptor and tissue specificity of FGF21 in comparison to FGF19 by using direct, sensitive and quantitative binding kinetics, and downstream signal transduction and expression of early response gene upon administration of FGF19 and FGF21 in mice. We found that FGF21 binds FGFR1 with much higher affinity than FGFR4 in presence of KLB; while FGF19 binds both FGFR1 and FGFR4 in presence of KLB with comparable affinity. The interaction of FGF21 with FGFR4-KLB is very weak even at high concentration and could be negligible at physiological concentration. Both FGF19 and FGF21 but not FGF1 exhibit binding affinity to KLB. The binding of FGF1 is dependent on where FGFRs are present. Both FGF19 and FGF21 are unable to displace the FGF1 binding, and conversely FGF1 cannot displace FGF19 and FGF21 binding. These results indicate that KLB is an indispensable mediator for the binding of FGF19 and FGF21 to FGFRs that is not required for FGF1. Although FGF19 can predominantly activate the responses of the liver and to a less extent the adipose tissue, FGF21 can do so significantly only in the adipose tissue and adipocytes. Among several metabolic and endocrine tissues, the response of adipose tissue to FGF21 is predominant, and can be blunted by the ablation of KLB or FGFR1. CONCLUSIONS: Our results indicate that unlike FGF19, FGF21 is unable to bind FGFR4-KLB complex with affinity comparable to FGFR1-KLB, and therefore, at physiological concentration less likely to directly and significantly target the liver where FGFR4-KLB

  6. Uronyl 2-O sulfotransferase potentiates Fgf2-induced cell migration.

    Science.gov (United States)

    Nikolovska, Katerina; Spillmann, Dorothe; Seidler, Daniela G

    2015-02-01

    Fibroblast growth factor 2 (Fgf2) is involved in several biological functions. Fgf2 requires glycosaminoglycans, like chondroitin and dermatan sulfates (hereafter denoted CS/DS) as co-receptors. CS/DS are linear polysaccharides composed of repeating disaccharide units [-4GlcUAb1-3-GalNAc-b1-] and [-4IdoUAa1-3-GalNAc-b1-],which can be sulfated. Uronyl 2-O-sulfotransferase (Ust)introduces sulfation at the C2 of IdoUA and GlcUA resulting inover-sulfated units. Here, we investigated the role of Ust-mediated CS/DS 2-O sulfation in Fgf2-induced cell migration. We found that CHO-K1 cells overexpressing Ust contain significantly more CS/DS2-O sulfated units, whereas Ust knockdown abolished CS/DS 2-O sulfation. These structural differences in CS/DS resulted in altered Fgf2 binding and increased phosphorylation of ERK1/2 (also known as MAPK3 and MAPK1, respectively). As a functional consequence of CS/DS 2-O sulfation and altered Fgf2 binding, cell migration and paxillin activation were increased. Inhibition of sulfation, knockdown of Ust and inhibition of FgfR resulted in reduced migration. Similarly, in 3T3 cells Fgf2 treatment increased migration, which was abolished by Ust knockdown. The proteoglycan controlling the CHO migration was syndecan 1. Knockdown of Sdc1 in CHO-K1 cells overexpressing Ust abolished cell migration.We conclude that the presence of distinctly sulfated CS/DS can tune the Fgf2 effect on cell migration.

  7. CYTOCHROMES P450,NUCLEAR RECEPTORS AND FIBROBLAST GROWTH FACTORS- NEW ENDOCRINE AXES AS POTENCIAL DRUG TARGETS TO TREAT METABOLIC DISORDERS

    Directory of Open Access Journals (Sweden)

    Klementina Fon Tacer

    2009-06-01

    Full Text Available background Coordinate action of endocrine and nervous system enables adaptation of higher organisms to constant changes in the environment. Fibroblast growth factors (FGFs primarily regulate embryonic and organ development, however, FGF19 subfamily members despite the name act in an endocrine fashion. The studies of endocrine FGFs resulted in the discovery of new endocrine axes, composed of small lipophilic molecules and members of three protein families: cytochromes P450, nuclear receptors, and FGFs. Cytochromes P450 are enzymes responsible for metabolism of different lipid molecules. Nuclear receptors bind lipid metabolites and act as metabolic sensors. They become activated and as transcriptional factors turn on expression of endocrine FGFs. eFGFs regulate metabolic pathways in target organs that express specific FGF receptor/coreceptor pair. FGF15/19 is expressed in the small intestine and is involved in the postprandial bile acid negative feedback loop in the liver. FGF21 is liver-borne fasting hormone that induces fat utilization. FGF23 is expressed in bone and acts on kidney to regulate phosphate and vitamin D metabolism.Conclusions We describe herein three new endocrine axes that were probably developed for fine tuning metabolite concentration within narrow physiological limits and prevent their toxicity in excess. They play important role in the pathophysiology underlying diverse metabolic disorders and are expected to be potential targets for therapeutic interventions.

  8. Fibroblast growth factor receptor 4 (FGFR4) deficiency improves insulin resistance and glucose metabolism under diet-induced obesity conditions.

    Science.gov (United States)

    Ge, Hongfei; Zhang, Jun; Gong, Yan; Gupte, Jamila; Ye, Jay; Weiszmann, Jennifer; Samayoa, Kim; Coberly, Suzanne; Gardner, Jonitha; Wang, Huilan; Corbin, Tim; Chui, Danny; Baribault, Helene; Li, Yang

    2014-10-31

    The role of fibroblast growth factor receptor 4 (FGFR4) in regulating bile acid synthesis has been well defined; however, its reported role on glucose and energy metabolism remains unresolved. Here, we show that FGFR4 deficiency in mice leads to improvement in glucose metabolism, insulin sensitivity, and reduction in body weight under high fat conditions. Mechanism of action studies in FGFR4-deficient mice suggest that the effects are mediated in part by increased plasma levels of adiponectin and the endocrine FGF factors FGF21 and FGF15, the latter of which increase in response to an elevated bile acid pool. Direct actions of increased bile acids on bile acid receptors, and other potential indirect mechanisms, may also contribute to the observed metabolic changes. The results described herein suggest that FGFR4 antagonists alone, or in combination with other agents, could serve as a novel treatment for diabetes.

  9. Activation of GR but not PXR by dexamethasone attenuated acetaminophen hepatotoxicities via Fgf21 induction.

    Science.gov (United States)

    Vispute, Saurabh G; Bu, Pengli; Le, Yuan; Cheng, Xingguo

    2017-03-01

    Glucocorticoid receptor (GR) signaling is indispensable for cell growth and development, and plays important roles in drug metabolism. Fibroblast growth factor (Fgf) 21, an important regulator of glucose, lipid, and energy metabolism, plays a cytoprotective role by attenuating toxicities induced by chemicals such as dioxins, acetaminophen (APAP), and alcohols. The present study investigates the impact of dexamethasone (DEX)-activated GR on Fgf21 expression and how it affects the progression of APAP-induced hepatotoxicity. Our results showed that DEX dose/concentration- and time-dependently increased Fgf21 mRNA and protein expression in mouse liver as well as cultured mouse and human hepatoma cells. By using PXR-null mouse model, we demonstrated that DEX induced Fgf21 expression by a PXR-independent mechanism. In cultured mouse and human hepatoma cells, inhibition of GR signaling, by RU486 (Mifepristone) or GR silencing using GR-specific siRNA, attenuated DEX-induced Fgf21 expression. In addition, DEX increased luciferase reporter activity driven by the 3.0-kb mouse and human Fgf21/FGF21 gene promoter. Further, ChIP-qPCR assays demonstrated that DEX increased the binding of GR to the specific cis-regulatory elements located in the 3.0-kb mouse and human Fgf21/FGF21 gene promoter. Pretreatment of 2mg/kg DEX ameliorated APAP-induced liver injury in wild-type but not Fgf21-null mice. In conclusion, via GR activation, DEX induced Fgf21 expression in mouse liver and human hepatoma cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Inhibition of FGF signaling accelerates neural crest cell differentiation of human pluripotent stem cells.

    Science.gov (United States)

    Jaroonwitchawan, Thiranut; Muangchan, Pattamon; Noisa, Parinya

    2016-12-02

    Neural crest (NC) is a transient population, arising during embryonic development and capable of differentiating into various somatic cells. The defects of neural crest development leads to neurocristopathy. Several signaling pathways were revealed their significance in NC cell specification. Fibroblast growth factor (FGF) is recognized as an important signaling during NC development, for instance Xenopus and avian; however, its contributions in human species are remained elusive. Here we used human pluripotent stem cells (hPSCs) to investigate the consequences of FGF inhibition during NC cell differentiation. The specific-FGF receptor inhibitor, SU5402, was used in this investigation. The inhibition of FGF did not found to affect the proliferation or death of hPSC-derived NC cells, but promoted hPSCs to commit NC cell fate. NC-specific genes, including PAX3, SLUG, and TWIST1, were highly upregulated, while hPSC genes, such as OCT4, and E-CAD, rapidly reduced upon FGF signaling blockage. Noteworthy, TFAP-2α, a marker of migratory NC cells, abundantly presented in SU5402-induced cells. This accelerated NC cell differentiation could be due to the activation of Notch signaling upon the blockage of ERK1/2 phosphorylation, since NICD was increased by SU5402. Altogether, this study proposed the contributions of FGF signaling in controlling human NC cell differentiation from hPSCs, the crosstalk between FGF and Notch, and might imply to the influences of FGF signaling in neurocristophatic diseases.

  11. FGF15/19 protein levels in the portal blood do not reflect changes in the ileal FGF15/19 or hepatic CYP7A1 mRNA levels.

    Science.gov (United States)

    Shang, Quan; Guo, Grace L; Honda, Akira; Saumoy, Monica; Salen, Gerald; Xu, Guorong

    2013-10-01

    It has been proposed that bile acid suppression of CYP7A1 gene expression is mediated through a gut-liver signaling pathway fibroblast growth factor (FGF)15/19-fibroblast growth factor receptor 4 which is initiated by activation of farnesoid X receptor in the ileum but not in the liver. This study evaluated whether FGF15/19 protein levels in the portal blood reflected changes in FGF15/19 mRNA in the ileum. Studies were conducted in Sprague Dawley rats and New Zealand white rabbits fed regular chow (controls), supplemented with cholesterol (Ch) or cholic acid (CA). After feeding CA, ileal FGF15 mRNA increased 8.5-fold in rats and FGF19 rose 16-fold in rabbits associated with 62 and 75% reduction of CYP7A1 mRNA, respectively. Neither FGF15 nor FGF19 protein levels changed in the portal blood to correspond with the marked increase of FGF15/19 mRNA levels in the ileum or inhibited CYP7A1 expression in the liver. Further, in Ch-fed rats, CYP7A1 mRNA increased 1.9-fold (P CYP7A1 mRNA declined 49% (P CYP7A1 in the liver change significantly.

  12. Ontogeny of expression of basic fibroblast growth factor and its receptors in human fetal skin

    Institute of Scientific and Technical Information of China (English)

    CHEN Wei; FU Xiao-bing; GE Shi-li; SUN Tong-zhu; SHENG Zhi-yong

    2005-01-01

    Objective : To investigate the expression characteristics of basic fibroblast growth factor (bFGF)and its receptors, flg ( FGFR1 ) and bek ( FGFR2), in fetal skin at different gestational ages underlying the relevance of these 3 proteins to skin development and the mechanisms underlying the phenotypic transition from scarless to scarforming healing.Methods: Eighteen specimens of fetal skin biopsies of human embryo were obtained from spontaneous abortions at different gestational ages of 13-32 weeks. Gene expression of bFGF, bek and flg was examined with reverse transcription-polymerase chain reaction (RT-PCR). The dynamic expression and distribution of these 3 proteins were detected with streptavidin peroxidase ( SP )immunohistochemical staining method.Results: In the early gestational fetal skin, genes of bFGF and flg were strongly expressed and more protein contents of these 2 proteins were found as compared with the genes at late gestation fetal skin (2.446 ± 0.116 and 2.066 ± 0. 152 versus 2.157 ± 0. 101 and 1.818 ± 0.086,respectively, P < 0.05). On the contrary, the levels of gene expression and protein content of bek were not differently expressed in the early gestational fetal skin versus the late ones. Protein particles of bFGF were mainly distributed in the epidermal cells and some fibroblasts. Bek was mainly located in the cell membrane and cytoplasm of epidermal cells while flg protein was principally located in the epidermal cells, endothelial cells and some fibroblasts.Conclusions: The endogenous bFGF and their receptors might be involved in the cutaneous development at fetal stage. The differently expressing levels of bFGF and flg during gestation may be related to scarless or scarforming repair during gestation.

  13. Extracellular interactome of the FGF receptor-ligand system: complexities and the relative simplicity of the worm.

    Science.gov (United States)

    Polanska, Urszula M; Fernig, David G; Kinnunen, Tarja

    2009-02-01

    Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate a multitude of biological functions in embryonic development and in adult. A major question is how does one family of growth factors and their receptors control such a variety of functions? Classically, specificity was thought to be imparted by alternative splicing of the FGFRs, resulting in isoforms that bind specifically to a subset of the FGFs, and by different saccharide sequences in the heparan sulfate proteoglycan (HSPG) co-receptor. A growing number of noncanonical co-receptors such as integrins and neural cell adhesion molecule (NCAM) are now recognized as imparting additional complexity to classic FGFR signaling. This review will discuss the noncanonical FGFR ligands and speculate on the possibility that they provide additional and alternative means to determining the functional specificity of FGFR signaling. We will also discuss how invertebrate models such as C. elegans may advance our understanding of noncanonical FGFR signaling.

  14. Lacrimal gland development and Fgf10-Fgfr2b signaling are controlled by 2-O- and 6-O-sulfated heparan sulfate

    NARCIS (Netherlands)

    Qu, X.; Carbe, C.; Tao, C.; Powers, A.; Lawrence, R.; Kuppevelt, A.H.M.S.M. van; Cardoso, W.V.; Grobe, K.; Esko, J.D.; Zhang, X.

    2011-01-01

    Heparan sulfate, an extensively sulfated glycosaminoglycan abundant on cell surface proteoglycans, regulates intercellular signaling through its binding to various growth factors and receptors. In the lacrimal gland, branching morphogenesis depends on the interaction of heparan sulfate with Fgf10-Fg

  15. Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4.

    Science.gov (United States)

    Gattineni, Jyothsna; Alphonse, Priyatharshini; Zhang, Qiuyu; Mathews, Nisha; Bates, Carlton M; Baum, Michel

    2014-02-01

    Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that acts on the proximal tubule to decrease phosphate reabsorption and serum levels of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂ Vitamin D₃]. Abnormal FGF23 metabolism has been implicated in several debilitating hypophosphatemic and hyperphosphatemic disorders. The renal receptors responsible for the phosphaturic actions of FGF23 have not been elucidated. There are four fibroblast growth factor receptors (FGFR); 1-4 with "b" and "c" isoforms for receptors 1, 2, and 3. FGFR1, 3, and 4 are expressed in the mouse proximal tubule, and deletion of any one receptor did not affect serum phosphate levels, suggesting that more than one receptor is involved in mediating the phosphaturic actions of FGF23. To determine the receptors responsible for the phosphaturic actions of FGF23, we studied Fgfr1 (kidney conditional) and Fgfr4 (global) double mutant mice (Fgfr1⁻/⁻/Fgfr4⁻/⁻). Fgfr1⁻/⁻/Fgfr4⁻/⁻ mice have higher FGF23 levels than their wild-type counterparts (108.1 ± 7.3 vs. 4,953.6 ± 675.0 pg/ml; P Fgfr4⁻/⁻ mice have elevated serum phosphorus levels, increased brush-border membrane vesicle (BBMV) phosphate transport, and increased Na-P(i) cotransporter 2c (NaPi-2c) protein expression compared with wild-type mice. These data are consistent with FGFR1 and FGFR4 being the critical receptors for the phosphaturic actions of FGF23.

  16. FGFR3 and FGFR4 do not mediate renal effects of FGF23.

    Science.gov (United States)

    Liu, Shiguang; Vierthaler, Luke; Tang, Wen; Zhou, Jianping; Quarles, L Darryl

    2008-12-01

    Fibroblast growth factor 23 (FGF23) is a phosphaturic factor that suppresses both sodium-dependent phosphate transport and production of 1,25-dihydroxyvitamin D [1,25(OH)(2)D] in the proximal tubule. In vitro studies suggest that FGFR3 is the physiologically relevant receptor for FGF23 in the kidney, but this has not been established in vivo. Here, immunohistochemical analysis of the mouse kidney revealed that the proximal tubule expresses FGF receptor 3 (FGFR3) but not FGFR1, FGFR2, or FGFR4. Compared with wild-type mice, Hyp mice, which have elevated circulating levels of FGF23, exhibited low levels of serum phosphate and 1,25(OH)(2)D, reduced expression of the sodium-dependent phosphate transporter NPT2a in the proximal tubules, and low bone mineral density as a result of osteomalacia. In contrast, neither the serum phosphate nor 1,25(OH)(2)D levels were altered in FGFR3-null mice. For examination of the role of FGFR3 in mediating the effects of FGF23, Hyp mice were crossed with FGFR3-null mice; interestingly, this failed to correct the aforementioned metabolic abnormalities of Hyp mice. Ablation of FGFR4 also failed to correct hypophosphatemia in Hyp mice. Because the ablation of neither FGFR3 nor FGFR4 inhibited the renal effects of excess FGF23, the kidney localization of FGFR1 was investigated. FGFR1 co-localized with Klotho, the co-factor required for FGF23-dependent FGFR activation, in the distal tubule. In summary, neither FGFR3 nor FGFR4 is the principal mediator of FGF23 effects in the proximal tubule, and co-localization of FGFR1 and Klotho suggests that the distal tubule may be an effector site of FGF23.

  17. MiR-577 inhibits pancreatic β-cell function and survival by targeting fibroblast growth factor 21 (FGF-21) in pediatric diabetes.

    Science.gov (United States)

    Chen, X Y; Li, G M; Dong, Q; Peng, H

    2015-12-01

    Pancreatic β-cell dysfunction is a central component of the pathogenesis of pediatric diabetes. MicroRNA (miRNA) have become one of the most encouraging and fruitful fields in biological research, and have been implicated as new players in the pathogenesis of diabetes and diabetes-associated complications. The role of miRNA in diabetes begins with the development of pancreatic islets. Fibroblast growth factor (FGF)-21 enhances glucose uptake in adipocytes, protecting transgenic animals from diet-induced obesity when overexpressed, and lowers blood glucose and triglyceride levels in diabetic animals (when administered); therefore, it is a good way to treat diabetes. However, the mechanism of miRNA in regulation of FGF21 is not known. In this study, FGF-21 was predicted to be the target of miR-577. Therefore, we investigated the effects of miR-577 on β-cell function and survival by targeting FGF-21. We demonstrated that, although FGF-21 does not acutely stimulate insulin secretion in isolated islets from normal rats, it increases insulin secretion and insulin content in diabetic islets and protects β-cells from apoptosis via the activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways.

  18. FGF signaling pathway in the developing chick lung: expression and inhibition studies.

    Directory of Open Access Journals (Sweden)

    Rute S Moura

    Full Text Available BACKGROUND: Fibroblast growth factors (FGF are essential key players during embryonic development. Through their specific cognate receptors (FGFR they activate intracellular cascades, finely regulated by modulators such as Sprouty. Several FGF ligands (FGF1, 2, 7, 9, 10 and 18 signaling through the four known FGFRs, have been implicated in lung morphogenesis. Although much is known about mammalian lung, so far, the avian model has not been explored for lung studies. METHODOLOGY/PRINCIPAL FINDINGS: In this study we provide the first description of fgf10, fgfr1-4 and spry2 expression patterns in early stages of chick lung development by in situ hybridization and observe that they are expressed similarly to their mammalian counterparts. Furthermore, aiming to determine a role for FGF signaling in chick lung development, in vitro FGFR inhibition studies were performed. Lung explants treated with an FGF receptor antagonist (SU5402 presented an impairment of secondary branch formation after 48 h of culture; moreover, abnormal lung growth with a cystic appearance of secondary bronchi and reduction of the mesenchymal tissue was observed. Branching and morphometric analysis of lung explants confirmed that FGFR inhibition impaired branching morphogenesis and induced a significant reduction of the mesenchyme. CONCLUSIONS/SIGNIFICANCE: This work demonstrates that FGFRs are essential for the epithelial-mesenchymal interactions that determine epithelial branching and mesenchymal growth and validate the avian embryo as a good model for pulmonary studies, namely to explore the FGF pathway as a therapeutic target.

  19. Identification of fibroblast growth factor receptor 3 (FGFR3 as a protein receptor for botulinum neurotoxin serotype A (BoNT/A.

    Directory of Open Access Journals (Sweden)

    Birgitte P S Jacky

    Full Text Available Botulinum neurotoxin serotype A (BoNT/A causes transient muscle paralysis by entering motor nerve terminals (MNTs where it cleaves the SNARE protein Synaptosomal-associated protein 25 (SNAP25206 to yield SNAP25197. Cleavage of SNAP25 results in blockage of synaptic vesicle fusion and inhibition of the release of acetylcholine. The specific uptake of BoNT/A into pre-synaptic nerve terminals is a tightly controlled multistep process, involving a combination of high and low affinity receptors. Interestingly, the C-terminal binding domain region of BoNT/A, HC/A, is homologous to fibroblast growth factors (FGFs, making it a possible ligand for Fibroblast Growth Factor Receptors (FGFRs. Here we present data supporting the identification of Fibroblast Growth Factor Receptor 3 (FGFR3 as a high affinity receptor for BoNT/A in neuronal cells. HC/A binds with high affinity to the two extra-cellular loops of FGFR3 and acts similar to an agonist ligand for FGFR3, resulting in phosphorylation of the receptor. Native ligands for FGFR3; FGF1, FGF2, and FGF9 compete for binding to FGFR3 and block BoNT/A cellular uptake. These findings show that FGFR3 plays a pivotal role in the specific uptake of BoNT/A across the cell membrane being part of a larger receptor complex involving ganglioside- and protein-protein interactions.

  20. Identification of fibroblast growth factor receptor 3 (FGFR3 as a protein receptor for botulinum neurotoxin serotype A (BoNT/A.

    Directory of Open Access Journals (Sweden)

    Birgitte P S Jacky

    Full Text Available Botulinum neurotoxin serotype A (BoNT/A causes transient muscle paralysis by entering motor nerve terminals (MNTs where it cleaves the SNARE protein Synaptosomal-associated protein 25 (SNAP25206 to yield SNAP25197. Cleavage of SNAP25 results in blockage of synaptic vesicle fusion and inhibition of the release of acetylcholine. The specific uptake of BoNT/A into pre-synaptic nerve terminals is a tightly controlled multistep process, involving a combination of high and low affinity receptors. Interestingly, the C-terminal binding domain region of BoNT/A, HC/A, is homologous to fibroblast growth factors (FGFs, making it a possible ligand for Fibroblast Growth Factor Receptors (FGFRs. Here we present data supporting the identification of Fibroblast Growth Factor Receptor 3 (FGFR3 as a high affinity receptor for BoNT/A in neuronal cells. HC/A binds with high affinity to the two extra-cellular loops of FGFR3 and acts similar to an agonist ligand for FGFR3, resulting in phosphorylation of the receptor. Native ligands for FGFR3; FGF1, FGF2, and FGF9 compete for binding to FGFR3 and block BoNT/A cellular uptake. These findings show that FGFR3 plays a pivotal role in the specific uptake of BoNT/A across the cell membrane being part of a larger receptor complex involving ganglioside- and protein-protein interactions.

  1. Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis

    DEFF Research Database (Denmark)

    Cao, Renhai; Ji, Hong; Feng, Ninghan

    2012-01-01

    Interplay between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis remains poorly understood. Here we show that FGF-2 and VEGF-C, two lymphangiogenic factors, collaboratively promote angiogenesis and lymphangiogenesis in the tumor microenvironment, leading...... to widespread pulmonary and lymph-node metastases. Coimplantation of dual factors in the mouse cornea resulted in additive angiogenesis and lymphangiogenesis. At the molecular level, we showed that FGFR-1 expressed in lymphatic endothelial cells is a crucial receptor that mediates the FGF-2-induced...... lymphangiogenesis. Intriguingly, the VEGFR-3-mediated signaling was required for the lymphatic tip cell formation in both FGF-2- and VEGF-C-induced lymphangiogenesis. Consequently, a VEGFR-3-specific neutralizing antibody markedly inhibited FGF-2-induced lymphangiogenesis. Thus, the VEGFR-3-induced lymphatic...

  2. FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase - FGFR4 complex

    OpenAIRE

    Sugiyama, N.; Varjosalo, M.; Meller, P.; Lohi, J; Chan, K.M.; Zhou, Z.; Alitalo, K; Taipale, J; Keski-Oja, J.; Lehti, K

    2010-01-01

    Tumor cells use membrane type 1 matrix metalloproteinase (MT1-MMP) for invasion and metastasis. However, the signaling mechanisms that underlie MT1-MMP regulation in cancer have remained unclear. Using a systematic gain-of-function kinome screen for MT1-MMP activity, we have here identified kinases that significantly enhance MT1-MMP activity in tumor cells. In particular, we discovered an MT1-MMP/FGF receptor-4 (FGFR4) membrane complex that either stimulates or suppresses MT1-MMP and FGFR4 ac...

  3. EXPRESSION OF BASIC FIBROBLAST GROWTH FACTOR,TRANSFORMING GROWTH FACTOR β1 AND THEIR RECEPTORS IN OSTEOSARCOMA AND ITS RELATIONSHIP TO ANGIOGENESIS

    Institute of Scientific and Technical Information of China (English)

    WANG Dong; XIAO Hualiang; LI Zengpeng; CHEN Li

    1999-01-01

    Objective: To investigate the expression of angiogenic factors, basic fibroblast growth factor (bFGF)and transforming growth factor (TGF)-β1 in osteosarcoma, its association with neovascularization and prognosis. Methods: The expression of bFGF, TGFβ1 and their receptors, as well as intratumoral microvessel count (MVD) were studied in 80osteosarcomas by immunohistochemical staining and morphometry. The relationship between the angiogenic factors expression and prognosis was evaluated by a multivariate analysis using Cox proportion hazard model. Results: Among 80 cases of osteosarcoma, 46cases were positive for bFGF/bFGFr (57.5%), and 31cases for TGF-β1/TGF-β (RI)(38.8%) respectively. The MVD and bFGF, TGF-β1 were important indicators to predict the prognosis of patients with osteosarcoma by the Cox proportion hazard model analysis. Conclusion:The angiogenic factors bFGF and TGF-β1 are involved in the angiogenesis of osteosarcoma, and the angiogenesis influences the prognosis. Also they may be useful in the evaluation of the prognosis of patients with osteosarcoma.

  4. Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kook Hwan [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Jeong, Yeon Taek [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Kim, Seong Hun [Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Jung, Hye Seung; Park, Kyong Soo [Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-744 (Korea, Republic of); Lee, Hae-Youn [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Lee, Myung-Shik, E-mail: mslee0923@skku.edu [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of)

    2013-10-11

    Highlights: •Metformin induces FGF21 expression in an AMPK independent manner. •Metformin enhances FGF21 expression by inhibiting mitochondrial complex I activity. •The PERK-eIF2α-ATF4 axis is required for metformin-induced FGF21 expression. •Metformin activates the ATF4-FGF21 axis in the liver of mouse. •Metformin increases serum FGF21 level in diabetic human subjects. -- Abstract: Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-obesity and anti-diabetes effects. Because metformin is widely used as a glucose-lowering agent in patients with type 2 diabetes (T2D), we investigated whether metformin modulates FGF21 expression in cell lines, and in mice or human subjects. We found that metformin increased the expression and release of FGF21 in a diverse set of cell types, including rat hepatoma FaO, primary mouse hepatocytes, and mouse embryonic fibroblasts (MEFs). Intriguingly, AMP-activated protein kinase (AMPK) was dispensable for the induction of FGF21 by metformin. Mammalian target of rapamycin complex 1 (mTORC1) and peroxisome proliferator-activated receptor α (PPARα), which are additional targets of metformin, were not involved in metformin-induced FGF21 expression. Importantly, inhibition of mitochondrial complex I activity by metformin resulted in FGF21 induction through PKR-like ER kinase (PERK)-eukaryotic translation factor 2α (eIF2α)-activating transcription factor 4 (ATF4). We showed that metformin activated ATF4 and increased FGF21 expression in the livers of mice, which led to increased serum levels of FGF21. We also found that serum FGF21 level was increased in human subjects with T2D after metformin therapy for 6 months. In conclusion, our results indicate that metformin induced expression of FGF21 through an ATF4-dependent mechanism by inhibiting mitochondrial respiration independently of AMPK. Therefore, FGF21 induction by metformin might explain a portion of the beneficial metabolic effects of metformin.

  5. Zebrafish fgf10b has a complementary function to fgf10a in liver and pancreas development.

    Science.gov (United States)

    Yan, Chuan; Zheng, Weiling; Gong, Zhiyuan

    2015-04-01

    Fgf10 is a critical growth factor in mammals for development of endodermal organs such as the liver, pancreas, lung, and gut. Due to whole genome duplication, the zebrafish has two fgf10 orthologs, fgf10a and fgf10b. While fgf10a has a role in development of the esophagus and swimbladder, we found in the present study that fgf10b had a complementary expression pattern in the liver, pancreas, and gut. Morpholino knockdown of Fgf10b further confirmed its essential role in the normal development of liver and pancreas. Thus, our data provide another example of functional partition of two duplicated othologous genes during evolution.

  6. Blocking the FGF/FGFR system as a "two-compartment" antiangiogenic/antitumor approach in cancer therapy.

    Science.gov (United States)

    Giacomini, Arianna; Chiodelli, Paola; Matarazzo, Sara; Rusnati, Marco; Presta, Marco; Ronca, Roberto

    2016-05-01

    Fibroblast growth factors (FGFs) are a family of pleiotropic factors produced by stromal and parenchymal tumor cells. Even though FGFs have been firstly characterized as angiogenic factors, they exert autocrine and paracrine functions not only on endothelial cells but also on tumor cells and other stromal components. Thus, the FGF/FGF receptor (FGFR) pathway may represent a key player in tumor growth by regulating the complex cross-talk between stromal and tumor compartments. The ligand dependent or independent activation of the FGF/FGFR system by gene upregulation, oncogenic mutation or amplification occurs in a variety of human tumors and is implicated in various key steps of tumor growth and progression. In addition, FGF/FGFR activation has been described as a mechanism of tumor escape in response to antiangiogenic/anti-VEGF therapies. Experimental and clinical evidences provide a compelling biologic rationale for the development of anti-FGF/FGFR targeting agents in cancer therapy. However, the development of drugs specifically targeting the FGF/FGFR pathway proved to be difficult, also due to the high redundancy and pleiotropic effects of FGF and FGFR family members. On the other hand, the possibility to develop "two-compartment" targeting agents endowed with both antiangiogenic and antitumor activities remains promising. Here we will review the preclinical and clinical approaches and potential therapeutics currently available to block the FGF/FGFR system in human cancer.

  7. The effect of aloe vera on the expression of wound healing factors (TGFβ1 and bFGF) in mouse embryonic fibroblast cell: In vitro study.

    Science.gov (United States)

    Hormozi, Maryam; Assaei, Raheleh; Boroujeni, Mandana Beigi

    2017-04-01

    Aloe vera (A.v) have been used traditionally for topical treatment of wounds and burns in different countries for centuries, but the mechanism of this effect is not well understood. Various growth factors are implicated in the process of wound healing. Among the different growth factors involved in the process, TGFβ1 and bFGF are the most importantly expressed in fibroblast cells. The aim of this study was to evaluate the effect of A.v on the expression of angiogenesis growth factors in mouse embryonic fibroblast cells. We exposed mouse embryonic fibroblast cells to different concentrations of A.v (50, 100 and 150μg/ml) at two different time of 12 and 24h. Fibroblast cell without A.v treatment serves as the control. The expression of TGFβ1and bFGF was measured by real time-polymerase chain reaction (real-time-PCR) and enzyme-linked immunosorbent assay (ELISA) at the level of gene and protein. We observed that A.v gel at first up-regulated the expression of TGFβ1 and bFGF, but, these genes were later repressed after a particular time. Our results demonstrated that A.v was dose-dependent and time-dependent on the expression of bFGF and TGFβ1 in fibroblast cell in vitro. This mechanism can be employed in the prospective treatment of physical lesion. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. Fibroblast Growth Factor Receptor-2 Contributes to the Basic Fibroblast Growth Factor-Induced Neuronal Differentiation in Canine Bone Marrow Stromal Cells via Phosphoinositide 3-Kinase/Akt Signaling Pathway.

    Directory of Open Access Journals (Sweden)

    Rei Nakano

    Full Text Available Bone marrow stromal cells (BMSCs are considered as candidates for regenerative therapy and a useful model for studying neuronal differentiation. The role of basic fibroblast growth factor (bFGF in neuronal differentiation has been previously studied; however, the signaling pathway involved in this process remains poorly understood. In this study, we investigated the signaling pathway in the bFGF-induced neuronal differentiation of canine BMSCs. bFGF induced the mRNA expression of the neuron marker, microtubule associated protein-2 (MAP2 and the neuron-like morphological change in canine BMSCs. In the presence of inhibitors of fibroblast growth factor receptors (FGFR, phosphatidylinositol 3-kinase (PI3K and Akt, i.e., SU5402, LY294002, and MK2206, respectively, bFGF failed to induce the MAP2 mRNA expression and the neuron-like morphological change. bFGF induced Akt phosphorylation, but it was attenuated by the FGFR inhibitor SU5402 and the PI3K inhibitor LY294002. In canine BMSCs, expression of FGFR-1 and FGFR-2 was confirmed, but only FGFR-2 activation was detected by cross-linking and immunoprecipitation analysis. Small interfering RNA-mediated knockdown of FGFR-2 in canine BMSCs resulted in the attenuation of bFGF-induced Akt phosphorylation. These results suggest that the FGFR-2/PI3K/Akt signaling pathway is involved in the bFGF-induced neuronal differentiation of canine BMSCs.

  9. ShcA regulates neurite outgrowth stimulated by neural cell adhesion molecule but not by fibroblast growth factor 2: evidence for a distinct fibroblast growth factor receptor response to neural cell adhesion molecule activation

    DEFF Research Database (Denmark)

    Hinsby, Anders M; Lundfald, Line; Ditlevsen, Dorte K;

    2004-01-01

    by two principal routes of signaling: NCAM/Fyn and NCAM/fibroblast growth factor receptor (FGFR), respectively. Previous studies have shown that activation of mitogen-activated protein kinases is a pivotal point of convergence in NCAM signaling, but the mechanisms behind this activation are not clear....... Here, we investigated the involvement of adaptor proteins in NCAM and fibroblast growth factor 2 (FGF2)-mediated neurite outgrowth in the PC12-E2 cell line. We found that both FGFR substrate-2 and Grb2 play important roles in NCAM as well as in FGF2-stimulated events. In contrast, the docking protein...... ShcA was pivotal to neurite outgrowth induced by NCAM, but not by FGF2, in PC12 cells. Moreover, in rat cerebellar granule neurons, phosphorylation of ShcA was stimulated by an NCAM mimicking peptide, but not by FGF2. This activation was blocked by inhibitors of both FGFR and Fyn, indicating that NCAM...

  10. Effect of Fibroblast Growth Factor 2 (FGF2 and Insulin Transferrin Selenium (ITS on In Vitro Maturation, Fertilization and Embryo Development in Sheep

    Directory of Open Access Journals (Sweden)

    Sukanta Mondal

    2015-08-01

    Full Text Available The present study evaluated the effect of fibroblast growth factor 2 (FGF2 and insulin-transferrin-selenium (ITS to the in vitro maturation and embryo culture media on ovine oocyte maturation, cleavage and embryo development. Oocytes having more than five layers of unexpanded cumulus cells and granular homogenous ooplasm were cultured into 50 μL droplets of eight different culture systems: (i TCM-199 (Tissue Culture Medium-199; (ii TCM-199+10 ng/mL FGF2; (iii TCM-199+20 ng/mL FGF2; (iv TCM-199+30 ng/mL FGF2; (v TCM-199+10 ng/mL ITS; (vi TCM-199+20 ng/mL ITS; (vii TCM-199+30 ng/mL ITS and (viii TCM-199+20 ng/mL ITS+20 ng/mL FGF2 in a CO2 incubator at 38.50C for 24 h. All the oocyte culture media were supplemented with 10% FBS, FSH (10 μg/mL and gentamicin (50 µg/mL. The maturation rate was assessed based on the degree of expansion of cumulus cells and identifying first polar body extrusion into perivitelline space. The matured oocytes were inseminated with 1 to 2 million spermatozoa/mL in Brackett and Oliphant medium and the cleavage rate was checked after 42-48 h post insemination and further cultured for 6-7 days. Maturation and cleavage rates were significantly higher (P<0.05 in the oocytes cultured in TCM-199 +10% FBS+FSH (10 μg/mL supplemented with both 20 ng/mL ITS and 20 ng/mL FGF2 as compared to the control. It was concluded that the supplementation of ITS and FGF2 in maturation medium was beneficial for improving maturation and cleavage rates of sheep oocytes. The addition of ITS and FGF2 in embryo culture medium did not improve the development of sheep embryos.

  11. 血清FGF-21标记物在线粒体疾病的应用价值及临床意义%Diagnostic Value and Clinical Significance of Fibroblast Growth Factor 2 1 in Mitochondrial Disease

    Institute of Scientific and Technical Information of China (English)

    谷伟; 杨继雪; 崔玉环; 赵宝民

    2014-01-01

    Objective To investigate the value of serum fibroblast growth factor21(FGF-21)as an early diagnostic marker for mitochondrial disease.Methods Serum FGF-2 1 ,lactate and crea-tine kinase levels and lactate to pyruvate(L/P)ratio were determined in 16 patients with mito-chondrial disease,31 patients without mitochondrial disease and 41 normal subjects between Sep-tember 2009 and October 2013 to confirm FGF-21 as an effective and reliable biomarker for mito-chondrial disease.The sensitivity,odds ratio(OR)and reliability of FGF-21 for diagnosing mito-chondrial disease were analyzed.Results Compared with patients without mitochondrial disease or normal subj ects,serum FGF-2 1 concentrations significantly increased in patients with mito-chondrial disease.Furthermore,FGF-2 1 showed a markedly higher diagnostic OR than other bio-markers(45.7,P<0.000 1).The sensitivity and receiver operating characteristic curve analysis showed that serum FGF-2 1 was the best predictor of mitochondrial disease.After control for po-tential confounders,multivariate logistic regression analysis showed that only serum FGF-2 1 could predict and assess mitochondrial disease.Conclusion Serum FGF-2 1 is the most sensitive marker for diagnosing mitochondrial disease.Compared with lactate,creatine kinase and L/P rati-o,serum FGF-2 1 is the best predictor of mitochondrial disease.%目的:探讨血清 FGF-21标记物对线粒体疾病早期诊断价值。方法收集2009年9月至2013年10月间16例线粒体疾病患者,31例非线粒体疾病患者(疾病对照组),41例正常成人(正常对照组),比较血清 FGF-21、乳酸盐、肌酸激酶及乳酸盐丙酮酸盐,明确血清 FGF-21是诊断线粒体疾病有效及可靠性的生物标记物,通过统计学分析血清 FGF-21标记物诊断线粒体疾病的敏感性、优势比及可靠性。结果在线粒体疾病血清 FGF-21浓度明显增高,所有实验组血清 FGF-21明显表达不同,与其他生

  12. Fibroblast Growth Factor-10 (FGF-10) Mobilizes Lung-resident Mesenchymal Stem Cells and Protects Against Acute Lung Injury.

    Science.gov (United States)

    Tong, Lin; Zhou, Jian; Rong, Linyi; Seeley, Eric J; Pan, Jue; Zhu, Xiaodan; Liu, Jie; Wang, Qin; Tang, Xinjun; Qu, Jieming; Bai, Chunxue; Song, Yuanlin

    2016-02-12

    FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs.

  13. Advanced Research of Fibroblast Growth Factor Receptor 
in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Dan PU

    2013-11-01

    Full Text Available Lung cancer is severely threatening human health. In recent years, the treatment for lung adenocarcinoma has made a great progress, targeted therapy has been widely applied in clinic, and benefits amount of patients. However, in squamous cell lung cancer, the incidence of epidermal growth factor receptor (EGFR gene mutant and ALK fusion gene are low,and targeted therapy like Tarceva and crizotinib, can hardly work. Since the fibroblast growth factors (fibroblast growth factor, FGF pathway is considered to be related to tumor cell proliferation, metastasis and angiogenesis, more and more researches proved the amplification of fibroblast growth factor receptor (FGFR in squamous cell lung cancer. Experiments in vivo and in vitro found that blocking FGF pathway could reduce the proliferation of tumor cells and inhibit metastasis. The FGF pathway might be a new target for treatment of squamous cell lung cancer. This article reviews the effect of FGFR in tumorigenesis,as well as the prospect as a therapeutic target in non-small cell lung cancer.

  14. Chlamydia trachomatis co-opts the FGF2 signaling pathway to enhance infection.

    Directory of Open Access Journals (Sweden)

    Jung Hwa Kim

    2011-10-01

    Full Text Available The molecular details of Chlamydia trachomatis binding, entry, and spread are incompletely understood, but heparan sulfate proteoglycans (HSPGs play a role in the initial binding steps. As cell surface HSPGs facilitate the interactions of many growth factors with their receptors, we investigated the role of HSPG-dependent growth factors in C. trachomatis infection. Here, we report a novel finding that Fibroblast Growth Factor 2 (FGF2 is necessary and sufficient to enhance C. trachomatis binding to host cells in an HSPG-dependent manner. FGF2 binds directly to elementary bodies (EBs where it may function as a bridging molecule to facilitate interactions of EBs with the FGF receptor (FGFR on the cell surface. Upon EB binding, FGFR is activated locally and contributes to bacterial uptake into non-phagocytic cells. We further show that C. trachomatis infection stimulates fgf2 transcription and enhances production and release of FGF2 through a pathway that requires bacterial protein synthesis and activation of the Erk1/2 signaling pathway but that is independent of FGFR activation. Intracellular replication of the bacteria results in host proteosome-mediated degradation of the high molecular weight (HMW isoforms of FGF2 and increased amounts of the low molecular weight (LMW isoforms, which are released upon host cell death. Finally, we demonstrate the in vivo relevance of these findings by showing that conditioned medium from C. trachomatis infected cells is enriched for LMW FGF2, accounting for its ability to enhance C. trachomatis infectivity in additional rounds of infection. Together, these results demonstrate that C. trachomatis utilizes multiple mechanisms to co-opt the host cell FGF2 pathway to enhance bacterial infection and spread.

  15. Molecular basis for the Kallmann syndrome-linked fibroblast growth factor receptor mutation

    Energy Technology Data Exchange (ETDEWEB)

    Thurman, Ryan D.; Kathir, Karuppanan Muthusamy; Rajalingam, Dakshinamurthy [Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701 (United States); Kumar, Thallapuranam K. Suresh, E-mail: sthalla@uark.edu [Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701 (United States)

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer The structural basis of the Kallmann syndrome is elucidated. Black-Right-Pointing-Pointer Kallmann syndrome mutation (A168S) induces a subtle conformational change(s). Black-Right-Pointing-Pointer Structural interactions mediated by beta-sheet G are most perturbed. Black-Right-Pointing-Pointer Ligand (FGF)-receptor interaction(s) is completely abolished by Kallmann mutation. Black-Right-Pointing-Pointer Kallmann mutation directly affects the FGF signaling process. -- Abstract: Kallmann syndrome (KS) is a developmental disease that expresses in patients as hypogonadotropic hypogonadism and anosmia. KS is commonly associated with mutations in the extracellular D2 domain of the fibroblast growth factor receptor (FGFR). In this study, for the first time, the molecular basis for the FGFR associated KS mutation (A168S) is elucidated using a variety of biophysical experiments, including multidimensional NMR spectroscopy. Secondary and tertiary structural analysis using far UV circular dichroism, fluorescence and limited trypsin digestion assays suggest that the KS mutation induces subtle tertiary structure change in the D2 domain of FGFR. Results of isothermal titration calorimetry experiments show the KS mutation causes a 10-fold decrease in heparin binding affinity and also a complete loss in ligand (FGF-1) binding. {sup 1}H-{sup 15}N chemical perturbation data suggest that complete loss in the ligand (FGF) binding affinity is triggered by a subtle conformational change that disrupts crucial structural interactions in both the heparin and the FGF binding sites in the D2 domain of FGFR. The novel findings reported in this study are expected to provide valuable clues toward a complete understanding of the other genetic diseases linked to mutations in the FGFR.

  16. Identification of neural cell adhesion molecule L1-derived neuritogenic ligands of the fibroblast growth factor receptor

    DEFF Research Database (Denmark)

    Kulahin, Nikolaj; Li, Shizhong; Kiselyov, Vladislav

    2009-01-01

    The neural cell adhesion molecule L1 plays an important role in axon growth, neuronal survival, and synaptic plasticity. We recently demonstrated that the L1 fibronectin type III (FN3) modules interact directly with the fibroblast growth factor (FGF) receptor (FGFR). Sequence alignment of individ......The neural cell adhesion molecule L1 plays an important role in axon growth, neuronal survival, and synaptic plasticity. We recently demonstrated that the L1 fibronectin type III (FN3) modules interact directly with the fibroblast growth factor (FGF) receptor (FGFR). Sequence alignment...... of individual L1 FN3 modules with various FGFs suggested that four sequence motifs located in the third and fifth L1 FN3 modules might be involved in interactions with FGFR. The present study found that corresponding synthetic peptides, termed elcamins 1, 2, 3, and 4, bind and activate FGFR in the absence...... of FGF1. Conversely, in the presence of FGF1, elcamins inhibited receptor phosphorylation, indicating that the peptides are FGFR partial agonists. Elcamins 1, 3, and 4 dose dependently induced neurite outgrowth in cultured primary cerebellar neurons. The neuritogenic effect of elcamins was dependent...

  17. Fibroblast growth factors 7 and 10 are involved in ameloblastoma proliferation via the mitogen-activated protein kinase pathway.

    Science.gov (United States)

    Nakao, Yu; Mitsuyasu, Takeshi; Kawano, Shintaro; Nakamura, Norifumi; Kanda, Shiori; Nakamura, Seiji

    2013-11-01

    Ameloblastoma is an epithelial benign tumor of the odontogenic apparatus and its growth mechanisms are not well understood. Fibroblast growth factor (FGF) 3, FGF7 and FGF10, which are expressed by the neural crest-derived ectomesenchymal cells, induce the proliferation of odontogenic epithelial cells during tooth development. Therefore, we examined the expression and function of these FGFs in ameloblastoma. We examined 32 cases of ameloblastoma as well as AM-1 cells (an ameloblastoma cell line) and studied the expression of FGF3, FGF7, FGF10 and their specific receptors, namely, FGF receptor (FGFR) 1 and FGFR2. Proliferation, mitogen-activated protein kinase (MAPK) signaling and PI3K signaling were examined in AM-1 cells after the addition of FGF7, FGF10 and these neutralizing antibodies. The expression of FGF7, FGF10, FGFR1 and FGFR2 was detected in ameloblastoma cells and AM-1 cells, while that of FGF3 was not. FGF7 and FGF10 stimulated AM-1 cell proliferation and phosphorylation of p44/42 MAPK. However, Akt was not phosphorylated. Blocking the p44/42 MAPK pathway by using a specific mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor (U0126) completely neutralized the effects of FGF7 and FGF10 on AM-1 cell proliferation. However, Anti FGF7 and FGF10 neutralizing antibodies did not decrease cell proliferation and MAPK phosphorylation of AM-1 cells. These results suggested that FGF7 and FGF10 are involved in the proliferation of ameloblastoma cells through the MAPK pathway.

  18. Renal expression of FGF23 in progressive renal disease of diabetes and the effect of ACE inhibitor.

    Directory of Open Access Journals (Sweden)

    Cristina Zanchi

    Full Text Available Fibroblast growth factor 23 (FGF23 is a phosphaturic hormone mainly produced by bone that acts in the kidney through FGF receptors and Klotho. Here we investigated whether the kidney was an additional source of FGF23 during renal disease using a model of type 2 diabetic nephropathy. Renal expression of FGF23 and Klotho was assessed in Zucker diabetic fatty (ZDF and control lean rats at 2, 4, 6, 8 months of age. To evaluate whether the renoprotective effect of angiotensin converting enzyme (ACE inhibitor in this model was associated with changes in FGF23 and Klotho, ZDF rats received ramipril from 4, when proteinuric, to 8 months of age. FGF23 mRNA was not detectable in the kidney of lean rats, nor of ZDF rats at 2 months of age. FGF23 became measurable in the kidney of diabetic rats at 4 months and significantly increased thereafter. FGF23 protein localized in proximal and distal tubules. Renal Klotho mRNA and protein decreased during time in ZDF rats. As renal disease progressed, serum phosphate levels increased in parallel with decline of fractional phosphorus excretion. Ramipril limited proteinuria and renal injury, attenuated renal FGF23 upregulation and ameliorated Klotho expression. Ramipril normalized serum phosphate levels and tended to increase fractional phosphorus excretion. These data indicate that during progressive renal disease the kidney is a site of FGF23 production which is limited by ACE inhibition. Interfering pharmacologically with the delicate balance of FGF23 and phosphorus in diabetes may have implications in clinics.

  19. Stem cells with FGF4-bFGF fused gene enhances the expression of bFGF and improves myocardial repair in rats

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiang-Qi; Chen, Liang-Long, E-mail: xhzlyx@126.com; Fan, Lin; Fang, Jun; Chen, Zhao-Yang; Li, Wei-Wei

    2014-04-25

    Highlights: • BFGF exists only in the cytoplasm of live cells. • BFGF cannot be secreted into the extracellular space to promote cell growth. • We combine the secretion-promoting signal peptide of FGF4. • We successfully modified BMSCs with the fused genes of FGF4-bFGF. • We promoted the therapeutic effects of transplanted BMSCs in myocardial infarction. - Abstract: The aim of this study was to investigate whether the modification of bone marrow-derived mesenchymal stem cells (BMSCs) with the fused FGF4 (fibroblast growth factor 4)-bFGF (basic fibroblast growth factor) gene could improve the expression and secretion of BFGF, and increase the efficacies in repairing infarcted myocardium. We used In-Fusion technique to construct recombinant lentiviral vectors containing the individual gene of bFGF, enhanced green fluorescent protein (EGFP), or genes of FGF4-bFGF and EGFP, and then transfected these lentiviruses into rat BMSCs. We conducted an in vitro experiment to compare the secretion of bFGF in BMSCs infected by these lentiviruses and also examined their therapeutic effects in the treatment of myocardial infraction in a rodent study. Sixty rats were tested in the following five conditions: Group-SHAM received only sham operation as controls; Group-AMI received only injection of placebo PBS buffer; Group-BMSC, Group-bFGF and Group-FGF4-bFGF received implantation of BMSCs with empty lentivirus, bFGF lentivirus, and FGF4-bFGF lentivirus, respectively. Our results found out that the transplanted FGF4-bFGF BMSCs had the highest survival rate, and also the highest myocardial expression of bFGF and microvascular density as evidenced by Western blotting and immunohistochemistry, respectively. As compared to other groups, the Group-FGF4-BFGF rats had the lowest myocardial fibrotic fraction, and the highest left ventricular ejection fraction. These results suggest that the modification of BMSCs with the FGF4-bFGF fused gene can not only increase the expression of

  20. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation.

    Science.gov (United States)

    Ghoussaini, Maya; French, Juliet D; Michailidou, Kyriaki; Nord, Silje; Beesley, Jonathan; Canisus, Sander; Hillman, Kristine M; Kaufmann, Susanne; Sivakumaran, Haran; Moradi Marjaneh, Mahdi; Lee, Jason S; Dennis, Joe; Bolla, Manjeet K; Wang, Qin; Dicks, Ed; Milne, Roger L; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Alonso, M Rosario; Pita, Guillermo; Neuhausen, Susan L; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Tessier, Daniel C; Vincent, Daniel; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Wu, Anna H; Van Den Berg, David; Lambrechts, Diether; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J; Hallberg, Emily; Giles, Graham G; Haiman, Christopher A; Le Marchand, Loic; Goldberg, Mark S; Teo, Soo H; Yip, Cheng Har; Borresen-Dale, Anne-Lise; Zheng, Wei; Cai, Qiuyin; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L; Devilee, Peter; Tollenaar, Rob A E M; García-Closas, Montserrat; Figueroa, Jonine; Hall, Per; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J; Koppert, Linetta B; Li, Jingmei; Shu, Xiao-Ou; Zheng, Ying; Cox, Angela; Cross, Simon S; Shah, Mitul; Rhenius, Valerie; Choi, Ji-Yeob; Kang, Daehee; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Luccarini, Craig; Conroy, Don M; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Olswold, Curtis; Slager, Susan; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Schoemaker, Minouk J; Simard, Jacques; Pharoah, Paul D P; Kristensen, Vessela; Chenevix-Trench, Georgia; Easton, Douglas F; Dunning, Alison M; Edwards, Stacey L

    2016-10-06

    Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER(+)) breast cancer (per-g allele OR ER(+) = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10(-30)). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER(-)) breast cancer (lead SNP rs6864776: per-a allele OR ER(-) = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10(-12)), and a single signal 3 SNP (rs200229088: per-t allele OR ER(+) = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10(-05)). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

  1. Mifepristone inhibits MPA-and FGF2-induced mammary tumor growth but not FGF2-induced mammary hyperplasia La mifepristona inhibe el crecimiento de carcinomas mamarios inducidos por MPA o por FGF2 pero no las hiperplasias mamarias inducidas por FGF2

    Directory of Open Access Journals (Sweden)

    Juan P. Cerliani

    2010-12-01

    Full Text Available We have previously demonstrated a crosstalk between fibroblast growth factor 2 (FGF2 and progestins inducing experimental breast cancer growth. The aim of the present study was to compare the effects of FGF2 and of medroxyprogesterone acetate (MPA on the mouse mammary glands and to investigate whether the antiprogestin RU486 was able to reverse the MPA- or FGF2-induced effects on both, mammary gland and tumor growth. We demonstrate that FGF2 administered locally induced an intraductal hyperplasia that was not reverted by RU486, suggesting that FGF2-induced effects are progesterone receptor (PR-independent. However, MPA-induced paraductal hyperplasia was reverted by RU486 and a partial agonistic effect was observed in RU486-treated glands. Using C4-HD tumors which only grow in the presence of MPA, we showed that FGF2 administered intratumorally was able to stimulate tumor growth as MPA. The histology of FGF2-treated tumors showed different degrees of gland differentiation. RU486 inhibited both, MPA or FGF2 induced tumor growth. However, only complete regression was observed in MPA-treated tumors. Our results support the hypothesis that stromal FGF2 activates PR inducing hormone independent tumor growth.Hemos demostrado previamente que la vía de señalización del factor de crecimiento fibroblástico 2 (FGF2 interactúa con la vía de los receptores de progesterona (RP induciendo el crecimiento del cáncer de mama experimental, y hemos postulado que el FGF2 estromal activaría los RP en los tumores hormono independientes. El objetivo de este trabajo es comparar los efectos del FGF2 y del acetato de medroxiprogesterona (MPA en la glándula mamaria de ratón e investigar si el antiprogestágeno RU486 induce la regresión del tumor hormono dependiente C4-HD que crece con MPA o con la administración intratumoral de FGF2. Demostramos que la administración diaria local de FGF2 induce una hiperplasia intraductal mamaria que no es revertida por el

  2. Key role of the kidney in the regulation of fibroblast growth factor 23

    DEFF Research Database (Denmark)

    Mace, Maria L; Gravesen, Eva; Hofman-Bang, Jacob

    2015-01-01

    High circulating levels of fibroblast growth factor 23 (FGF23) have been demonstrated in kidney failure, but mechanisms of this are not well understood. Here we examined the impact of the kidney on the early regulation of intact FGF23 in acute uremia as induced by bilateral or unilateral...... nephrectomy (BNX and UNX, respectively) in the rat. BNX induced a significant increase in plasma intact FGF23 levels from 112 to 267 pg/ml within 15 min, which remained stable thereafter. UNX generated intact FGF23 levels between that seen in BNX and sham-operated rats. The intact to C-terminal FGF23 ratio...... was significantly increased in BNX rats. The rapid rise in FGF23 after BNX was independent of parathyroid hormone or FGF receptor signaling. No evidence of early stimulation of FGF23 gene expression in the bone was found. Furthermore, acute severe hyperphosphatemia or hypercalcemia had no impact on intact FGF23...

  3. Disruption of the suprachiasmatic nucleus in fibroblast growth factor signaling-deficient mice

    OpenAIRE

    Ann Virginia Miller; Scott eKavanaugh; Pei-San eTsai

    2016-01-01

    Fibroblast growth factor (Fgf) 8 is essential for the development of multiple brain regions. Previous studies from our laboratory showed that reduced Fgf8 signaling led to the developmental alterations of neuroendocrine nuclei that originated within the diencephalon, including the paraventricular (PVN) and supraoptic (SON) nuclei. To further understand the role of Fgf8 in the development of other hypothalamic nuclei, we examined if Fgf8 and its cognate receptor, Fgfr1, also impact the integ...

  4. Disruption of the Suprachiasmatic Nucleus in Fibroblast Growth Factor Signaling-Deficient Mice

    OpenAIRE

    Miller, Ann V.; Kavanaugh, Scott I.; Tsai, Pei-San

    2016-01-01

    Fibroblast growth factor (Fgf) 8 is essential for the development of multiple brain regions. Previous studies from our laboratory showed that reduced Fgf8 signaling led to the developmental alterations of neuroendocrine nuclei that originated within the diencephalon, including the paraventricular (PVN) and supraoptic (SON) nuclei. To further understand the role of Fgf8 in the development of other hypothalamic nuclei, we examined if Fgf8 and its cognate receptor, Fgfr1, also impact the integri...

  5. Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy.

    Science.gov (United States)

    Walters, Julian R F

    2014-07-01

    Chronic diarrhoea induced by bile acids is common and the underlying mechanisms are linked to homeostatic regulation of hepatic bile acid synthesis by fibroblast growth factor 19 (FGF19). Increasing evidence, including that from several large case series using SeHCAT (selenium homocholic acid taurine) tests for diagnosis, indicates that bile acid diarrhoea (BAD) accounts for a sizeable proportion of patients who would otherwise be diagnosed with IBS. Studies of other approaches for diagnosis of BAD have shown increased bile acid synthesis, increased faecal levels of primary bile acids, dysbiosis and different urinary volatile organic compounds when compared with healthy controls or with other diseases. The role of the ileal hormone FGF19 in BAD has been strengthened: a prospective clinical study has confirmed low FGF19 levels in BAD, and so a test to measure these levels could be developed for diagnosis. In animal models, FGF19 depletion by antibodies produces severe diarrhoea. Bile acids affect colonic function through farnesoid X receptor (FXR) and TGR5 receptors. As well as these effects in the colon, FXR-dependent stimulation of ileal FGF19 production could be a logical mechanism to provide therapeutic benefit in BAD. Further studies of FGF19 in humans hold promise in providing novel treatments for this cause of chronic diarrhoea.

  6. Numerous isoforms of Fgf8 reflect its multiple roles in the developing brain

    OpenAIRE

    Sunmonu, N. Abimbola; Li, Kairong; Li, James Y.H.

    2011-01-01

    Soluble growth factors play an important role in the coordination and integration of cell proliferation, differentiation, fate determination and morphogenesis during development of multicellular organisms. Fibroblast Growth Factors (FGFs) are a large family of polypeptide growth factors that are present in organisms ranging from nematodes to humans. RNA alternative splicing of FGFs and their receptors further enhances the complexity of this ligand-receptor system. The mouse Fgf8 gene produces...

  7. Identification of a novel aFGF-binding peptide with anti-tumor effect on breast cancer from phage display library

    Energy Technology Data Exchange (ETDEWEB)

    Dai, Xiaoyong; Cai, Cuizan [College of Pharmacy, Jinan University, Guangzhou 510632, Guangdong (China); Xiao, Fei [Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, Guangdong (China); Xiong, Yaoling [College of Pharmacy, Jinan University, Guangzhou 510632, Guangdong (China); Huang, Yadong; Zhang, Qihao [Department of Biopharmaceutical Research and Development Centre, Institute of Biomedicine, Jinan University, Guangzhou 510632, Guangdong (China); Xiang, Qi [College of Pharmacy, Jinan University, Guangzhou 510632, Guangdong (China); Lou, Guofeng [Department of Biopharmaceutical Research and Development Centre, Institute of Biomedicine, Jinan University, Guangzhou 510632, Guangdong (China); Lian, Mengyang [College of Pharmacy, Jinan University, Guangzhou 510632, Guangdong (China); Su, Zhijian, E-mail: tjnuszj@jnu.edu.cn [Department of Biopharmaceutical Research and Development Centre, Institute of Biomedicine, Jinan University, Guangzhou 510632, Guangdong (China); Zheng, Qing, E-mail: tzhengq@jnu.edu.cn [College of Pharmacy, Jinan University, Guangzhou 510632, Guangdong (China)

    2014-03-21

    Highlights: • A specific aFGF-binding peptide AP8 was identified from a phage display library. • AP8 could inhibit aFGF-stimulated cell proliferation in a dose-dependent manner. • AP8 arrested the cell cycle at the G0/G1 phase by suppressing Cyclin D1. • AP8 could block the activation of Erk1/2 and Akt kinase. • AP8 counteracted proliferation and cell cycle via influencing PA2G4 and PCNA. - Abstract: It has been reported that acidic fibroblast growth factor (aFGF) is expressed in breast cancer and via interactions with fibroblast growth factor receptors (FGFRs) to promote the stage and grade of the disease. Thus, aFGF/FGFRs have been considered essential targets in breast cancer therapy. We identified a specific aFGF-binding peptide (AGNWTPI, named AP8) from a phage display heptapeptide library with aFGF after four rounds of biopanning. The peptide AP8 contained two (TP) amino acids identical and showed high homology to the peptides of the 182–188 (GTPNPTL) site of high-affinity aFGF receptor FGFR1. Functional analyses indicated that AP8 specifically competed with the corresponding phage clone A8 for binding to aFGF. In addition, AP8 could inhibit aFGF-stimulated cell proliferation, arrested the cell cycle at the G0/G1 phase by increasing PA2G4 and suppressing Cyclin D1 and PCNA, and blocked the aFGF-induced activation of Erk1/2 and Akt kinase in both breast cancer cells and vascular endothelial cells. Therefore, these results indicate that peptide AP8, acting as an aFGF antagonist, is a promising therapeutic agent for the treatment of breast cancer.

  8. NH2-terminal cleavage of xenopus fibroblast growth factor 3 is necessary for optimal biological activity and receptor binding.

    Science.gov (United States)

    Antoine, M; Daum, M; Köhl, R; Blecken, V; Close, M J; Peters, G; Kiefer, P

    2000-11-01

    Fibroblast growth factor 3 (FGF3) was originally identified as the mouse proto-oncogene Int-2, which is activated by proviral insertion in tumors induced by mouse mammary tumor virus. To facilitate the biological characterization of the ligand, we have analyzed its homologue in Xenopus laevis, XFGF3. Here we confirm that the X. laevis genome contains two distinct FGF3 alleles, neither of which is capable of encoding the NH2-terminally extended forms specified by the mouse and human FGF3 genes. Unlike the mammalian proteins, XFGF3 is efficiently secreted as a Mr 31,000 glycoprotein, gp31, which undergoes proteolytic cleavage to produce an NH2-terminally truncated product, gp27. Processing removes a segment of 18 amino acids immediately distal to the signal peptide that is not present in the mammalian homologues. By inserting an epitope-tag adjacent to the cleavage site, we show that a substantial amount of the gp27 is generated intracellularly, although processing can also occur in the extracellular matrix. Two residues are also removed from the COOH terminus. To compare the biological properties of the different forms, cDNAs were constructed that selectively give rise to the larger, gp31, or smaller, gp27, forms of XFGF3. As judged by their ability to cause morphological transformation of NIH3T3 cells, their mitogenicity on specific cell types, and their affinity for the IIIb and IIIc isoforms of Xenopus FGF receptors, gp27 has a much higher biological activity than gp31. Sequence comparison revealed an intriguing similar cleavage motif immediately downstream of the signal peptide cleavage site in the NH2-terminus of mouse and human FGF3. Analysis of secreted mutant mouse FGF3 confirmed an additional NH2-terminal processing at the corresponding sequence motif. NH2-terminal trimming of Xenopus and mammalian FGF3s may therefore be a prerequisite of optimal biological activity.

  9. Fibroblast Growth Factor Receptor (FGFR): A New Target for Non-small Cell Lung Cancer Therapy.

    Science.gov (United States)

    Biello, Federica; Burrafato, Giovanni; Rijavec, Erika; Genova, Carlo; Barletta, Giulia; Truini, Anna; Coco, Simona; Bello, Maria Giovanna Dal; Alama, Angela; Boccardo, Francesco; Grossi, Francesco

    2016-01-01

    Lung cancer is still the leading cause of cancer related death worldwide. Fibroblast growth factor receptor (FGFR) is a tirosine-kinase receptor that is seen to be amplified or mutated in non-small cell lung cancer (NSCLC) and it plays a crucial role in tumour development and maintenance. The authors analyzed the state of the art of FGFR by reviewing the current literature. Fibroblast growth factor (FGF)-FGFR pathway and their aberrations are described, with the evaluation of their possible prognostic role in NSCLC and in particular in squamous cell carcinomas, in which FGFR is more often amplified. New therapeutic agents targeting FGFR signaling have been developed and are now in clinical evaluation. Dysregulation of FGF signaling in tumour cells is related to FGFR gene amplification or mutation, although it is still uncertain which of these aberrations represents a real predictor of response to specific inhibitors. However, recent evidence has questioned whether FGFR is a real target in squamous cell histology. The effectiveness of FGFR inhibitors is also still unclear since there are no clinical data on selected patients. Moreover, the management of specific side effects related to inhibition of the physiological role of FGF should be more thorough.

  10. Gene expression profiles of mouse submandibular gland development: FGFR1 regulates branching morphogenesis in vitro through BMP- and FGF-dependent mechanisms.

    Science.gov (United States)

    Hoffman, Matthew P; Kidder, Benjamin L; Steinberg, Zachary L; Lakhani, Saba; Ho, Susan; Kleinman, Hynda K; Larsen, Melinda

    2002-12-01

    Analyses of gene expression profiles at five different stages of mouse submandibular salivary gland development provide insight into gland organogenesis and identify genes that may be critical at different stages. Genes with similar expression profiles were clustered, and RT-PCR was used to confirm the developmental changes. We focused on fibroblast growth factor receptor 1 (FGFR1), as its expression is highest early in gland development. We extended our array results and analyzed the developmental expression patterns of other FGFR and FGF isoforms. The functional significance of FGFR1 was confirmed by submandibular gland organ culture. Antisense oligonucleotides decreased expression of FGFR1 and reduced branching morphogenesis of the glands. Inhibiting FGFR1 signaling with SU5402, a FGFR1 tyrosine kinase inhibitor, reduced branching morphogenesis. SU5402 treatment decreased cell proliferation but did not increase apoptosis. Fgfr, Fgf and Bmp gene expression was localized to either the mesenchyme or the epithelium by PCR, and then measured over time by real time PCR after SU5402 treatment. FGFR1 signaling regulates Fgfr1, Fgf1, Fgf3 and Bmp7 expression and indirectly regulates Fgf7, Fgf10 and Bmp4. Exogenous FGFs and BMPs added to glands in culture reveal distinct effects on gland morphology. Glands cultured with SU5402 were then rescued with exogenous BMP7, FGF7 or FGF10. Taken together, our results suggest specific FGFs and BMPs play reciprocal roles in regulating branching morphogenesis and FGFR1 signaling plays a central role by regulating both FGF and BMP expression.

  11. Elucidation of the mechanism of the regulatory function of the Ig1 module of the fibroblast growth factor receptor 1

    DEFF Research Database (Denmark)

    Kiselyov, Vladislav; Kochoyan, Artur; Poulsen, Flemming

    2006-01-01

    The extracellular part of the fibroblast growth factor (FGF) receptor (FGFR) consists of up to three Ig modules (Ig1-Ig3), in which the Ig2 and Ig3 modules determine affinity and specificity for FGF and heparin. The FGFR isoforms lacking the Ig1 module have higher affinity for FGF and heparin than....... The identified binding site in the Ig2 module was found to be in the area of the FGF-Ig2 and Ig2-heparin contact sites, thus providing direct structural evidence that the Ig1 module functions as a competitive autoinhibitor of the FGFR-ligand interaction. Furthermore, the Ig1 binding site of the Ig2 module...... overlaps the Ig2-Ig2 contact site. This suggests that the function of the Ig1 module is not only regulation of the FGFR-ligand binding affinity but also prevention of spontaneous FGFR dimerization (through a direct Ig2-Ig2 interaction) in the absence of FGF....

  12. FGF21 as an Endocrine Regulator in Lipid Metabolism: From Molecular Evolution to Physiology and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Yusuke Murata

    2011-01-01

    Full Text Available The FGF family comprises twenty-two structurally related proteins with functions in development and metabolism. The Fgf21 gene was generated early in vertebrate evolution. FGF21 acts as an endocrine regulator in lipid metabolism. Hepatic Fgf21 expression is markedly induced in mice by fasting or a ketogenic diet. Experiments with Fgf21 transgenic mice and cultured cells indicate that FGF21 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes via cell surface FGF receptors. However, experiments with Fgf21 knockout mice indicate that FGF21 inhibits lipolysis in adipocytes during fasting and attenuates torpor induced by a ketogenic diet but maybe not a physiological regulator for these hepatic functions. These findings suggest the pharmacological effects to be distinct from the physiological roles. Serum FGF21 levels are increased in patients with metabolic diseases having insulin resistance, indicating that FGF21 is a metabolic regulator and a biomarker for these diseases.

  13. Structural Basis by Which Alternative Splicing Modulates the Organizer Activity of FGF8 in the Brain

    Energy Technology Data Exchange (ETDEWEB)

    Olsen,S.; Li, J.; Eliseenkova, A.; Ibrahimi, O.; Lao, Z.; Zhang, F.; Linhardt, R.; Joyner, A.; Mohammadi, M.

    2006-01-01

    Two of the four human FGF8 splice isoforms, FGF8a and FGF8b, are expressed in the mid-hindbrain region during development. Although the only difference between these isoforms is the presence of an additional 11 amino acids at the N terminus of FGF8b, these isoforms possess remarkably different abilities to pattern the midbrain and anterior hindbrain. To reveal the structural basis by which alternative splicing modulates the organizing activity of FGF8, we solved the crystal structure of FGF8b in complex with the 'c' splice isoform of FGF receptor 2 (FGFR2c). Using surface plasmon resonance (SPR), we also characterized the receptor-binding specificity of FGF8a and FGF8b, the 'b' isoform of FGF17 (FGF17b), and FGF18. The FGF8b-FGFR2c structure shows that alternative splicing permits a single additional contact between phenylalanine 32 (F32) of FGF8b and a hydrophobic groove within Ig domain 3 of the receptor that is also present in FGFR1c, FGFR3c, and FGFR4. Consistent with the structure, mutation of F32 to alanine reduces the affinity of FGF8b toward all these receptors to levels characteristic of FGF8a. More importantly, analysis of the mid-hindbrain patterning ability of the FGF8b{sup F32A} mutant in chick embryos and murine midbrain explants shows that this mutation functionally converts FGF8b to FGF8a. Moreover, our data suggest that the intermediate receptor-binding affinities of FGF17b and FGF18, relative to FGF8a and FGF8b, also account for the distinct patterning abilities of these two ligands. We also show that the mode of FGF8 receptor-binding specificity is distinct from that of other FGFs and provide the first biochemical evidence for a physiological FGF8b-FGFR1c interaction during mid-hindbrain development. Consistent with the indispensable role of FGF8 in embryonic development, we show that the FGF8 mode of receptor binding appeared as early as in nematodes and has been preserved throughout evolution.

  14. Basic fibroblast growth factor-loaded, mineralized biopolymer-nanofiber scaffold improves adhesion and proliferation of rat mesenchymal stem cells.

    Science.gov (United States)

    Kim, Tae-Hyun; Kim, Jung-Ju; Kim, Hae-Won

    2014-02-01

    Nanofibrous matrices are attractive scaffolding platforms for tissue regeneration. Modification of the nanofiber surface, particularly with biological proteins, improves cellular interactions. Here, we loaded basic fibroblast growth factor (bFGF) onto mineralized nanofibers and investigated the effect on adhesion and proliferation of rat mesenchymal stem cells. bFGF loading was significantly higher on the mineralized nanofiber than on the non-mineralized one. Release of bFGF from the mineralized nanofibers was continuous over 2 weeks. Cells cultured on the bFGF-loaded nanofiber attached and proliferated in significantly higher numbers than those on the bFGF-free nanofiber. bFGF-receptor inhibition study confirmed the biological role played by the loaded bFGF. This study details the advantages of the mineralized nanofiber surface for the loading and delivery bFGF, and thus the bFGF-loaded nanofiber scaffold may be useful for tissue repair and regeneration.

  15. [FGF/FGFR signalling: Implication in oncogenesis and perspectives].

    Science.gov (United States)

    Flippot, Ronan; Kone, Moumini; Magné, Nicolas; Vignot, Stéphane

    2015-06-01

    Deregulation of FGF (fibroblast growth factor)/FGFR (fibroblast growth factor receptor) signalling leads to the promotion of several oncogenic mechanisms: proliferation, epithelial-mesenchymal transition, cytoskeleton modifications, migration and angiogenesis. Deregulation of this pathway is reported in various cancers at early stages, and can therefore be responsible for the emergence of the hallmarks of cancer. It is necessary to precise downstream pathways of FGFR signalling to understand its oncogenic potential. We will then describe its implications in different cancer types. Oncogenic mechanisms will be studied through the example of melanoma, in which deregulation of FGF/FGFR pathway is considered as a driver event and occurs in nearly 90% of cases. The FGF/FGFR signalling pathway is a putative therapeutic target. Numerous agents are in active development, operating through a selective or multi-targeted approach. Recent studies have shown rather disappointing results in non-selected patients, but promising results in patients with FGF/FGFR pathway alterations. A careful screening of patients is the key to a valuable evaluation of these new targeted molecular therapies.

  16. Follow-up study of Gambian children with rickets-like bone deformities and elevated plasma FGF23: possible aetiological factors.

    Science.gov (United States)

    Braithwaite, Vickie; Jarjou, Landing M A; Goldberg, Gail R; Jones, Helen; Pettifor, John M; Prentice, Ann

    2012-01-01

    We have previously reported on a case-series of children (n=46) with suspected calcium-deficiency rickets who presented in The Gambia with rickets-like bone deformities. Biochemical analyses discounted vitamin D-deficiency as an aetiological factor but indicated a perturbation of Ca-P metabolism involving low plasma phosphate and high circulating fibroblast growth factor-23 (FGF23) concentrations. A follow-up study was conducted 5 years after presentation to investigate possible associated factors and characterise recovery. 35 children were investigated at follow-up (RFU). Clinical assessment of bone deformities, overnight fasted 2 h urine and blood samples, 2-day weighed dietary records and 24 h urine collections were obtained. Age- and season-matched data from children from the local community (LC) were used to calculate standard deviation scores (SDS) for RFU children. None of the RFU children had radiological signs of active rickets. However, over half had residual leg deformities consistent with rickets. Dietary Ca intake (SDS-Ca=-0.52 (0.98) p=0.04), dietary Ca/P ratio (SDS-Ca/P=-0.80 (0.82) p=0.0008) and TmP:GFR (SDS-TmP:GFR=-0.48 (0.81) p=0.04) were significantly lower in RFU children compared with LC children and circulating FGF23 concentration was elevated in 19% of RFU children. Furthermore an inverse relationship was seen between haemoglobin and FGF23 (R(2)=25.8, p=0.004). This study has shown differences in biochemical and dietary profiles between Gambian children with a history of rickets-like bone deformities and children from the local community. This study provided evidence in support of the calcium deficiency hypothesis leading to urinary phosphate wasting and rickets and identified glomerular filtration rate and iron status as possible modulators of FGF23 metabolic pathways.

  17. bFGF Protects Pre-oligodendrocytes from Oxygen/Glucose Deprivation Injury to Ameliorate Demyelination.

    Science.gov (United States)

    Qu, Xuebin; Guo, Rui; Zhang, Zhenzhong; Ma, Li; Wu, Xiuxiang; Luo, Mengjiao; Dong, Fuxing; Yao, Ruiqin

    2015-10-01

    One of the pathological hallmarks of periventricular white matter injury is the vulnerability of pre-oligodendrocytes (preOLs) to hypoxia-ischemia (HI). There is increasing evidence that basic fibroblast growth factor (bFGF) is an important signaling molecule for neurogenesis and neuroprotection in the central nervous system. However, it is unknown whether bFGF protects preOLs from oxygen/glucose deprivation (OGD) damage in vitro and promotes remyelination in HI-induced rats. In this present study, bFGF exerted a protective effect on myelin by increasing the myelin thickness, the number of myelinated axons, and myelin basic protein expression in the HI-induced demyelinated neonatal rat corpus callosum. In vitro, bFGF ameliorated the impaired mitochondria and cell processes induced by OGD to promote the survival of isolated O4-positive preOLs. Additionally, the expression of fibroblast growth factor receptor 3 (FGFR3) was dramatically up-regulated in the preOLs after bFGF administration in vivo and in vitro. Thus, bFGF-stimulated remyelination in HI-induced rats by protecting the preOLs from hypoxic injury, and the mechanism involved may be mediated by FGFR3.

  18. 碱性成纤维细胞生长因子与肝素结合性质的研究进展%Advances in the research of bFGF binding to heparin

    Institute of Scientific and Technical Information of China (English)

    熊盛; 林剑; 姚汝华; 宗敏华

    2002-01-01

    Basic fibroblast growth factor (bFGF) is a multi-potential growth factor whose biological activities depend on its receptor's intrinsic tyrosine kinase activity and second messengers such as the mitogen activated protein kinases. Heparin sulfate proteoglycans (HSPGs) have been demonstrated to enhance or inhibit bFGF activity. The response elicited by HSPG is related to the relative concentrations and binding kinetics for bFGF of the various pools of HSPG. The type of cellular response might depend on the specific HSPG and FGF receptor expressed on the cell surface. The specific core protein of HSPG, and tissue specific differences in heparin sulfate modification result in altered bFGF regulation.

  19. Basic fibroblast growth factor increases the number of endogenous neural stem cells and inhibits the expression of amino methyl isoxazole propionic acid receptors in amyotrophic lateral sclerosis mice

    Institute of Scientific and Technical Information of China (English)

    Weihui Huang; Dawei Zang; Yi Lu; Ping Jiang

    2012-01-01

    This study aimed to investigate the number of amino methyl isoxazole propionic acid (AMPA) re-ceptors and production of endogenous neural stem cells in the SOD1G93AG1H transgenic mouse model of amyotrophic lateral sclerosis, at postnatal day 60 following administration of basic fibroblast growth factor (FGF-2). A radioligand binding assay and immunohistochemistry were used to estimate the number of AMPA receptors and endogenous neural stem cells respectively. Results showed that the number of AMPA receptors and endogenous neural stem cells in the brain stem and sensorimotor cortex were significantly increased, while motor function was significantly decreased at postnatal days 90 and 120. After administration of FGF-2 into mice, numbers of endogenous neural stem cells increased, while expression of AMPA receptors decreased, whilst motor functions were recovered. At postnatal day 120, the number of AMPA receptors was negatively correlated with the number of endogenous neural stem cells in model mice and FGF-2-treated mice. Our experimental findings indicate that FGF-2 can inhibit AMPA receptors and increase the number of endogenous neural stem cells, thus repairing neural injury in amyotrophic lateral sclerosis mice.

  20. Fibroblast growth factor 2 inhibits up-regulation of bone morphogenic proteins and their receptors during osteoblastic differentiation of human mesenchymal stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Biver, Emmanuel, E-mail: ebiver@yahoo.fr [Physiopathology of Inflammatory Bone Diseases, EA 4490, University Lille North of France, Quai Masset, Bassin Napoleon, BP120, 62327 Boulogne sur Mer (France); Department of Rheumatology, Lille University Hospital, Roger Salengro Hospital, 59037 Lille cedex (France); Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva 14 (Switzerland); Soubrier, Anne-Sophie [Physiopathology of Inflammatory Bone Diseases, EA 4490, University Lille North of France, Quai Masset, Bassin Napoleon, BP120, 62327 Boulogne sur Mer (France); Department of Rheumatology, Lille University Hospital, Roger Salengro Hospital, 59037 Lille cedex (France); Thouverey, Cyril [Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva 14 (Switzerland); Cortet, Bernard [Physiopathology of Inflammatory Bone Diseases, EA 4490, University Lille North of France, Quai Masset, Bassin Napoleon, BP120, 62327 Boulogne sur Mer (France); Department of Rheumatology, Lille University Hospital, Roger Salengro Hospital, 59037 Lille cedex (France); Broux, Odile [Physiopathology of Inflammatory Bone Diseases, EA 4490, University Lille North of France, Quai Masset, Bassin Napoleon, BP120, 62327 Boulogne sur Mer (France); Caverzasio, Joseph [Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva 14 (Switzerland); Hardouin, Pierre [Physiopathology of Inflammatory Bone Diseases, EA 4490, University Lille North of France, Quai Masset, Bassin Napoleon, BP120, 62327 Boulogne sur Mer (France)

    2012-11-02

    Highlights: Black-Right-Pointing-Pointer FGF modulates BMPs pathway in HMSCs by down-regulating BMP/BMPR expression. Black-Right-Pointing-Pointer This effect is mediated by ERK and JNK MAPKs pathways. Black-Right-Pointing-Pointer Crosstalk between FGF and BMPs must be taken into account in skeletal bioengineering. Black-Right-Pointing-Pointer It must also be considered in the use of recombinant BMPs in orthopedic and spine surgeries. -- Abstract: Understanding the interactions between growth factors and bone morphogenic proteins (BMPs) signaling remains a crucial issue to optimize the use of human mesenchymal stem cells (HMSCs) and BMPs in therapeutic perspectives and bone tissue engineering. BMPs are potent inducers of osteoblastic differentiation. They exert their actions via BMP receptors (BMPR), including BMPR1A, BMPR1B and BMPR2. Fibroblast growth factor 2 (FGF2) is expressed by cells of the osteoblastic lineage, increases their proliferation and is secreted during the healing process of fractures or in surgery bone sites. We hypothesized that FGF2 might influence HMSC osteoblastic differentiation by modulating expressions of BMPs and their receptors. BMP2, BMP4, BMPR1A and mainly BMPR1B expressions were up-regulated during this differentiation. FGF2 inhibited HMSCs osteoblastic differentiation and the up-regulation of BMPs and BMPR. This effect was prevented by inhibiting the ERK or JNK mitogen-activated protein kinases which are known to be activated by FGF2. These data provide a mechanism explaining the inhibitory effect of FGF2 on osteoblastic differentiation of HMSCs. These crosstalks between growth and osteogenic factors should be considered in the use of recombinant BMPs in therapeutic purpose of fracture repair or skeletal bioengineering.

  1. Heparan sulfate proteoglycan isoforms of the CD44 hyaluronan receptor induced in human inflammatory macrophages can function as paracrine regulators of fibroblast growth factor action.

    Science.gov (United States)

    Jones, M; Tussey, L; Athanasou, N; Jackson, D G

    2000-03-17

    The CD44 glycoprotein is expressed in multiple isoforms on a variety of cell types where it functions as a receptor for hyaluronan-mediated motility. Recently, interest has centered on CD44 heparan sulfate proteoglycan (HSPG) isoforms because of their potential to sequester heparin-binding growth factors and chemokines. Expression of these isoforms on ectodermal cells has recently been shown to regulate limb morphogenesis via presentation of fibroblast growth factor (FGF) 4/FGF 8 while expression on tumor cells was shown to sequester hepatocyte growth factor and promote tumor dissemination. To date, however, CD44 HSPG expression in tissue macrophages and lymphocytes has not been adequately investigated, despite the fact these cells actively synthesize growth factors and chemokines and indirect evidence that monocyte CD44 sequesters macrophage inflammatory protein-1beta. Here we show primary human monocytes rather than lymphocytes express CD44 HSPGs, but only following in vitro differentiation to macrophages or activation with the proinflammatory cytokine interleukin-1alpha or bacterial lipopolysaccharide. Furthermore, we show these isoforms are preferentially modified with heparan rather than chondroitin sulfate, bind the macrophage-derived growth factors FGF-2, vascular endothelial growth factor, and heparin-binding epidermal growth factor with varying affinities (K(d) 25-330 nM) and in the case of FGF-2, can stimulate productive binding to the high affinity tyrosine kinase FGF receptor 1 (FGFR1). In contrast, we find no evidence for significant binding to C-C chemokines. Last, we confirm by immunofluorescent antibody staining that inflamed synovial membrane macrophages express CD44 HSPGs and that expression is greatest in cells containing high FGF-2 levels. These results suggest a paracrine role for macrophage CD44 HSPG isoforms in the regulation of growth factor action during inflammation.

  2. Defective FGF signaling causes coloboma formation and disrupts retinal neurogenesis

    Institute of Scientific and Technical Information of China (English)

    Shuyi Chen; Hua Li; Karin Gaudenz; Ariel Paulson; Fengli Guo; Rhonda Trimble; Allison Peak

    2013-01-01

    The optic fissure (OF) is a transient opening on the ventral side of the developing vertebrate eye that closes before nearly all retinal progenitor cell differentiation has occurred.Failure to close the OF results in coloboma,a congenital disease that is a major cause of childhood blindness.Although human genetic studies and animal models have linked a number of genes to coloboma,the cellular and molecular mechanisms driving the closure of the OF are still largely unclear.In this study,we used Cre-LoxP-mediated conditional removal of fibroblast growth factor (FGF) receptors,Fgfr1 and Fgfr2,from the developing optic cup (OC) to show that FGF signaling regulates the closing of the OF.Our molecular,cellular and transcriptome analyses of Fgfr1 and Fgfr2 double conditional knockout OCs suggest that FGF signaling controls the OF closure through modulation of retinal progenitor cell proliferation,fate specification and morphological changes.Furthermore,Fgfr1 and Fgfr2 double conditional mutant retinal progenitor cells fail to initiate retinal ganglion cell (RGC) genesis.Taken together,our mouse genetic studies reveal that FGF signaling is essential for OF morphogenesis and RGC development.

  3. Expression of fibroblast growth factor-2 and fibroblast growth factor receptor-1 protein in the hippocampus in rats exhibiting chronic stress-induced depression

    Institute of Scientific and Technical Information of China (English)

    Gonglin Hou; Mingming Tang

    2011-01-01

    There is evidence that the expression of members of the fibroblast growth factor (FGF) protein family is altered in post-mortem brains of humans suffering from major depressive disorder. The present study examined whether the expression of fibroblast growth factor-2 (FGF2) and fibroblast growth factor receptor-1 (FGFR1) protein is altered following chronic stress in an animal model. Rats were exposed to 35 days of chronic unpredictable mild stress, and then tested using open-field and sucrose consumption tests. Compared with the control group, rats in the chronic stress group exhibited obvious depressive-like behaviors, including anhedonia, anxiety and decreased mobility. The results of western blot analysis and immunohistochemical analysis revealed a downregulation of the expression of FGF2 and FGFR1 in the hippocampus of rats, particularly in the CA1, CA3 and dentate gyrus. This decreased expression is in accord with the results of post-mortem studies in humans with major depressive disorder. These findings suggest that FGF2 and FGFR1 proteins participate in the pathophysiology of depressive-like behavior, and may play an important role in the mechanism of chronic stress-induced depression.

  4. Expression of transcripts for fibroblast growth factor 18 and its possible receptors during postnatal dentin formation in rat molars.

    Science.gov (United States)

    Baba, Otto; Ota, Masato S; Terashima, Tatsuo; Tabata, Makoto J; Takano, Yoshiro

    2015-05-01

    Fibroblast growth factors (FGFs) regulate the proliferation and differentiation of various cells via their respective receptors (FGFRs). During the early stages of tooth development in fetal mice, FGFs and FGFRs have been shown to be expressed in dental epithelia and mesenchymal cells at the initial stages of odontogenesis and to regulate cell proliferation and differentiation. However, little is known about the expression patterns of FGFs in the advanced stages of tooth development. In the present study, we focused on FGF18 expression in the rat mandibular first molar (M1) during the postnatal crown and root formation stages. FGF18 signals by RT-PCR using cDNAs from M1 were very weak at postnatal day 5 and were significantly up-regulated at days 7, 9 and 15. Transcripts were undetectable by in situ hybridization (ISH) but could be detected by in situ RT-PCR in the differentiated odontoblasts and cells of the sub-odontoblastic layer in both crown and root portions of M1 at day 15. The transcripts of FGFR2c and FGFR3, possible candidate receptors of FGF18, were detected by RT-PCR and ISH in differentiated odontoblasts throughout postnatal development. These results suggest the continual involvement of FGF18 signaling in the regulation of odontoblasts during root formation where it may contribute to dentin matrix formation and/or mineralization.

  5. Diagnostic Modalities for FGF23-Producing Tumors in Patients with Tumor-Induced Osteomalacia

    Directory of Open Access Journals (Sweden)

    Seiji Fukumoto

    2014-06-01

    Full Text Available Fibroblast growth factor 23 (FGF23 is a hormone that is produced by osteocytes and regulates phosphate and vitamin D metabolism through binding to the Klotho-FGF receptor complex. Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. Tumor-induced rickets/osteomalacia (TIO is a paraneoplastic syndrome caused by overproduction of FGF23 from the responsible tumors. Because TIO is cured by complete resection of the causative tumors, it is of great clinical importance to locate these tumors. Several imaging methods including skeletal survey by magnetic resonance imaging and octreotide scintigraphy have been used to identify the tumors that cause TIO. However, none of these imaging studies indicate that the detected tumors are actually producing FGF23. Recently, systemic venous sampling was conducted for locating FGF23-producing tumor in suspected patients with TIO and demonstrated that this test might be beneficial to a subset of patient. Further studies with more patients are necessary to establish the clinical utility of venous sampling in patients with TIO.

  6. FGF signaling supports Drosophila fertility by regulating development of ovarian muscle tissues.

    Science.gov (United States)

    Irizarry, Jihyun; Stathopoulos, Angelike

    2015-08-01

    The thisbe (ths) gene encodes a Drosophila fibroblast growth factor (FGF), and mutant females are viable but sterile suggesting a link between FGF signaling and fertility. Ovaries exhibit abnormal morphology including lack of epithelial sheaths and muscle tissues that surround ovarioles. Here we investigated how FGF influences Drosophila ovary morphogenesis and identified several roles. Heartless (Htl) FGF receptor was found to be expressed within somatic cells at the larval and pupal stages, and phenotypes were uncovered using RNAi. Differentiation of terminal filament cells was affected, but this effect did not alter the ovariole number. In addition, proliferation of epithelial sheath progenitors, the apical cells, was decreased in both htl and ths mutants, while ectopic expression of the Ths ligand led to these cells' over-proliferation suggesting that FGF signaling supports ovarian muscle sheath formation by controlling apical cell number in the developing gonad. Additionally, live imaging of adult ovaries was used to show that htl RNAi mutants, hypomorphic mutants in which epithelial sheaths are present, exhibit abnormal muscle contractions. Collectively, our results demonstrate that proper formation of ovarian muscle tissues is regulated by FGF signaling in the larval and pupal stages through control of apical cell proliferation and is required to support fertility.

  7. Increased innervation of forebrain targets by midbrain dopaminergic neurons in the absence of FGF-2.

    Science.gov (United States)

    Rumpel, R; Baron, O; Ratzka, A; Schröder, M-L; Hohmann, M; Effenberg, A; Claus, P; Grothe, C

    2016-02-09

    Fibroblast growth factors (FGFs) regulate development and maintenance, and reduce vulnerability of neurons. FGF-2 is essential for survival of midbrain dopaminergic (DA) neurons and is responsible for their dysplasia and disease-related degeneration. We previously reported that FGF-2 is involved in adequate forebrain (FB) target innervation by these neurons in an organotypic co-culture model. It remains unclear, how this ex-vivo phenotype relates to the in vivo situation, and which FGF-related signaling pathway is involved in this process. Here, we demonstrate that lack of FGF-2 results in an increased volume of the striatal target area in mice. We further add evidence that the low molecular weight (LMW) FGF-2 isoform is responsible for this phenotype, as this isoform is predominantly expressed in the embryonic ventral midbrain (VM) as well as in postnatal striatum (STR) and known to act via canonical transmembrane FGF receptor (FGFR) activation. Additionally, we confirm that the phenotype with an enlarged FB-target area by DA neurons can be mimicked in an ex-vivo explant model by inhibiting the canonical FGFR signaling, which resulted in decreased extracellular signal-regulated kinase (ERK) activation, while AKT activation remained unchanged.

  8. FGF18 augments osseointegration of intra-medullary implants in osteopenic FGFR3-/- mice

    Directory of Open Access Journals (Sweden)

    A Carli

    2012-07-01

    Full Text Available Enhancement of endogenous bone regeneration is a priority for integration of joint replacement hardware with host bone for stable fixation of the prosthesis. Fibroblast Growth Factor (FGF 18 regulates skeletal development and could therefore have applications for bone regeneration and skeletal repair. This study was designed to determine if treatment with FGF 18 would promote bone regeneration and integration of orthopedic hardware in FGF receptor 3 deficient (FGFR3-/- mice, previously characterized with impaired bone formation. Rigid nylon rods coated with 200 nm of titanium were implanted bilaterally in the femora of adult FGFR3-/- and FGFR3+/+ mice to mimic human orthopedic hardware. At the time of surgery, LEFT femora received an intramedullary injection of 0.5 μg FGF18 (Merck Serono and RIGHT femora received PBS as a control. Treatment with FGF18 resulted in a significant increase in peri-implant bone formation in both FGFR3+/+ and FGFR3-/- mice, with the peri-implant fibrous tissue frequently seen in FGFR3-/- mice being largely replaced by bone. The results of this pre-clinical study support the conjecture that FGF18 could be used in the clinical setting to promote integration of orthopedic hardware in poor quality bone.

  9. Editing Fibroblast Growth Factor 5 Gene in Ovine Fibroblasts Using TALENs%TALENs编辑绵羊成纤维细胞FGF 5基因

    Institute of Scientific and Technical Information of China (English)

    皮文辉; 周平; 王立民; 唐红; 郭延华; 张译元; 刘守仁; 王新华

    2015-01-01

    类转录激活因子效应物(Transcription activator-like effector,TALE)已经成为基因组编辑和基因转录调控的有效工具,在多个物种的基因组中实现特定位点的删除、插入和突变.针对绵羊成纤维细胞生长因子5 (Fibroblast growth factor 5,FGF 5)基因起始密码子ATG位点,设计构建TALENs(Transcription activator-like effector nucleases,TALENs).通过比较分析正常培养和基因组编辑处理的绵羊成纤维细胞,电转TALENs组合,Surveyor突变检测,筛选获得1对有效的TALENs.有限稀释细胞传代培养,PCR扩增FGF 5基因片段,经PAGE检测筛选发生突变的细胞,测序确认FGF 5基因ATG位点产生缺失突变细胞.获得具有编辑活性的TALENs,为该基因的定点编辑奠定基础.Surveyor检测和测序结果表明,在绵羊FGF 5基因ATG起始密码子上游104碱基位点,存在1个G/C单核苷酸多态.

  10. Identification of Receptor and Heparin Binding Sites in Fibroblast Growth Factor 4 by Structure-Based Mutagenesis

    OpenAIRE

    Bellosta, Paola; Iwahori, Akiyo; Plotnikov, Alexander N.; Eliseenkova, Anna V.; Basilico, Claudio; Mohammadi, Moosa

    2001-01-01

    Fibroblast growth factors (FGFs) comprise a large family of multifunctional, heparin-binding polypeptides that show diverse patterns of interaction with a family of receptors (FGFR1 to -4) that are subject to alternative splicing. FGFR binding specificity is an essential mechanism in the regulation of FGF signaling and is achieved through primary sequence differences among FGFs and FGFRs and through usage of two alternative exons, IIIc and IIIb, for the second half of immunoglobulin-like doma...

  11. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

    DEFF Research Database (Denmark)

    Ghoussaini, Maya; French, Juliet D; Michailidou, Kyriaki

    2016-01-01

    expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers......, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis....

  12. A novel fibroblast growth factor receptor family member promotes neuronal outgrowth and synaptic plasticity in aplysia.

    Science.gov (United States)

    Pollak, Daniela D; Minh, Bui Quang; Cicvaric, Ana; Monje, Francisco J

    2014-11-01

    Fibroblast Growth Factor (FGF) Receptors (FGFRs) regulate essential biological processes, including embryogenesis, angiogenesis, cellular growth and memory-related long-term synaptic plasticity. Whereas canonical FGFRs depend exclusively on extracellular Immunoglobulin (Ig)-like domains for ligand binding, other receptor types, including members of the tropomyosin-receptor-kinase (Trk) family, use either Ig-like or Leucine-Rich Repeat (LRR) motifs, or both. Little is known, however, about the evolutionary events leading to the differential incorporation of LRR domains into Ig-containing tyrosine kinase receptors. Moreover, although FGFRs have been identified in many vertebrate species, few reports describe their existence in invertebrates. Information about the biological relevance of invertebrate FGFRs and evolutionary divergences between them and their vertebrate counterparts is therefore limited. Here, we characterized ApLRRTK, a neuronal cell-surface protein recently identified in Aplysia. We unveiled ApLRRTK as the first member of the FGFRs family deprived of Ig-like domains that instead contains extracellular LRR domains. We describe that ApLRRTK exhibits properties typical of canonical vertebrate FGFRs, including promotion of FGF activity, enhancement of neuritic outgrowth and signaling via MAPK and the transcription factor CREB. ApLRRTK also enhanced the synaptic efficiency of neurons known to mediate in vivo memory-related defensive behaviors. These data reveal a novel molecular regulator of neuronal function in invertebrates, provide the first evolutionary linkage between LRR proteins and FGFRs and unveil an unprecedented mechanism of FGFR gene diversification in primeval central nervous systems.

  13. The effect of fibroblast growth factor 21 on type 2 diabetic inflammation biomarkers%FGF-21对2型糖尿病大鼠心肌炎症因子影响的研究

    Institute of Scientific and Technical Information of China (English)

    欧阳驰; 刘微; 廖昆; 曹明艳; 刘剑萍

    2012-01-01

    目的:探讨成纤维细胞生长因子-21(FGF-21)对2型糖尿病大鼠心肌炎症因子的影响.方法:采用高热量脂肪饮食联合小剂量链脲佐菌素建立2型糖尿病大鼠模型,随机分成2型糖尿病组与FGF-21治疗组,并与正常对照组比较.测定三组间大鼠血浆及心肌组织葡萄糖糖、胰岛素、FGF-21、脂质产物及炎症因子水平的变化.结果:2型糖尿病组血糖、胰岛素、游离脂肪酸(FFAs)、甘油三酯、FGF-21及炎症因子平均水平较其他两组显著增高(P<0.05).FGF-21治疗组血糖、胰岛素、FFAs、甘油三酯及炎症因子平均水平较2型糖尿病组显著降低(P<0.05),与对照组无差异.结论:FGF-21可以改善2型糖尿病大鼠心肌炎症因子水平,并参与调控2型糖尿病代谢紊乱.%To Observe effect of fibroblast growth factor 21 (FGF-21) on type 2 diabetic inflammation biomarkers. Methods Establishing type 2 diabetic animal model with high calorific fat diet and low dose streptozotocin (STZ) injection. Then, dividing them into type 2 diabetic rats and FGF-21 treatment rats, compare to the control rats. Measure the changes of serum insulin, glucose, FGF-21, lipid and inflammation biomarkers among the three groups. Results Type 2 diabetic rats serum insulin, glucose, FGF-21, triglyeride, free fatty acids (FFAs) and inflammation biomarkers significantly increased compared with the others (P< 0.05). However, these biomarkers of FGF-21 treatment rats were significantly lower than that of type 2 diabetic rats (P< 0.05), and no significant difference with the control rats. Conclusion FGF-21 ameliorates type 2 diabetic rat inflammation biomarkers and was related with their metabolic disorders regulation.

  14. Characterization of FGF23-Dependent Egr-1 Cistrome in the Mouse Renal Proximal Tubule.

    Directory of Open Access Journals (Sweden)

    Anthony A Portale

    Full Text Available Fibroblast growth factor 23 (FGF23 is a potent regulator of phosphate (Pi and vitamin D homeostasis. The transcription factor, early growth response 1 (egr-1, is a biomarker for FGF23-induced activation of the ERK1/2 signaling pathway. We have shown that ERK1/2 signaling blockade suppresses renal egr-1 gene expression and prevents FGF23-induced hypophosphatemia and 1,25-dihydroxyvitamin D (1,25(OH2D suppression in mice. To test whether egr-1 itself mediates these renal actions of FGF23, we administered FGF23 to egr-1-/- and wild-type (WT mice. In WT mice, FGF23 induced hypophosphatemia and suppressed expression of the renal Na/Pi cotransporters, Npt2a and Npt2c. In FGF23-treated egr-1-/- mice, hypophosphatemic response was greatly blunted and Na/Pi cotransporter expression was not suppressed. In contrast, FGF23 induced equivalent suppression of serum 1,25(OH2D concentrations by suppressing renal cyp27b1 and stimulating cyp24a1 mRNA expression in both groups of mice. Thus, downstream of receptor binding and ERK1/2 signaling, we can distinguish the effector pathway that mediates FGF23-dependent inhibition of Pi transport from the pathway that mediates inhibition of 1,25(OH2D synthesis in the kidney. Furthermore, we demonstrate that the hypophosphatemic effect of FGF23 is significantly blunted in Hyp/egr-1-/- mice; specifically, serum Pi concentrations and renal Npt2a and Npt2c mRNA expression are significantly higher in Hyp/egr-1-/- mice than in Hyp mice. We then characterized the egr-1 cistrome in the kidney using ChIP-sequencing and demonstrate recruitment of egr-1 to regulatory DNA elements in proximity to several genes involved in Pi transport. Thus, our data demonstrate that the effect of FGF23 on Pi homeostasis is mediated, at least in part, by activation of egr-1.

  15. Basic fibroblast growth factor and its receptors in human embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Ales Hampl

    2005-12-01

    Full Text Available Human embryonic stem cells (hESCs are pluripotent stem cells with long-lasting capacity to self-renew and differentiate into various cell types of endodermal, ectodermal or mesodermal origin. Unlike mouse ESCs (mESCs, which can be maintained in an undifferentiated state simply by adding leukemia inhibitory factor (LIF into the culture medium, hESCs are notorious for the sustained willingness to differentiate and not yet clearly defined signaling pathways that are crucial for their "stemness". Presently, our knowledge involves only limited number of growth factor signaling pathways that appear to be biologically relevant for stem cell functions in vitro. These include BMP, TGFbeta, Wnt, and FGF signaling pathway. The purpose of this review is to summarize recent data on the expression of FGFs and their receptors in hESCs, and critically evaluate the potential effects of FGF signals for their undifferentiated growth and/or differentiation in context with our current understanding of FGF/FGFR biology.

  16. Stimulation of α7 nicotinic acetylcholine receptor regulates glutamate transporter GLAST via basic fibroblast growth factor production in cultured cortical microglia.

    Science.gov (United States)

    Morioka, Norimitsu; Harano, Sakura; Tokuhara, Masato; Idenoshita, Yuko; Zhang, Fang Fang; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

    2015-11-01

    The α7 nicotinic acetylcholine (nACh) receptor expressed in microglia has a crucial role in neuroprotection. Simulation of α7 nACh receptor leads to increased expression of glutamate/aspartate transporter (GLAST), which in turn decreases synaptic glutamate levels. However, the upregulation of GLAST in cultured rat cortical microglia appears long after (over 18 h) stimulation of the α7 nACh receptor with nicotine. Thus, the current study elucidated the pathway responsible for the induction of GLAST expression in cultured cortical microglia. Nicotine-induced GLAST mRNA expression was significantly inhibited by cycloheximide pretreatment, indicating that a protein intermediary, such as a growth factor, is required for GLAST expression. The expression of fibroblast growth factor-2 (FGF-2) mRNA in cortical microglia was significantly increased 6 and 12h after treatment with nicotine, and this increase was potently inhibited by pretreatment with methyllycaconitine, a selective α7 nACh receptor antagonist. The treatment with nicotine also significantly increased FGF-2 protein expression. Furthermore, treatment with recombinant FGF-2 increased GLAST mRNA, protein expression and (14)C-glutamate uptake, a functional measurement of GLAST activity. Conversely, pretreatment with PD173074, an inhibitor of FGF receptor (FGFR) tyrosine kinase, significantly prevented the nicotine-induced expression of GLAST mRNA, its protein and (14)C-glutamate uptake. Reverse transcription polymerase chain reaction confirmed FGFR1 mRNA expression was confined to cultured cortical microglia. Together, the current findings demonstrate that the neuroprotective effect of activation of microglial α7 nACh receptors could be due to the expression of FGF-2, which in turn increases GLAST expression, thereby clearing glutamate from synapse and decreasing glutamate neurotransmission.

  17. Efficacy of fragmin/protamine microparticles containing fibroblast growth factor-2 (F/P MPs/FGF-2) to induce collateral vessels in a rabbit model of hindlimb ischemia.

    Science.gov (United States)

    Horio, Takuya; Fujita, Masanori; Tanaka, Yoshihiro; Ishihara, Masayuki; Kishimoto, Satoko; Nakamura, Shingo; Hase, Kazuo; Maehara, Tadaaki

    2011-09-01

    The localized delivery of exogenous, angiogenic growth factors such as fibroblast growth factor (FGF)-2 has become a promising alternative treatment of peripheral artery disease (PAD) and critical limb ischemia (CLI). The present study describes the efficacy of fragmin/protamine microparticles containing FGF-2 (F/P-MPs/FGF-2) to promote vessel growth in a rabbit model of hindlimb ischemia. A total of 24 rabbits were used to construct a model of hindlimb ischemia by resection of the left femoral artery. The rabbits were randomly divided into four groups 10 days after surgery (day 0); group A: control (non-treated; 1 mL of phosphate-buffered saline [PBS]); group B: FGF-2 (100 μg FGF-2 in 1 mL PBS)-treated; group C: F/P-MPs (12 mg dried F/P MPs in 1 mL PBS)-treated; and group D; F/P MPs/FGF-2 (100 μg FGF-2 and 12 mg dried F/P MPs in 1 mL PBS)-treated (n = 6 each). The drugs were administered intramuscularly to each group. Blood flow and blood pressure were measured in each group on days 0, 14, and 28. Angiography was performed to assess arteriogenesis on day 28. The number of capillaries on day 28 was determined by direct counting CD31(-) and α-smooth muscle antibody (α-SMA)-positive vessels. Neither death nor wound infection was observed throughout the experiment. The F/P MPs/FGF-2-treated group showed marked improvement in the blood flow ratio, blood pressure ratio, and capillary number in comparison to the control group, FGF-2-treated group, and F/P MPs-treated group. The F/P MPs-treated group showed intermediate improvement in blood flow ratio and capillary number in comparison to the control group and FGF-2-treated group. The F/P MPs/FGF-2-treated group strongly induced functional collateral vessels in the rabbit model of hindlimb ischemia, indicating a possible therapy for PAD. Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  18. FGF-1/-3/FGFR4 signaling in cancer-associated fibroblasts promotes tumor progression in colon cancer through Erk and MMP-7

    Science.gov (United States)

    Bai, Yu-Pan; Shang, Kun; Chen, Huan; Ding, Fei; Wang, Zhen; Liang, Chen; Xu, Ye; Sun, Meng-Hong; LI, Ying-Yi

    2015-01-01

    Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in the tumor stroma, are important modifiers of tumour progression. In the present study, we observed that azoxymethane and dextran sodium sulfate treatments induced increasingly severe colorectal mucosal inflammation and the intratumoural accumulation of CAFs. Fibroblast growth factor (FGF)-1 and FGF-3 were detected in infiltrating cells, and FGFR4, the specific receptor for FGF-1 and FGF-3, was detected in colon cancer tissues. The phosphorylation of FGFR4 enhanced the production of metalloproteinase (MMP)-7 and mitogen-activated protein kinase kinase (Mek)/extracellular signal-regulated kinase (Erk), which was accompanied by excessive vessel generation and cell proliferation. Moreover, we separated CAFs, pericarcinoma fibroblasts (PFs), and normal fibroblasts (NFs) from human colon tissue specimens to characterize the function of CAFs. We observed that CAFs secrete more FGF-1/-3 than NFs and PFs and promote cancer cell growth and angiogenesis through the activation of FGFR4, which is followed by the activation of Mek/Erk and the modulation of MMP-7 expression. The administration of FGF-1/-3-neutralizing antibodies or the treatment of cells with FGFR4 siRNA or the FGFR4 inhibitor PD173074 markedly suppressed colon cancer cell proliferation and neovascularization. These observations suggest a crucial role for CAFs and FGF signaling in the initiation and progression of colorectal cancer. The inhibition of the FGF signaling pathway may be a useful strategy for the treatment of colon cancer. PMID:26183471

  19. FGF-1/-3/FGFR4 signaling in cancer-associated fibroblasts promotes tumor progression in colon cancer through Erk and MMP-7.

    Science.gov (United States)

    Bai, Yu-Pan; Shang, Kun; Chen, Huan; Ding, Fei; Wang, Zhen; Liang, Chen; Xu, Ye; Sun, Meng-Hong; Li, Ying-Yi

    2015-10-01

    Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in the tumor stroma, are important modifiers of tumour progression. In the present study, we observed that azoxymethane and dextran sodium sulfate treatments induced increasingly severe colorectal mucosal inflammation and the intratumoural accumulation of CAFs. Fibroblast growth factor (FGF)-1 and FGF-3 were detected in infiltrating cells, and FGFR4, the specific receptor for FGF-1 and FGF-3, was detected in colon cancer tissues. The phosphorylation of FGFR4 enhanced the production of metalloproteinase (MMP)-7 and mitogen-activated protein kinase kinase (Mek)/extracellular signal-regulated kinase (Erk), which was accompanied by excessive vessel generation and cell proliferation. Moreover, we separated CAFs, pericarcinoma fibroblasts (PFs), and normal fibroblasts (NFs) from human colon tissue specimens to characterize the function of CAFs. We observed that CAFs secrete more FGF-1/-3 than NFs and PFs and promote cancer cell growth and angiogenesis through the activation of FGFR4, which is followed by the activation of Mek/Erk and the modulation of MMP-7 expression. The administration of FGF-1/-3-neutralizing antibodies or the treatment of cells with FGFR4 siRNA or the FGFR4 inhibitor PD173074 markedly suppressed colon cancer cell proliferation and neovascularization. These observations suggest a crucial role for CAFs and FGF signaling in the initiation and progression of colorectal cancer. The inhibition of the FGF signaling pathway may be a useful strategy for the treatment of colon cancer.

  20. Tumor Angiogenesis Correlated with bFGF and FGFR-1 in Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    ZHOUTao; PANTiecheng

    2005-01-01

    Objective: To study the relationship between angiogenesis and the expression of bFGF and FGFR-1 in lung cancer. Methods: The specimens of 56 patients with lung cancer treated with surgery were collected. Anti-Von Willebrand factor antibody was used to measure microvascular density (MVD) by means of SABC immunohistochemical technique, and antibody to basic fibroblast growth factor (bFGF)and its receptor (FGFR-1) to detect the expression of these three proteins in the tumor tissues. The survival time was compared between low MVD and high MVD groups by the Kaplan-Meier method. Results: (1)The expression of MVD showed no significant difference in some clinical characteristics, including sex,age, T stage, M stage and pathologic type, but significant difference in N stage (P<0.01) and clinical stage (P<0.05). (2) Survival analysis showed that high MVD group was associated with a risk of death (P<0.01). (3) The expression of bFGF and FGFR-1 were both related to lymphatic metastasis and clinical staging (P<0.05). (4) Significant difference was seen between low MVD and high MVD groups in the bFGF expression in lung cancer (P<0.01), whereas no correlation in FGFR-1. (5) High co-expression of bFGF and FGFR-1 was consistent in tumor cells. Conclusion: (1) MVD is a good prognostic factor for patients of lung cancer, and the same as bFGF. (2) The angiogenesis may be induced after bFGF binding to FGFR-1.

  1. Asymmetric Receptor Contact is Required for Tyrosine Autophosphorylation of Fibroblast Growth Factor Receptor in Living Cells

    Energy Technology Data Exchange (ETDEWEB)

    Bae, J.; Boggon, T; Tomé, F; Mandiyan, V; Lax, I; Schlessinge, J

    2010-01-01

    Tyrosine autophosphorylation of receptor tyrosine kinases plays a critical role in regulation of kinase activity and in recruitment and activation of intracellular signaling pathways. Autophosphorylation is mediated by a sequential and precisely ordered intermolecular (trans) reaction. In this report we present structural and biochemical experiments demonstrating that formation of an asymmetric dimer between activated FGFR1 kinase domains is required for transphosphorylation of FGFR1 in FGF-stimulated cells. Transphosphorylation is mediated by specific asymmetric contacts between the N-lobe of one kinase molecule, which serves as an active enzyme, and specific docking sites on the C-lobe of a second kinase molecule, which serves a substrate. Pathological loss-of-function mutations or oncogenic activating mutations in this interface may hinder or facilitate asymmetric dimer formation and transphosphorylation, respectively. The experiments presented in this report provide the molecular basis underlying the control of transphosphorylation of FGF receptors and other receptor tyrosine kinases.

  2. Evolution of developmental regulation in the vertebrate FgfD subfamily.

    Science.gov (United States)

    Jovelin, Richard; Yan, Yi-Lin; He, Xinjun; Catchen, Julian; Amores, Angel; Canestro, Cristian; Yokoi, Hayato; Postlethwait, John H

    2010-01-15

    Fibroblast growth factors (Fgfs) encode small signaling proteins that help regulate embryo patterning. Fgfs fall into seven families, including FgfD. Nonvertebrate chordates have a single FgfD gene; mammals have three (Fgf8, Fgf17, and Fgf18); and teleosts have six (fgf8a, fgf8b, fgf17, fgf18a, fgf18b, and fgf24). What are the evolutionary processes that led to the structural duplication and functional diversification of FgfD genes during vertebrate phylogeny? To study this question, we investigated conserved syntenies, patterns of gene expression, and the distribution of conserved noncoding elements (CNEs) in FgfD genes of stickleback and zebrafish, and compared them with data from cephalochordates, urochordates, and mammals. Genomic analysis suggests that Fgf8, Fgf17, Fgf18, and Fgf24 arose in two rounds of whole genome duplication at the base of the vertebrate radiation; that fgf8 and fgf18 duplications occurred at the base of the teleost radiation; and that Fgf24 is an ohnolog that was lost in the mammalian lineage. Expression analysis suggests that ancestral subfunctions partitioned between gene duplicates and points to the evolution of novel expression domains. Analysis of CNEs, at least some of which are candidate regulatory elements, suggests that ancestral CNEs partitioned between gene duplicates. These results help explain the evolutionary pathways by which the developmentally important family of FgfD molecules arose and the deduced principles that guided FgfD evolution are likely applicable to the evolution of developmental regulation in many vertebrate multigene families.

  3. Fgf3 and Fgf10a work in concert to promote maturation of the epibranchial placodes in zebrafish.

    Directory of Open Access Journals (Sweden)

    Matthew N McCarroll

    Full Text Available Essential cellular components of the paired sensory organs of the vertebrate head are derived from transient thickenings of embryonic ectoderm known as cranial placodes. The epibranchial (EB placodes give rise to sensory neurons of the EB ganglia that are responsible for relaying visceral sensations form the periphery to the central nervous system. Development of EB placodes and subsequent formation of EB ganglia is a multistep process regulated by various extrinsic factors, including fibroblast growth factors (Fgfs. We discovered that two Fgf ligands, Fgf3 and Fgf10a, cooperate to promote EB placode development. Whereas EB placodes are induced in the absence of Fgf3 and Fgf10a, they fail to express placode specific markers Pax2a and Sox3. Expression analysis and mosaic rescue experiments demonstrate that Fgf3 signal is derived from the endoderm, whereas Fgf10a is emitted from the lateral line system and the otic placode. Further analyses revealed that Fgf3 and Fgf10a activities are not required for cell proliferation or survival, but are required for placodal cells to undergo neurogenesis. Based on these data, we conclude that a combined loss of these Fgf factors results in a failure of the EB placode precursors to initiate a transcriptional program needed for maturation and subsequent neurogenesis. These findings highlight the importance and complexity of reiterated Fgf signaling during cranial placode formation and subsequent sensory organ development.

  4. FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex.

    Science.gov (United States)

    Sugiyama, Nami; Varjosalo, Markku; Meller, Pipsa; Lohi, Jouko; Chan, Kui Ming; Zhou, Zhongjun; Alitalo, Kari; Taipale, Jussi; Keski-Oja, Jorma; Lehti, Kaisa

    2010-09-07

    Tumor cells use membrane type 1 matrix metalloproteinase (MT1-MMP) for invasion and metastasis. However, the signaling mechanisms that underlie MT1-MMP regulation in cancer have remained unclear. Using a systematic gain-of-function kinome screen for MT1-MMP activity, we have here identified kinases that significantly enhance MT1-MMP activity in tumor cells. In particular, we discovered an MT1-MMP/FGF receptor-4 (FGFR4) membrane complex that either stimulates or suppresses MT1-MMP and FGFR4 activities, depending on a tumor progression-associated polymorphism in FGFR4. The FGFR4-R388 allele, linked to poor cancer prognosis, increased collagen invasion by decreasing lysosomal MT1-MMP degradation. FGFR4-R388 induced MT1-MMP phosphorylation and endosomal stabilization, and surprisingly, the increased MT1-MMP in return enhanced FGFR4-R388 autophosphorylation. A phosphorylation-defective MT1-MMP was stabilized on the cell surface, where it induced simultaneous FGFR4-R388 internalization and dissociation of cell-cell junctions. In contrast, the alternative FGFR4-G388 variant down-regulated MT1-MMP, and the overexpression of MT1-MMP and particularly its phosphorylation-defective mutant vice versa induced FGFR4-G388 degradation. These results provide a mechanistic basis for FGFR4-R388 function in cancer invasion.

  5. FGF1-mediated cardiomyocyte cell cycle reentry depends on the interaction of FGFR-1 and Fn14.

    Science.gov (United States)

    Novoyatleva, Tatyana; Sajjad, Amna; Pogoryelov, Denys; Patra, Chinmoy; Schermuly, Ralph T; Engel, Felix B

    2014-06-01

    Fibroblast growth factors (FGFs) signal through FGF receptors (FGFRs) mediating a broad range of cellular functions during embryonic development, as well as disease and regeneration during adulthood. Thus, it is important to understand the underlying molecular mechanisms that modulate this system. Here, we show that FGFR-1 can interact with the TNF receptor superfamily member fibroblast growth factor-inducible molecule 14 (Fn14) resulting in cardiomyocyte cell cycle reentry. FGF1-induced cell cycle reentry in neonatal cardiomyocytes could be blocked by Fn14 inhibition, while TWEAK-induced cell cycle activation was inhibited by blocking FGFR-1 signaling. In addition, costimulation experiments revealed a synergistic effect of FGF1 and TWEAK in regard to cardiomyocyte cell cycle induction via PI3K/Akt signaling. Overexpression of Fn14 with either FGFR-1 long [FGFR-1(L)] or FGFR-1 short [FGFR-1(S)] isoforms resulted after FGF1/TWEAK stimulation in cell cycle reentry of >40% adult cardiomyocytes. Finally, coimmunoprecipitation and proximity ligation assays indicated that endogenous FGFR-1 and Fn14 interact with each other in cardiomyocytes. This interaction was strongly enhanced in the presence of their corresponding ligands, FGF1 and TWEAK. Taken together, our data suggest that FGFR-1/Fn14 interaction may represent a novel endogenous mechanism to modulate the action of these receptors and their ligands and to control cardiomyocyte cell cycle reentry.

  6. The fibroblast growth factor-2 (F.G.F.-2) expression predicts the tumoral response and the local of non at small cells bronchi cancers after chemoradiotherapy; L'expression de FGF-2 predit la reponse tumorale et le controle local des cancers bronchiques non a petites cellules apres chimioradiotherapie

    Energy Technology Data Exchange (ETDEWEB)

    Massabeau, C.; Toulas, C.; Moyal, E. [Institut Claudius-Regaud, 31 - Toulouse (France); Rouquette, I.; Lauwers-Cances, V.; Mazieres, J. [Centre Hospitalier Universitaire, 31 - Toulouse (France)

    2007-11-15

    The tumoral expression of the fibroblast growth factor-2 is correlated with a bad response to chemotherapy and a strong rate of local recurrence. F.G.F.-2 would define a radioresistant phenotype of non at small cells bronchi carcinoma. (N.C.)

  7. Duplication and divergence of fgf8 functions in teleost development and evolution.

    Science.gov (United States)

    Jovelin, Richard; He, Xinjun; Amores, Angel; Yan, Yi-Lin; Shi, Ruihua; Qin, Baifang; Roe, Bruce; Cresko, William A; Postlethwait, John H

    2007-12-15

    Fibroblast growth factors play critical roles in many aspects of embryo patterning that are conserved across broad phylogenetic distances. To help understand the evolution of fibroblast growth factor functions, we identified members of the Fgf8/17/18-subfamily in the three-spine stickleback Gasterosteus aculeatus, and investigated their evolutionary relationships and expression patterns. We found that fgf17b is the ortholog of tetrapod Fgf17, whereas the teleost genes called fgf8 and fgf17a are duplicates of the tetrapod gene Fgf8, and thus should be called fgf8a and fgf8b. Phylogenetic analysis supports the view that the Fgf8/17/18-subfamily expanded during the ray-fin fish genome duplication. In situ hybridization experiments showed that stickleback fgf8 duplicates exhibited common and unique expression patterns, indicating that tissue specialization followed the gene duplication event. Moreover, direct comparison of stickleback and zebrafish embryonic expression patterns of fgf8 co-orthologs suggested lineage-specific independent subfunction partitioning and the acquisition or the loss of ortholog functions. In tetrapods, Fgf8 plays an important role in the apical ectodermal ridge of the developing pectoral appendage. Surprisingly, differences in the expression of fgf8a in the apical ectodermal ridge of the pectoral fin bud in zebrafish and stickleback, coupled with the role of fgf16 and fgf24 in teleost pectoral appendage show that different Fgf genes may play similar roles in limb development in various vertebrates.

  8. Elucidation of the mechanism of the regulatory function of the Ig1 module of the fibroblast growth factor receptor 1

    DEFF Research Database (Denmark)

    Kiselyov, Vladislav; Kochoyan, Artur; Poulsen, Flemming;

    2006-01-01

    The extracellular part of the fibroblast growth factor (FGF) receptor (FGFR) consists of up to three Ig modules (Ig1-Ig3), in which the Ig2 and Ig3 modules determine affinity and specificity for FGF and heparin. The FGFR isoforms lacking the Ig1 module have higher affinity for FGF and heparin than...... the triple Ig-module isoforms, suggesting that the Ig1 module is involved in the regulation of the FGFR-ligand interaction. We show here by surface plasmon resonance and NMR analyses that the Ig1 module binds to the Ig2 module, and identify by NMR the binding sites involved in the Ig1-Ig2 interaction....... The identified binding site in the Ig2 module was found to be in the area of the FGF-Ig2 and Ig2-heparin contact sites, thus providing direct structural evidence that the Ig1 module functions as a competitive autoinhibitor of the FGFR-ligand interaction. Furthermore, the Ig1 binding site of the Ig2 module...

  9. Role of FGF/FGFR signaling in skeletal development and homeostasis:learning from mouse models

    Institute of Scientific and Technical Information of China (English)

    Nan Su; Min Jin; Lin Chen

    2014-01-01

    Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling plays essential roles in bone development and diseases. Missense mutations in FGFs and FGFRs in humans can cause various congenital bone diseases, including chondrodysplasia syndromes, craniosynostosis syndromes and syndromes with dysregulated phosphate metabolism. FGF/FGFR signaling is also an important pathway involved in the maintenance of adult bone homeostasis. Multiple kinds of mouse models, mimicking human skeleton diseases caused by missense mutations in FGFs and FGFRs, have been established by knock-in/out and transgenic technologies. These genetically modified mice provide good models for studying the role of FGF/FGFR signaling in skeleton development and homeostasis. In this review, we summarize the mouse models of FGF signaling-related skeleton diseases and recent progresses regarding the molecular mechanisms, underlying the role of FGFs/FGFRs in the regulation of bone development and homeostasis. This review also provides a perspective view on future works to explore the roles of FGF signaling in skeletal development and homeostasis.

  10. Stilbene glycosides are natural product inhibitors of FGF-2-induced angiogenesis

    Directory of Open Access Journals (Sweden)

    Naz Humera

    2009-04-01

    Full Text Available Abstract Background Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with pathological processes, in particular tumour development, and is a target for the development of new therapies. We have investigated the anti-angiogenic potential of two naturally occurring stilbene glycosides (compounds 1 and 2 isolated from the medicinal plant Boswellia papyriferai using large and smallvessel-derived endothelial cells. Compound 1 (trans-4',5'-dihydroxy-3-methoxystilbene-5-O-{α-L-rhamnopyranosyl-(1→2-[α-L-rhamnopyranosyl-(1→6}-β-D-glucopyranoside was the more hydrophilic and inhibited FGF-2-induced proliferation, wound healing, invasion in Matrigel, tube formation and angiogenesis in large and small vessel-derived endothelial cells and also in the chick chorioallantoic membrane assay. Using a binding assay we were able to show compound 1 reduced binding of FGF-2 to fibroblast growth factor receptors-1 and -2. In all cases the concentration of compound 1 which caused 50% inhibition (IC50 was determined. The effect of compound 1 on EGF and VEGF-induced proliferation was also investigated. Results Compound 1 inhibited all stages of FGF-2 induced angiogenesis with IC50 values in the range 5.8 ± 0.18 – 48.90 ± 0.40 μM but did not inhibit EGF or VEGF-induced angiogenesis. It also inhibited FGF-2 binding to FGF receptor-1 and -2 with IC50 values of 5.37 ± 1.04 and 9.32 ± 0.082 μM respectively and with concommotant down-regulation of phosphorylated-ERK-1/-2 expression. Compound 2 was an ineffective inhibitor of angiogenesis despite its structural homology to compound 1. Conclusion Compound 1 inhibited FGF-2 induced angiogenesis by binding to its cognate receptors and is an addition to the small number of natural product inhibitors of angiogenesis

  11. Metabolic Effects of FGF-21: Thermoregulation and Beyond.

    Science.gov (United States)

    Ni, Bin; Farrar, Jared S; Vaitkus, Janina A; Celi, Francesco S

    2015-01-01

    Fibroblast growth factor (FGF)-21, a member of the FGF family, is a novel hormone involved in the control of metabolism by modulating glucose homeostasis, insulin sensitivity, ketogenesis, and promoting adipose tissue "browning." Recent studies demonstrated that brown adipose tissue is not only a target for FGF-21, but is also a potentially important source of systemic FGF-21. These findings support the hypothesis that FGF-21 plays a physiologic role in thermogenesis and thermogenic recruitment of white adipose tissue by an autocrine-paracrine axis. This review examines the role of FGF-21 in thermogenesis from the perspective of cell-based, animal model, and human studies. We also present recent advances in the characterization of FGF-21's regulation of metabolism.

  12. Dimerization effect of sucrose octasulfate on rat FGF1

    DEFF Research Database (Denmark)

    Kulahin, Nikolaj; Kiselyov, Vladislav; Kochoyan, Artur

    2008-01-01

    Fibroblast growth factors (FGFs) constitute a family of at least 23 structurally related heparin-binding proteins that are involved in regulation of cell growth, survival, differentiation and migration. Sucrose octasulfate (SOS), a chemical analogue of heparin, has been demonstrated to activate FGF...... signalling pathways. The structure of rat FGF1 crystallized in the presence of SOS has been determined at 2.2 A resolution. SOS-mediated dimerization of FGF1 was observed, which was further supported by gel-filtration experiments. The major contributors to the sulfate-binding sites in rat FGF1 are Lys113......, Lys118, Arg122 and Lys128. An arginine at position 116 is a consensus residue in mammalian FGF molecules; however, it is a serine in rat FGF1. This difference may be important for SOS-mediated FGF1 dimerization in rat....

  13. FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis.

    Science.gov (United States)

    Perry, Rachel J; Lee, Sangwon; Ma, Lie; Zhang, Dongyan; Schlessinger, Joseph; Shulman, Gerald I

    2015-04-28

    Fibroblast growth factor-1 (FGF1) and FGF19 have been shown to improve glucose metabolism in diabetic rodents, but how this occurs is unknown. Here to investigate the mechanism of action of these growth factors, we perform intracerebroventricular (i.c.v.) injections of recombinant FGF1 or FGF19 in an awake rat model of type 1 diabetes (T1D) and measure rates of whole-body lipolysis, hepatic acetyl CoA content, pyruvate carboxylase activity and hepatic glucose production. We show that i.c.v. injection of FGF19 or FGF1 leads to a ∼60% reduction in hepatic glucose production, hepatic acetyl CoA content and whole-body lipolysis, which results from decreases in plasma ACTH and corticosterone concentrations. These effects are abrogated by an intra-arterial infusion of corticosterone. Taken together these studies identify suppression of the HPA axis and ensuing reductions in hepatic acetyl CoA content as a common mechanism responsible for mediating the acute, insulin-independent, glucose-lowering effects of FGF1 and FGF19 in rodents with poorly controlled T1D.

  14. Pax9 regulates a molecular network involving Bmp4, Fgf10, Shh signaling and the Osr2 transcription factor to control palate morphogenesis.

    Science.gov (United States)

    Zhou, Jing; Gao, Yang; Lan, Yu; Jia, Shihai; Jiang, Rulang

    2013-12-01

    Cleft palate is one of the most common birth defects in humans. Whereas gene knockout studies in mice have shown that both the Osr2 and Pax9 transcription factors are essential regulators of palatogenesis, little is known about the molecular mechanisms involving these transcription factors in palate development. We report here that Pax9 plays a crucial role in patterning the anterior-posterior axis and outgrowth of the developing palatal shelves. We found that tissue-specific deletion of Pax9 in the palatal mesenchyme affected Shh expression in palatal epithelial cells, indicating that Pax9 plays a crucial role in the mesenchyme-epithelium interactions during palate development. We found that expression of the Bmp4, Fgf10, Msx1 and Osr2 genes is significantly downregulated in the developing palatal mesenchyme in Pax9 mutant embryos. Remarkably, restoration of Osr2 expression in the early palatal mesenchyme through a Pax9(Osr2KI) allele rescued posterior palate morphogenesis in the absence of Pax9 protein function. Our data indicate that Pax9 regulates a molecular network involving the Bmp4, Fgf10, Shh and Osr2 pathways to control palatal shelf patterning and morphogenesis.

  15. Fgf19 regulated by Hh signaling is required for zebrafish forebrain development.

    Science.gov (United States)

    Miyake, Ayumi; Nakayama, Yoshiaki; Konishi, Morichika; Itoh, Nobuyuki

    2005-12-01

    Fibroblast growth factor (Fgf) signaling plays important roles in brain development. Fgf3 and Fgf8 are crucial for the formation of the forebrain and hindbrain. Fgf8 is also required for the midbrain to form. Here, we identified zebrafish Fgf19 and examined its roles in brain development by knocking down Fgf19 function. We found that Fgf19 expressed in the forebrain, midbrain and hindbrain was involved in cell proliferation and cell survival during embryonic brain development. Fgf19 was also essential for development of the ventral telencephalon and diencephalon. Regional specification is linked to cell type specification. Fgf19 was also essential for the specification of gamma-aminobutyric acid (GABA)ergic interneurons and oligodendrocytes generated in the ventral telencephalon and diencephalon. The cross talk between Fgf and Hh signaling is critical for brain development. In the forebrain, Fgf19 expression was down-regulated on inhibition of Hh but not of Fgf3/Fgf8, and overexpression of Fgf19 rescued partially the phenotype on inhibition of Hh. The present findings indicate that Fgf19 signaling is crucial for forebrain development by interacting with Hh and provide new insights into the roles of Fgf signaling in brain development.

  16. Involvement of multiple elements in FXR-mediated transcriptional activation of FGF19.

    Science.gov (United States)

    Miyata, Masaaki; Hata, Tatsuya; Yamakawa, Hiroki; Kagawa, Tatehiro; Yoshinari, Kouichi; Yamazoe, Yasushi

    2012-10-01

    The intestinal endocrine hormone human fibroblast growth factor 19 (FGF19) is involved in the regulation of not only hepatic bile acid metabolism but also carbohydrate and lipid metabolism. In the present study, bile acid/farnesoid X receptor (FXR) responsiveness in the FGF19 promoter region was investigated by a reporter assay using the human colon carcinoma cell line LS174T. The assay revealed the presence of bile acid/FXR-responsive elements in the 5'-flanking region up to 8.8 kb of FGF19. Deletion analysis indicated that regions from -1866 to -1833, from -1427 to -1353, and from -75 to +262 were involved in FXR responsiveness. Four, four, and two consecutive half-sites of nuclear receptors were observed in the three regions, respectively. An electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay revealed FXR/retinoid X receptor α (RXRα) heterodimer binding in these three regions. EMSA and reporter assays using mutated constructs indicated that the nuclear receptor IR1, ER2, and DR8 motifs in the 5'-flanking region were involved in FXR responsiveness of FGF19. Lithocholic acid (LCA) (10 μM), chenodeoxycholic acid (CDCA) (10 μM), or GW4064 (0.1 μM) treatment increased reporter activity in a construct including the three motifs under FXR-expressing conditions whereas LCA and not CDCA or GW4064 treatment increased the reporter activity under pregnane X receptor (PXR)-expressing conditions. These results suggest that FGF19 is transcriptionally activated through multiple FXR-responsive elements in the promoter region.

  17. FGF23 and inflammation

    Science.gov (United States)

    Sharaf El Din, Usama A A; Salem, Mona M; Abdulazim, Dina O

    2017-01-01

    Systemic inflammation is a recognized feature in chronic kidney disease (CKD). The role of systemic inflammation in the pathogenesis of vascular calcification was recently settled. FGF23 was recently accused as a direct stimulus of systemic inflammation. This finding explains the strong association of FGF23 to vascular calcification and increased mortality among CKD. PMID:28101453

  18. Mutations in fibroblast growth factor receptors: Phenotypic consequences during eukaryotic development

    Energy Technology Data Exchange (ETDEWEB)

    Park, W.J.; Bellus, G.A.; Jabs, E.W. [Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)

    1995-10-01

    Recently, a tremendous amount of excitement and interest has been generated by the rapid succession of discoveries in the human fibroblast growth factor receptor (FGFR) field. In less than a year, mutations in three FGFRs (FGFR1-FGFR3) have been associated with three skeletal dysplasias and four craniosynostotic syndromes. FGFRs are members of the receptor tyrosine kinase family that bind fibroblast growth factors (FGFs). The FGF family consists of structurally related polypeptides that play a key role in numerous aspects of embryogenesis, growth, and homeostasis. FGFs have a potent growth stimulatory and/or differentiation-inducing effect on cells such as those derived from the early-embryonic mesoderm or ectoderm. In addition to mitogenesis and differentiation, FGFs also stimulate chemotaxis, cell survival, and angiogenesis. FGFs mediate cellular responses on binding to and activation of FGFRs. 45 refs., 2 figs., 1 tab.

  19. Fructose ingestion acutely stimulates circulating FGF21 levels in humans

    OpenAIRE

    Dushay, Jody R.; Toschi, Elena; Mitten, Emilie K.; Fisher, ffolliott M.; Herman, Mark A.; Maratos-Flier, Eleftheria

    2014-01-01

    Objective Fibroblast growth factor 21 (FGF21) is a hormone with pleiotropic metabolic activities which, in rodents, is robustly regulated by fasting and ketogenic diets. In contrast, similar dietary interventions have either no or minimal effects on circulating FGF21 in humans. Moreover, no intervention or dietary challenge has been shown to acutely stimulate circulating FGF21 in either humans or animals. Recent animal data suggest that the transcription factor Carbohydrate Responsive-Element...

  20. Fibroblast growth factor receptor 2 IIIc as a therapeutic target for colorectal cancer cells.

    Science.gov (United States)

    Matsuda, Yoko; Hagio, Masahito; Seya, Tomoko; Ishiwata, Toshiyuki

    2012-09-01

    A high percentage of colorectal carcinomas overexpress a lot of growth factors and their receptors, including fibroblast growth factor (FGF) and FGF receptor (FGFR). We previously reported that FGFR2 overexpression was associated with distant metastasis and that FGFR2 inhibition suppressed cell growth, migration, and invasion. The FGFR2 splicing isoform FGFR2IIIb is associated with well-differentiated histologic type, tumor angiogenesis, and adhesion to extracellular matrices. Another isoform, FGFR2IIIc, correlates with the aggressiveness of various types of cancer. In the present study, we examined the expression and roles of FGFR2IIIc in colorectal carcinoma to determine the effectiveness of FGFR2IIIc-targeting therapy. In normal colorectal tissues, FGFR2IIIc expression was weakly detected in superficial colorectal epithelial cells and was not detected in proliferative zone cells. FGFR2IIIc-positive cells were detected by immunohistochemistry in the following lesions, listed in the order of increasing percentage: hyperplastic polyps growth, soft agar colony formation, migration, and invasion, as well as decreased adhesion to extracellular matrices. Furthermore, FGFR2IIIc-transfected colorectal carcinoma cells formed larger tumors in subcutaneous tissues and the cecum of nude mice. Fully human anti-FGFR2IIIc monoclonal antibody inhibited the growth and migration of colorectal carcinoma cells through alterations in cell migration, cell death, and development-related genes. In conclusion, FGFR2IIIc plays an important role in colorectal carcinogenesis and tumor progression. Monoclonal antibody against FGFR2IIIc has promising potential in colorectal carcinoma therapy.

  1. Role of fibroblast growth factor 8 in neurite outgrowth from spiral ganglion neurons in vitro.

    Science.gov (United States)

    García-Hernández, Sofía; Potashner, Steven J; Morest, D Kent

    2013-09-05

    Many neurons degenerate after injuries resulting from overstimulation, drugs, genetic mutations, and aging. Although several growth factors and neurotrophins delay degeneration and promote regrowth of neural processes, the role of fibroblast growth factor 8 (FGF8) in mammalian spiral ganglion neurons (SGN) neurite outgrowth has not been examined. This study develops and uses SGN cell cultures suitable for experimental analysis, it investigates whether FGF8a and FGF8b isoforms affect the neurite outgrowth from SGN cultured in vitro. We found that both FGF8a and FGF8b promoted the outgrowth of neurites from cultured SGN. This response is mediated by FGF receptors and involves the activation of IκBα-mediated NFκB signaling pathway. These findings suggest that, besides its morphogenetic role during development, FGF8 may have trophic functions in the adult which are relevant to regeneration.

  2. Photoperiodic regulation of FGF21 production in the Siberian hamster.

    Science.gov (United States)

    Samms, Ricardo J; Fowler, Maxine J; Cooper, Scott; Emmerson, Paul; Coskun, Tamer; Adams, Andrew C; Kharitonenkov, Alexei; Tsintzas, Kostas; Ebling, Francis J P

    2014-06-01

    This article is part of a Special Issue "Energy Balance". FGF21 is an endocrine member of the fibroblast growth factor superfamily that has been shown to play an important role in the physiological response to nutrient deprivation. Food restriction enhances hepatic FGF21 production, which serves to engage an integrated response to energy deficit. Specifically, elevated FGF21 levels lead to reduced gluconeogenesis and increased hepatic ketogenesis. However, circulating FGF21 concentrations also paradoxically rise in states of metabolic dysfunction such as obesity. Furthermore, multiple peripheral tissues also produce FGF21 in addition to the liver, raising questions as to its endocrine and paracrine roles in the control of energy metabolism. The objectives of this study were to measure plasma FGF21 concentrations in the Siberian hamster, a rodent which undergoes a seasonal cycle of fattening and body weight gain in the long days (LD) of summer, followed by reduction of appetite and fat catabolism in the short days (SD) of winter. Groups of adult male hamsters were raised in long days, and then exposed to SD for up to 12 weeks. Chronic exposure of LD animals to SD led to a significant increase in circulating FGF21 concentrations. This elevation of circulating FGF21 was preceded by an increase in liver FGF21 protein production evident as early as 4 weeks of exposure to SD. FGF21 protein abundance was also increased significantly in interscapular brown adipose tissue, with a positive correlation between plasma levels of FGF21 and BAT protein abundance throughout the experimental period. Epididymal white adipose tissue and skeletal muscle (gastrocnemius) also produced FGF21, but levels did not change in response to a change in photoperiod. In summary, a natural programmed state of fat catabolism was associated with increased FGF21 production in the liver and BAT, consistent with the view that FGF21 has a role in adapting hamsters to the hypophagic winter state.

  3. The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation.

    Science.gov (United States)

    Acosta, Helena; Iliev, Dobromir; Grahn, Tan Hooi Min; Gouignard, Nadège; Maccarana, Marco; Griesbach, Julia; Herzmann, Svende; Sagha, Mohsen; Climent, Maria; Pera, Edgar M

    2015-03-15

    Germ layer formation and primary axis development rely on Fibroblast growth factors (FGFs). In Xenopus, the secreted serine protease HtrA1 induces mesoderm and posterior trunk/tail structures by facilitating the spread of FGF signals. Here, we show that the serpin Protease nexin-1 (PN1) is transcriptionally activated by FGF signals, suppresses mesoderm and promotes head development in mRNA-injected embryos. An antisense morpholino oligonucleotide against PN1 has the opposite effect and inhibits ectodermal fate. However, ectoderm and anterior head structures can be restored in PN1-depleted embryos when HtrA1 and FGF receptor activities are diminished, indicating that FGF signals negatively regulate their formation. We show that PN1 binds to and inhibits HtrA1, prevents degradation of the proteoglycan Syndecan 4 and restricts paracrine FGF/Erk signaling. Our data suggest that PN1 is a negative-feedback regulator of FGF signaling and has important roles in ectoderm and head development.

  4. Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound.

    Science.gov (United States)

    Gassaway, Madalee M; Jacques, Teresa L; Kruegel, Andrew C; Karpowicz, Richard J; Li, Xiaoguang; Li, Shu; Myer, Yves; Sames, Dalibor

    2016-01-15

    Modulation of growth factor signaling pathways in the brain represents a new experimental approach to treating neuropsychiatric disorders such as depression, anxiety, and addiction. Neurotrophins and growth factors exert synaptic, neuronal, and circuit level effects on a wide temporal range, which suggests a possibility of rapid and lasting therapeutic effects. Consequently, identification of small molecules that can either enhance the release of growth factors or potentiate their respective pathways will provide a drug-like alternative to direct neurotrophin administration or viral gene delivery and thus represents an important frontier in chemical biology and drug design. Glial cell line-derived neurotrophic factor (GDNF), in particular, has been implicated in marked reduction of alcohol consumption in rodent addiction models, and the natural product ibogaine, a substance used traditionally in ritualistic ceremonies, has been suggested to increase the synthesis and release of GDNF in the dopaminergic system in rats. In this report, we describe a novel iboga analog, XL-008, created by unraveling the medium size ring of the ibogamine skeleton, and its ability to induce release of GDNF in C6 glioma cells. Additionally, XL-008 potentiates the release of GDNF induced by fibroblast growth factor 2 (FGF2), another neurotrophin implicated in major depressive disorder, increasing potency more than 2-fold (from 7.85 ± 2.59 ng/mL to 3.31 ± 0.98 ng/mL) and efficacy more than 3-fold. The GDNF release by both XL-008 and the FGF2/XL-008 mixture was found to be mediated through the MEK and PI3K signaling pathways but not through PLCγ in C6 glioma cells.

  5. The diminished expression of proangiogenic growth factors and their receptors in gastric ulcers of cirrhotic patients.

    Directory of Open Access Journals (Sweden)

    Jiing-Chyuan Luo

    Full Text Available OBJECTIVES: The pathogenesis of the higher occurrence of peptic ulcer disease in cirrhotic patients is complex. Platelets can stimulate angiogenesis and promote gastric ulcer healing. We compared the expressions of proangiogenic growth factors and their receptors in the gastric ulcer margin between cirrhotic patients with thrombocytopenia and those of non-cirrhotic patients to elucidate possible mechanisms. METHODS: Eligible cirrhotic patients (n = 55 and non-cirrhotic patients (n = 55 who had gastric ulcers were enrolled. Mucosa from the gastric ulcer margin and non-ulcer areas were sampled and the mRNA expressions of the proangiogenic growth factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF], basic fibroblast growth factor [bFGF] and their receptors (VEGFR1, VEGFR2, PDGFRA, PDGFRB, FGFR1, FGFR2 were measured and compared. Platelet count and the expressions of these growth factors and their receptors were correlated with each other. RESULTS: The two groups were comparable in terms of gender, ulcer size and infection rate of Helicobacter pylori. However, the cirrhotic group were younger in age, had a lower platelet count than those in the non-cirrhotic group (p0.5, p<0.001. CONCLUSIONS: Our findings implied that diminished activity of proangiogenic factors and their receptors may contribute to the pathogenesis of gastric ulcers in cirrhotic patients.

  6. Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Miura Seiki

    2012-02-01

    Full Text Available Abstract Background Although fibroblast growth factor 19 (FGF19 can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC has not been well investigated. FGF19, a member of the FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC. Methods We investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7 using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA of FGF19 and FGFR4 to regulate their concentrations. Results We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P FGF19 mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (P n = 12 and invasion (P n = 6 capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P n = 12. Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P n = 12. The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P n = 29. Conclusions FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.

  7. Fasting-Induced FGF21 Is Repressed by LXR Activation via Recruitment of an HDAC3 Corepressor Complex in Mice

    Science.gov (United States)

    Archer, Amena; Venteclef, Nicolas; Mode, Agneta; Pedrelli, Matteo; Gabbi, Chiara; Clément, Karine; Parini, Paolo; Gustafsson, Jan-Åke

    2012-01-01

    The liver plays a pivotal role in the physiological adaptation to fasting and a better understanding of the metabolic adaptive responses may give hints on new therapeutic strategies to control the metabolic diseases. The liver X receptors (LXRs) are well-established regulators of lipid and glucose metabolism. More recently fibroblast growth factor 21 (FGF21) has emerged as an important regulator of energy homeostasis. We hypothesized that the LXR transcription factors could influence Fgf21 expression, which is induced in response to fasting. Wild-type, LXRα−/−, and LXRβ−/− mice were treated for 3 d with vehicle or the LXR agonist GW3965 and fasted for 12 h prior to the killing of the animals. Interestingly, serum FGF21 levels were induced after fasting, but this increase was blunted when the mice were treated with GW3965 independently of genotypes. Compared with wild-type mice, GW3965-treated LXRα−/− and LXRβ−/− mice showed improved insulin sensitivity and enhanced ketogenic response at fasting. Of note is that during fasting, GW3965 treatment tended to reduce liver triglycerides as opposed to the effect of the agonist in the fed state. The LXR-dependent repression of Fgf21 seems to be mainly mediated by the recruitment of LXRβ onto the Fgf21 promoter upon GW3965 treatment. This repression by LXRβ occurs through the recruitment and stabilization of the repressor complex composed of retinoid-related orphan receptor-α/Rev-Erbα/histone deacetylase 3 onto the Fgf21 promoter. Our data clearly demonstrate that there is a cross talk between the LXR and FGF21 signaling pathways in the adaptive response to fasting. PMID:23073827

  8. Soluble expression of disulfide bond containing proteins FGF15 and FGF19 in the cytoplasm of Escherichia coli.

    Science.gov (United States)

    Kong, Bo; Guo, Grace L

    2014-01-01

    Fibroblast growth factor 19 (FGF19) is the human ortholog of mouse FGF15, and both proteins function as an endocrine signal to regulate various liver functions. FGF15/FGF19 protein contains two disulfide bonds. It is unfavorable to form disulfide bonds in Escherichia coli (E. coli) cytoplasm because of the bacterial cytoplasmic reducing environment. Modification of the cytoplasmic reducing environment and/or co-expression of protein chaperones are common strategies to express disulfide bond containing proteins in E. coli. In the current study, we report a method to produce soluble FGF15/FGF19 protein in cytoplasm of E. coli. Several commercial available strains with the disruption of thiol-redox pathways, and/or co-expression of redoxase or refolding chaperones were used to develop this novel method for expression of FGF15/FGF19 in E. coli. Mutation of the thiol-disulfide bond reducing pathway in E. coli or N-terminal fusion of thioredox (TRX) alone is not enough to support disulfide bond formation in FGF15/19 proteins. However, TRX fusion protein improved FGF19 solubility in strains of thiol-redox system mutants. In addition, DsbC co-expressed in thiol-redox system mutants alone improved and further enhanced FGF19 solubility with combination of TRX fusion tag. The soluble FGF19 proteins were easily purified through Ni-NTA affinity chromatography and anion exchange chromatography, and the purified protein maintained its biological activities, confirmed by suppressing hepatic Cyp7a1 gene transcription in mice and by activating ERK1/2 signaling pathway in HepG2 cells. In contrast, soluble FGF15 protein in cytoplasm remained very low using these strategies. In summary, we have successfully developed a method to express functional FGF19 protein in prokaryotic cells, and this strategy may be adapted for the expression of other disulfide-containing proteins.

  9. Soluble expression of disulfide bond containing proteins FGF15 and FGF19 in the cytoplasm of Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Bo Kong

    Full Text Available Fibroblast growth factor 19 (FGF19 is the human ortholog of mouse FGF15, and both proteins function as an endocrine signal to regulate various liver functions. FGF15/FGF19 protein contains two disulfide bonds. It is unfavorable to form disulfide bonds in Escherichia coli (E. coli cytoplasm because of the bacterial cytoplasmic reducing environment. Modification of the cytoplasmic reducing environment and/or co-expression of protein chaperones are common strategies to express disulfide bond containing proteins in E. coli. In the current study, we report a method to produce soluble FGF15/FGF19 protein in cytoplasm of E. coli. Several commercial available strains with the disruption of thiol-redox pathways, and/or co-expression of redoxase or refolding chaperones were used to develop this novel method for expression of FGF15/FGF19 in E. coli. Mutation of the thiol-disulfide bond reducing pathway in E. coli or N-terminal fusion of thioredox (TRX alone is not enough to support disulfide bond formation in FGF15/19 proteins. However, TRX fusion protein improved FGF19 solubility in strains of thiol-redox system mutants. In addition, DsbC co-expressed in thiol-redox system mutants alone improved and further enhanced FGF19 solubility with combination of TRX fusion tag. The soluble FGF19 proteins were easily purified through Ni-NTA affinity chromatography and anion exchange chromatography, and the purified protein maintained its biological activities, confirmed by suppressing hepatic Cyp7a1 gene transcription in mice and by activating ERK1/2 signaling pathway in HepG2 cells. In contrast, soluble FGF15 protein in cytoplasm remained very low using these strategies. In summary, we have successfully developed a method to express functional FGF19 protein in prokaryotic cells, and this strategy may be adapted for the expression of other disulfide-containing proteins.

  10. Fgf16 is required for specification of GABAergic neurons and oligodendrocytes in the zebrafish forebrain.

    Directory of Open Access Journals (Sweden)

    Ayumi Miyake

    Full Text Available Fibroblast growth factor (Fgf signaling plays crucial roles in various developmental processes including those in the brain. We examined the role of Fgf16 in the formation of the zebrafish brain. The knockdown of fgf16 decreased cell proliferation in the forebrain and midbrain. fgf16 was also essential for development of the ventral telencephalon and diencephalon, whereas fgf16 was not required for dorsoventral patterning in the midbrain. fgf16 was additionally required for the specification and differentiation of γ-aminobutyric acid (GABAergic interneurons and oligodendrocytes, but not for those of glutamatergic neurons in the forebrain. Cross talk between Fgf and Hedgehog (Hh signaling was critical for the specification of GABAergic interneurons and oligodendrocytes. The expression of fgf16 in the forebrain was down-regulated by the inhibition of Hh and Fgf19 signaling, but not by that of Fgf3/Fgf8 signaling. The fgf16 morphant phenotype was similar to that of the fgf19 morphant and embryos blocked Hh signaling. The results of the present study indicate that Fgf16 signaling, which is regulated by the downstream pathways of Hh-Fgf19 in the forebrain, is involved in forebrain development.

  11. Amplification of fibroblast growth factor receptor-1 in breast cancer and the effects of brivanib alaninate.

    Science.gov (United States)

    Shiang, Christine Y; Qi, Yuan; Wang, Bailiang; Lazar, Vladimir; Wang, Jing; Fraser Symmans, W; Hortobagyi, Gabriel N; Andre, Fabrice; Pusztai, Lajos

    2010-10-01

    Fibroblast growth factor receptor-1 (FGFR-1) is amplified in 10% of human breast cancers. The goal of this study was to test the correlation between FGFR-1 amplification and expression and sensitivity to brivanib, an FGFR-1 small molecule inhibitor, in breast cancer cell lines in vitro. Using CGH array and gene expression profiling, FGFR-1 DNA copy number, mRNA, and protein expression were measured in 21 cell lines and correlated with growth inhibition by brivanib. We examined FGFR-1 autophosphorylation and kinase activity, as well as phosphorylation of downstream signaling molecules in response to bFGF and brivanib exposure. CAMA, MDA-MB-361, and HCC38 cells had FGFR-1 amplification and protein overexpression. Brivanib GI(50) values were significantly lower in the gene amplified (15.17 μM, n = 3) compared to normal copy number (69.09 μM, n = 11) or FGFR-1 deleted (76.14 μM, n = 7) cells (P = 0.0107). Among nonamplified cells, there was no correlation between FGFR-1 mRNA or protein expression levels and brivanib sensitivity. Two of three FGFR-1 amplified cells were sensitive to bFGF-induced growth stimulation, which was blocked by brivanib. In cells with amplified FGFR-1, brivanib decreased receptor autophosphorylation, inhibited bFGF-induced tyrosine kinase activity, and reduced phosphorylation of ERK and AKT. Breast cancer cell lines with FGFR-1 gene amplification and protein overexpression are more sensitive to growth inhibition by brivanib than nonamplified cells. These findings suggest that FGFR-1 amplification or protein overexpression in breast cancers may be an indicator for brivanib treatment, where it may have direct anti-proliferative effects in addition to its' anti-angiogenic effects.

  12. Expression of Fgf19 in the developing chick eye.

    Science.gov (United States)

    Francisco-Morcillo, Javier; Sánchez-Calderón, Hortensia; Kawakami, Yasuhiko; Izpisúa Belmonte, Juan Carlos; Hidalgo-Sánchez, Matías; Martín-Partido, Gervasio

    2005-04-21

    Fibroblast growth factor 19 (FGF19) is a new member of the FGF family of growth factors. Here, we describe the localization of Fgf19 mRNA in the developing chick retina and lens in stages from the Hamburger and Hamilton stage 15 (HH15) to postnatal day 30 (P30). Fgf19 was expressed in a transient manner in postmitotic neuroblasts during the migration from the ventricular surface to their final location. Moreover, from HH31 (embryonic day 7, E7) on, a subset of lined up Fgf19 expressing cells was distributed in the outer region of the presumptive INL. These cells were Pax6 immunoreactive horizontal cells. During the last third of embryogenesis, Fgf19 expression in the retina was progressively down-regulated and was not detected at P30. Also, it was transiently expressed in the equatorial region of the lens.

  13. S100B Engages RAGE or bFGF/FGFR1 in Myoblasts Depending on Its Own Concentration and Myoblast Density. Implications for Muscle Regeneration

    Science.gov (United States)

    Beccafico, Sara; Donato, Rosario

    2012-01-01

    In high-density myoblast cultures S100B enhances basic fibroblast growth factor (bFGF) receptor 1 (FGFR1) signaling via binding to bFGF and blocks its canonical receptor, receptor for advanced glycation end-products (RAGE), thereby stimulating proliferation and inhibiting differentiation. Here we show that upon skeletal muscle injury S100B is released from myofibers with maximum release at day 1 post-injury in coincidence with satellite cell activation and the beginning of the myoblast proliferation phase, and declining release thereafter in coincidence with reduced myoblast proliferation and enhanced differentiation. By contrast, levels of released bFGF are remarkably low at day 1 post-injury, peak around day 5 and decline thereafter. We also show that in low-density myoblast cultures S100B binds RAGE, but not bFGF/FGFR1 thereby simultaneously stimulating proliferation via ERK1/2 and activating the myogenic program via p38 MAPK. Clearance of S100B after a 24-h treatment of low-density myoblasts results in enhanced myotube formation compared with controls as a result of increased cell numbers and activated myogenic program, whereas chronic treatment with S100B results in stimulation of proliferation and inhibition of differentiation due to a switch of the initial low-density culture to a high-density culture. However, at relatively high doses, S100B stimulates the mitogenic bFGF/FGFR1 signaling in low-density myoblasts, provided bFGF is present. We propose that S100B is a danger signal released from injured muscles that participates in skeletal muscle regeneration by activating the promyogenic RAGE or the mitogenic bFGF/FGFR1 depending on its own concentration, the absence or presence of bFGF, and myoblast density. PMID:22276098

  14. Fibroblast growth factor 21 night watch: advances and uncertainties in the field.

    Science.gov (United States)

    Kharitonenkov, A; DiMarchi, R

    2017-03-01

    Fibroblast growth factor (FGF) 21 belongs to a hormone-like subgroup within the FGF superfamily. The members of this subfamily, FGF19, FGF21 and FGF23, are characterized by their reduced binding affinity for heparin that enables them to be transported in the circulation and function in an endocrine manner. It is likely that FGF21 also acts in an autocrine and paracrine fashion, as multiple organs can produce this protein and its plasma concentration seems to be below the level necessary to induce a pharmacological effect. FGF21 signals via FGF receptors, but for efficient receptor engagement it requires a cofactor, membrane-spanning βKlotho (KLB). The regulation of glucose uptake in adipocytes was the initial biological activity ascribed to FGF21, but this hormone is now recognized to stimulate many other pathways in vitro and display multiple pharmacological effects in metabolically compromised animals and humans. Understanding of the precise physiology of FGF21 and its potential medicinal role has evolved exponentially over the last decade, yet numerous aspects remain to be defined and others are a source of debate. Here we provide a historical overview of the advances in FGF21 biology focusing on the uncertainties in the mechanism of action as well as the differing viewpoints relating to this intriguing protein.

  15. Immunomodulator CD200 promotes neurotrophic activity by interacting with and activating the fibroblast growth factor receptor

    DEFF Research Database (Denmark)

    Pankratova, Stanislava; Bjornsdottir, Halla; Christensen, Claus;

    2016-01-01

    in the suppression of microglia activation. We for the first time demonstrated that CD200 can interact with and transduce signaling through activation of the fibroblast growth factor receptor (FGFR), thereby inducing neuritogenesis and promoting neuronal survival in primary neurons. CD200-induced FGFR...... phosphorylation was abrogated by CD200R, whereas FGF2-induced FGFR activation was inhibited by CD200. We also identified a sequence motif located in the first Ig-like module of CD200, likely representing the minimal CD200 binding site for FGFR. The FGFR binding motif overlaps with the CD200R binding site......, suggesting that they can compete for CD200 binding in cells that express both receptors. We propose that CD200 in neurons functions as a ligand of FGFR....

  16. Fibroblast growth factor receptor 2 plays an essential role in telencephalic progenitors.

    Science.gov (United States)

    Ever, Leah; Zhao, Rui-Jing; Eswarakumar, Veraragavan P; Gaiano, Nicholas

    2008-01-01

    We used loss-of-function analysis to determine the role of fibroblast growth factor receptor 2 (FGFR2) in telencephalic progenitors, and also to examine interactions between FGFR and Notch signaling. While the telencephalon of FGFR2 mutants appears grossly normal, mutant telencephalic progenitors exhibit altered proliferative behavior in vivo and in vitro. Based upon our prior finding that Notch1 activation increased neurosphere frequency in FGF2, we tested whether this effect is mediated by FGFR1 or FGFR2. We found that Notch1 activation increased neurosphere frequency in cells mutant for either FGFR1 or FGFR2, but had no effect on the reduced size of neurospheres mutant for those receptors. Additional analyses revealed biochemical changes in the adult neocortex mutant for the IIIc isoform of FGFR2, and essential roles for FGFR2 in nasopharynx, eyelid, and cornea development.

  17. Enhanced invasion and tumor growth of fibroblast growth factor 8b-overexpressing MCF-7 human breast cancer cells.

    Science.gov (United States)

    Ruohola, J K; Viitanen, T P; Valve, E M; Seppänen, J A; Loponen, N T; Keskitalo, J J; Lakkakorpi, P T; Härkönen, P L

    2001-05-15

    Fibroblast growth factor 8 (FGF-8) is a secreted heparin-binding protein, which has mitogenic and transforming activity. Increased expression of FGF-8 has been found in human breast cancer, and it has a potential autocrine role in its progression. Human FGF-8 is alternatively spliced to generate four protein isoforms (a, b, e, and f). Isoform b has been shown to be the most transforming. In this work, we studied the role of FGF-8b in the growth (in vitro and in vivo) of MCF-7 human breast cancer cells, which proliferate in an estrogen-dependent manner. Constitutive overexpression of FGF-8b in MCF-7 cells down-regulated FGF-8b-binding receptors FGF receptor (FGFR) 1IIIc, FGFR2IIIc, and FGFR4 found to be expressed in these cells. FGF-8b overexpression led to an increase in the anchorage-independent proliferation rate in suspension culture and colony formation in soft agar, when MCF-7 cells were cultured with or without estradiol. FGF-8b also provided an additional growth advantage for cells stimulated with estradiol. In addition, FGF-8b-transfected cells invaded more actively through Matrigel than did control cells. This was possibly due to the increased secretion of matrix metalloproteinase 9. In vivo, FGF-8b-transfected MCF-7 cells formed faster growing tumors than vector-only-transfected cells when xenografted into nude mice. The tumors formed by FGF-8b-transfected cells were more vascular than the tumors formed by vector-only-transfected cells. In conclusion, FGF-8b expression confers a growth advantage to MCF-7 breast carcinoma cells, both in vitro and in vivo. In addition to stimulation of proliferation, this growth advantage probably arises from increased invasion and tumor vascularization induced by FGF-8b. The results suggest that FGF-8b signaling may be an important factor in the regulation of tumorigenesis and progression of human breast cancer.

  18. Cell proliferation by silk gut incorporating FGF-2 protein microcrystals.

    Science.gov (United States)

    Kotani, Eiji; Yamamoto, Naoto; Kobayashi, Isao; Uchino, Keiro; Muto, Sayaka; Ijiri, Hiroshi; Shimabukuro, Junji; Tamura, Toshiki; Sezutsu, Hideki; Mori, Hajime

    2015-06-08

    Silk gut processed from the silk glands of the silkworm could be an ideal biodegradable carrier for cell growth factors. We previously demonstrated that polyhedra, microcrystals of Cypovirus 1 polyhedrin, can serve as versatile carrier proteins. Here, we report the generation of a transgenic silkworm that expresses polyhedrin together with human basic fibroblast growth factor (FGF-2) in its posterior silk glands to utilize silk gut as a proteinaceous carrier to protect and slowly release active cell growth factors. In the posterior silk glands, polyhedrin formed polyhedral microcrystals, and FGF-2 became encapsulated within the polyhedra due to a polyhedron-immobilization signal. Silk gut powder prepared from posterior silk glands containing polyhedron-encapsulated FGF-2 stimulated the phosphorylation of p44/p42 MAP kinase and induced the proliferation of serum-starved NIH3T3 cells by releasing bioactive FGF-2. Even after a one-week incubation at 25 °C, significantly higher biological activity of FGF-2 was observed for silk gut powder incorporating polyhedron-encapsulated FGF-2 relative to silk gut powder with non-encapsulated FGF-2. Our results demonstrate that posterior silk glands incorporating polyhedron-encapsulated FGF-2 are applicable to the preparation of biodegradable silk gut, which can protect and release FGF-2 that is produced in a virus- and serum-free expression system with significant application potential.

  19. Heparan Sulfate Proteoglycans Regulate Fgf Signaling and Cell Polarity during Collective Cell Migration

    Directory of Open Access Journals (Sweden)

    Marina Venero Galanternik

    2015-01-01

    Full Text Available Collective cell migration is a highly regulated morphogenetic movement during embryonic development and cancer invasion that involves the precise orchestration and integration of cell-autonomous mechanisms and environmental signals. Coordinated lateral line primordium migration is controlled by the regulation of chemokine receptors via compartmentalized Wnt/β-catenin and fibroblast growth factor (Fgf signaling. Analysis of mutations in two exostosin glycosyltransferase genes (extl3 and ext2 revealed that loss of heparan sulfate (HS chains results in a failure of collective cell migration due to enhanced Fgf ligand diffusion and loss of Fgf signal transduction. Consequently, Wnt/β-catenin signaling is activated ectopically, resulting in the subsequent loss of the chemokine receptor cxcr7b. Disruption of HS proteoglycan (HSPG function induces extensive, random filopodia formation, demonstrating that HSPGs are involved in maintaining cell polarity in collectively migrating cells. The HSPGs themselves are regulated by the Wnt/β-catenin and Fgf pathways and thus are integral components of the regulatory network that coordinates collective cell migration with organ specification and morphogenesis.

  20. Relevant use of Klotho in FGF19 subfamily signaling system in vivo.

    Science.gov (United States)

    Tomiyama, Ken-ichi; Maeda, Ryota; Urakawa, Itaru; Yamazaki, Yuji; Tanaka, Tomohiro; Ito, Shinji; Nabeshima, Yoko; Tomita, Tsutomu; Odori, Shinji; Hosoda, Kiminori; Nakao, Kazuwa; Imura, Akihiro; Nabeshima, Yo-ichi

    2010-01-26

    Alpha-Klotho (alpha-Kl) and its homolog, beta-Klotho (beta-Kl) are key regulators of mineral homeostasis and bile acid/cholesterol metabolism, respectively. FGF15/ humanFGF19, FGF21, and FGF23, members of the FGF19 subfamily, are believed to act as circulating metabolic regulators. Analyses of functional interactions between alpha- and beta-Kl and FGF19 factors in wild-type, alpha-kl(-/-), and beta-kl(-/-) mice revealed a comprehensive regulatory scheme of mineral homeostasis involving the mutually regulated positive/negative feedback actions of alpha-Kl, FGF23, and 1,25(OH)(2)D and an analogous regulatory network composed of beta-Kl, FGF15/humanFGF19, and bile acids that regulate bile acid/cholesterol metabolism. Contrary to in vitro data, beta-Kl is not essential for FGF21 signaling in adipose tissues in vivo, because (i) FGF21 signals are transduced in the absence of beta-Kl, (ii) FGF21 could not be precipitated by beta-Kl, and (iii) essential phenotypes in Fgf21(-/-) mice (decreased expressions of Hsl and Atgl in WAT) were not replicated in beta-kl(-/-) mice. These findings suggest the existence of Klotho-independent FGF21 signaling pathway(s) where undefined cofactors are involved. One-to-one functional interactions such as alpha-Klotho/FGF23, beta-Klotho/FGF15 (humanFGF19), and undefined cofactor/FGF21 would result in tissue-specific signal transduction of the FGF19 subfamily.

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

    Directory of Open Access Journals (Sweden)

    Shinsuke Kido

    2012-06-01

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

  2. Metabolic effects of FGF-21: thermoregulation and beyond

    Directory of Open Access Journals (Sweden)

    Bin eNi

    2015-09-01

    Full Text Available FGF-21, a member of the fibroblast growth factor (FGF family, is a novel hormone involved in the control of metabolism by modulating glucose homeostasis, insulin sensitivity, ketogenesis, and promoting adipose tissue browning. Recent studies demonstrated that brown adipose tissue is not only a target for, but is also a potentially important source of systemic FGF-21. These findings support the hypothesis that FGF-21 plays a physiologic role in thermogenesis and thermogenic recruitment of white adipose tissue by an autocrine-paracrine axis. This review examines the role of FGF-21 in thermogenesis from the perspective of cell-based, animal model, and human studies. We also present recent advances in the characterization of FGF-21’s regulation of metabolism.

  3. Understanding the structure-function relationship between FGF19 and its mitogenic and metabolic activities.

    Science.gov (United States)

    Wu, Xinle; Li, Yang

    2012-01-01

    FGF19 differs from the classical FGFs in that it has a much-reduced heparan sulfate proteoglycan binding affinity that allows it to act as endocrine hormone. Although FGF19 regulates several different metabolic activities, it still activates downstream signaling pathways through FGF receptors, in a similar manner to that seen in classical FGFs. Aberrant FGF signaling has been implicated in tumor development, and mouse models have confirmed that FGF19 has the potential to induce hepatocellular carcinoma. Treatment with anti-FGF19 antibody suppressed tumor progression in both FGF19 transgenic mice and colon cancer cell xenograft models. FGFR4, the predominant FGF receptor expressed in the liver, may play an important role in FGF19-mediated tumorigenesis. This review reports the current advances in understanding the structure-function relationship between FGF19 and its interactions with FGFRs, its physiological activities, and its differences from FGF21. The review also discusses strategies to separate the mitogenic and metabolic activities for the development of potential therapeutic molecules based on FGF19.

  4. Screening a phage display library for a novel FGF8b-binding peptide with anti-tumor effect on prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Wenhui; Chen, Xilei; Li, Tao; Li, Yanmei; Wang, Ruixue; He, Dan; Luo, Wu [Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou 510632 (China); Li, Xiaokun [Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou 510632 (China); School of Pharmaceutical Science, Wenzhou Medical College, Wenzhou 325035 (China); Wu, Xiaoping, E-mail: twxp@jnu.edu.cn [Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou 510632 (China); School of Pharmaceutical Science, Wenzhou Medical College, Wenzhou 325035 (China)

    2013-05-01

    Fibroblast growth factor 8b (FGF8b) is the major isoform of FGF8 expressed in prostate cancer and it correlates with the stage and grade of the disease. FGF8b has been considered as a potential target for prostate cancer therapy. Here we isolated 12 specific FGF8b-binding phage clones by screening a phage display heptapeptide library with FGF8b. The peptide (HSQAAVP, named as P12) corresponding to one of these clones showed high homology to the immunoglobulin-like (Ig-like) domain II(D2) of high-affinity FGF8b receptor (FGFR3c), contained 3 identical amino acids (AVP) to the authentic FGFR3 D2 sequence aa 163–169 (LLAVPAA) directly participating in ligand binding, carried the same charges as its corresponding motif (aa163–169) in FGFR3c, suggesting that P12 may have a greater potential to interrupt FGF8b binding to its receptors than other identified heptapeptides do. Functional analysis indicated that synthetic P12 peptides mediate significant inhibition of FGF8b-induced cell proliferation, arrest cell cycle at the G0/G1 phase via suppression of Cyclin D1 and PCNA, and blockade of the activations of Erk1/2 and Akt cascades in both prostate cancer cells and vascular endothelial cells. The results demonstrated that the P12 peptide acting as an FGF8b antagonist may have therapeutic potential in prostate cancer. - Highlights: ► A novel FGF8b-binding peptide P12 was isolated from a phage display library. ► The mechanisms for P12 peptide inhibiting cell proliferation were proposed. ► P12 caused cell cycle arrest at G0/G1 phase via suppression of Cyclin D1 and PCNA. ► P12 suppressed FGF8b-induced activations of Akt and MAP kinases. ► P12 acting as an FGF8b antagonist may have therapeutic potential in prostate cancer.

  5. Proliferation of neointimal smooth muscle cells after arterial injury. Dependence on interactions between fibroblast growth factor receptor-2 and fibroblast growth factor-9.

    Science.gov (United States)

    Agrotis, Alex; Kanellakis, Peter; Kostolias, Gina; Di Vitto, Giovanna; Wei, Chen; Hannan, Ross; Jennings, Garry; Bobik, Alex

    2004-10-01

    The growth factor signaling mechanisms responsible for neointimal smooth muscle cell (SMC) proliferation and accumulation, a characteristic feature of many vascular pathologies that can lead to restenosis after angioplasty, remain to be identified. Here, we examined the contribution of fibroblast growth factor receptors (FGFRs) 2 and 3 as well as novel fibroblast growth factors (FGFs) to such proliferation. Balloon catheter injury to the rat carotid artery stimulated the expression of two distinctly spliced FGFR-2 isoforms, differing only by the presence or absence of the acidic box, and two distinctly spliced FGFR-3 isoforms containing the acidic box and differing only by the presence of either the IIIb or IIIc exon. Post-injury arterial administration of recombinant adenoviruses expressing dominant negative mutant forms of these FGFRs were used to assess the roles of the endogenous FGFR isoforms in neointimal SMC proliferation. Dominant negative FGFR-2 containing the acidic box inhibited such proliferation by 40%, whereas the dominant negative FGFR-3 forms had little effect. Expression of FGF-9, known to be capable of binding to all four neointimal FGFR-2/-3 isoforms, was abundant within the neointima. FGF-9 markedly stimulated both the proliferation of neointimal SMCs and the activation of extracellular signal-related kinases 1/2, effects which were abrogated by the administration of antisense FGF-9 oligonucleotides to injured arteries and the expression of the dominant negative FGFR-2 adenovirus in cultured neointimal SMCs. These studies demonstrate that, although multiple FGFRs are induced in neointimal SMCs following arterial injury, specific interactions between distinctly spliced FGFR-2 isoforms and FGF-9 contribute to the proliferation of these SMCs.

  6. Microarray Analyses Reveal Marked Differences in Growth Factor and Receptor Expression Between 8-Cell Human Embryos and Pluripotent Stem Cells.

    Science.gov (United States)

    Vlismas, Antonis; Bletsa, Ritsa; Mavrogianni, Despina; Mamali, Georgina; Pergamali, Maria; Dinopoulou, Vasiliki; Partsinevelos, George; Drakakis, Peter; Loutradis, Dimitris; Kiessling, Ann A

    2016-01-15

    Previous microarray analyses of RNAs from 8-cell (8C) human embryos revealed a lack of cell cycle checkpoints and overexpression of core circadian oscillators and cell cycle drivers relative to pluripotent human stem cells [human embryonic stem cells/induced pluripotent stem (hES/iPS)] and fibroblasts, suggesting growth factor independence during early cleavage stages. To explore this possibility, we queried our combined microarray database for expression of 487 growth factors and receptors. Fifty-one gene elements were overdetected on the 8C arrays relative to hES/iPS cells, including 14 detected at least 80-fold higher, which annotated to multiple pathways: six cytokine family (CSF1R, IL2RG, IL3RA, IL4, IL17B, IL23R), four transforming growth factor beta (TGFB) family (BMP6, BMP15, GDF9, ENG), one fibroblast growth factor (FGF) family [FGF14(FH4)], one epidermal growth factor member (GAB1), plus CD36, and CLEC10A. 8C-specific gene elements were enriched (73%) for reported circadian-controlled genes in mouse tissues. High-level detection of CSF1R, ENG, IL23R, and IL3RA specifically on the 8C arrays suggests the embryo plays an active role in blocking immune rejection and is poised for trophectoderm development; robust detection of NRG1, GAB1, -2, GRB7, and FGF14(FHF4) indicates novel roles in early development in addition to their known roles in later development. Forty-four gene elements were underdetected on the 8C arrays, including 11 at least 80-fold under the pluripotent cells: two cytokines (IFITM1, TNFRSF8), five TGFBs (BMP7, LEFTY1, LEFTY2, TDGF1, TDGF3), two FGFs (FGF2, FGF receptor 1), plus ING5, and WNT6. The microarray detection patterns suggest that hES/iPS cells exhibit suppressed circadian competence, underexpression of early differentiation markers, and more robust expression of generic pluripotency genes, in keeping with an artificial state of continual uncommitted cell division. In contrast, gene expression patterns of the 8C embryo suggest that

  7. Microarray Analyses Reveal Marked Differences in Growth Factor and Receptor Expression Between 8-Cell Human Embryos and Pluripotent Stem Cells

    Science.gov (United States)

    Vlismas, Antonis; Bletsa, Ritsa; Mavrogianni, Despina; Mamali, Georgina; Pergamali, Maria; Dinopoulou, Vasiliki; Partsinevelos, George; Drakakis, Peter; Loutradis, Dimitris

    2016-01-01

    Previous microarray analyses of RNAs from 8-cell (8C) human embryos revealed a lack of cell cycle checkpoints and overexpression of core circadian oscillators and cell cycle drivers relative to pluripotent human stem cells [human embryonic stem cells/induced pluripotent stem (hES/iPS)] and fibroblasts, suggesting growth factor independence during early cleavage stages. To explore this possibility, we queried our combined microarray database for expression of 487 growth factors and receptors. Fifty-one gene elements were overdetected on the 8C arrays relative to hES/iPS cells, including 14 detected at least 80-fold higher, which annotated to multiple pathways: six cytokine family (CSF1R, IL2RG, IL3RA, IL4, IL17B, IL23R), four transforming growth factor beta (TGFB) family (BMP6, BMP15, GDF9, ENG), one fibroblast growth factor (FGF) family [FGF14(FH4)], one epidermal growth factor member (GAB1), plus CD36, and CLEC10A. 8C-specific gene elements were enriched (73%) for reported circadian-controlled genes in mouse tissues. High-level detection of CSF1R, ENG, IL23R, and IL3RA specifically on the 8C arrays suggests the embryo plays an active role in blocking immune rejection and is poised for trophectoderm development; robust detection of NRG1, GAB1, -2, GRB7, and FGF14(FHF4) indicates novel roles in early development in addition to their known roles in later development. Forty-four gene elements were underdetected on the 8C arrays, including 11 at least 80-fold under the pluripotent cells: two cytokines (IFITM1, TNFRSF8), five TGFBs (BMP7, LEFTY1, LEFTY2, TDGF1, TDGF3), two FGFs (FGF2, FGF receptor 1), plus ING5, and WNT6. The microarray detection patterns suggest that hES/iPS cells exhibit suppressed circadian competence, underexpression of early differentiation markers, and more robust expression of generic pluripotency genes, in keeping with an artificial state of continual uncommitted cell division. In contrast, gene expression patterns of the 8C embryo suggest that

  8. Fibroblast growth factor 21, fibroblast growth factor receptor 1, and β-Klotho expression in bovine growth hormone transgenic and growth hormone receptor knockout mice

    DEFF Research Database (Denmark)

    Brooks, Nicole E; Hjortebjerg, Rikke; Henry, Brooke E;

    2016-01-01

    of Fgf21, Fgfr1, and Klb mRNA in white adipose tissue (AT), brown AT, and liver were evaluated by reverse transcription quantitative PCR. RESULTS: As expected, bGH mice had increased body weight (p=3.70E(-8)) but decreased percent fat mass (p=4.87E(-4)). Likewise, GHR-/- mice had decreased body weight (p...... was to quantify circulating FGF21 and tissue specific expression of Fgf21, Fgfr1, and Klb in mice with modified GH action. Based on previous studies, we hypothesized that bovine GH transgenic (bGH) mice will be FGF21 resistant and GH receptor knockout (GHR-/-) mice will have normal FGF21 action. DESIGN: Seven......-month-old male bGH mice (n=9) and wild type (WT) controls (n=10), and GHR-/- mice (n=8) and WT controls (n=8) were used for all measurements. Body composition was determined before dissection, and tissue weights were measured at the time of dissection. Serum FGF21 levels were evaluated by ELISA. Expression...

  9. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer

    NARCIS (Netherlands)

    Suh, Jae Myoung; Jonker, Johan W; Ahmadian, Maryam; Goetz, Regina; Lackey, Denise; Osborn, Olivia; Huang, Zhifeng; Liu, Weilin; Yoshihara, Eiji; van Dijk, Theo H; Havinga, Rick; Fan, Weiwei; Yin, Yun-Qiang; Yu, Ruth T; Liddle, Christopher; Atkins, Annette R; Olefsky, Jerrold M; Mohammadi, Moosa; Downes, Michael; Evans, Ronald M

    2014-01-01

    Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a pote

  10. 3T3-L1脂肪细胞膜FGF-21结合蛋白的初步鉴定%Identification of Binding Partners of Fibroblast Growth Factor-21 in Cell Membrane of 3T3-L1 Cells

    Institute of Scientific and Technical Information of China (English)

    王文飞; 任桂萍; 侯玉婷; 李德山

    2008-01-01

    成纤维细胞生长因子(fibroblast growth factor,FGF)-21是最近发现的1个可以独立调节血糖的细胞因子,有望成为治疗2型糖尿病的备选药物,但是,FGF-21调解血糖的机理尚不十分清楚,为探讨该因子功能受体,应用偶联方法,以313-L1脂肪细胞为靶标,以FGF-21为诱饵,在3T3-L1脂肪细胞膜上寻找结合蛋白,结果表明,生物素标记的FGF-21可与脂肪细胞膜蛋白形成分子质量大小约300 kD以上两组复合物,竞争试验显示,非标记的FGF-21可与生物素标记的FGF-21竞争、抑制标记的FGF-21参入复合物;应用非标记FGF-21剂量越大,抑制后者参入复合物的程度越强,结果提示,该复合物是FGF-21特异性的,此外,随着生物素标记的FGF-21剂量增加,观察到的标记复合物越多;但是,当FGF-21剂量达12.5 mg/L以上时,观察到的复合物数量不再增加,实验结果提示,复合物形成与FGF-21剂量相关;FGF-21特异结合的蛋白质结合位点饱和后,复合物形成量最大,同时,采用FGF受体特异性抑制剂SU5402可特异性抑制FGF-21在3T3-L1脂肪细胞中的促进葡萄糖吸收作用,提示本实验所观察到的FGF-21-膜蛋白复合物可能就是FGF-21-FGF受体.

  11. FGF21 promotes metabolic homeostasis via white adipose and leptin in mice.

    Science.gov (United States)

    Véniant, Murielle M; Hale, Clarence; Helmering, Joan; Chen, Michelle M; Stanislaus, Shanaka; Busby, Jim; Vonderfecht, Steven; Xu, Jing; Lloyd, David J

    2012-01-01

    Fibroblast growth factor 21 (FGF21) is a potent metabolic regulator, and pharmacological administration elicits glucose and lipid lowering responses in mammals. To delineate if adipose tissue is the predominant organ responsible for anti-diabetic effects of FGF21, we treated mice with reduced body fat (lipodystrophy mice with adipose specific expression of active sterol regulatory element binding protein 1c; Tg) with recombinant murine FGF21 (rmuFGF21). Unlike wildtype (WT) mice, Tg mice were refractory to the beneficial effects of rmuFGF21 on body weight, adipose mass, plasma insulin and glucose tolerance. To determine if adipose mass was critical for these effects, we transplanted WT white adipose tissue (WAT) into Tg mice and treated the mice with rmuFGF21. After transplantation, FGF21 responsiveness was completely restored in WAT transplanted Tg mice compared to sham Tg mice. Further, leptin treatment alone was sufficient to restore the anti-diabetic effects of rmuFGF21 in Tg mice. Molecular analyses of Tg mice revealed normal adipose expression of Fgfr1, Klb and an 8-fold over-expression of Fgf21. Impaired FGF21-induced signaling indicated that residual adipose tissue of Tg mice was resistant to FGF21, whilst normal FGF21 signaling was observed in Tg livers. Together these data suggest that adipose tissue is required for the triglyceride and glucose, but not the cholesterol lowering efficacy of FGF21, and that leptin and FGF21 exert additive anti-diabetic effects in Tg mice.

  12. A peptide motif from the second fibronectin module of the neural cell adhesion molecule, NCAM, NLIKQDDGGSPIRHY, is a binding site for the FGF receptor

    DEFF Research Database (Denmark)

    Jacobsen, Jacob Hedemand; Kiselyov, Vladislav; Bock, Elisabeth

    2008-01-01

    The mechanism of fibroblast growth factor receptor (FGFR) activation by the neural cell adhesion molecule (NCAM) is not well understood. A motif in the second NCAM fibronectin type III (FN3) module, termed FGL, has by means of nuclear magnetic resonance (NMR) and surface plasmon resonance (SPR) a...

  13. Construction of a yeast artificial chromosome contig encompassing the human acidic fibroblast growth factor (FGF1) gene: Toward the cloning of the ANLL/MDS tumor-suppressor gene

    Energy Technology Data Exchange (ETDEWEB)

    Chiu, Ing-Ming; Gilmore, E.C.; Liu, Yang; Payson, R.A. (Ohio State Univ., Columbus, OH (United States))

    1994-02-01

    The region surrounding the human acidic fibroblast growth factor (FGF1) locus on chromosome 5q31 is of particular interest since it represents a critical region consistently lost in acute nonlymphocytic leukemia (ANLL) or myelodysplastic syndrome (MDS) patients who have a demonstrable deletion of the distal portion of the long arm of chromosome 5. It is proposed that an ANLL/MDS leukemia suppressor gene resides on 5q31. The authors have previously shown that the gene is most likely localized between FGF1 and PDGFRB/CSF1R loci. The region has also been linked to at least four other genetic diseases, Treacher Collins syndrome, diastrophic dysplasia, limb-girdle muscular dystrophy, and an autosomal dominant deafness, by linkage analysis. Here, they describe yeast artificial chromosomes (YAC) spanning 450 kb around the FGF1 gene. Six YAC clones were isolated from a human YAC library and their restriction enzyme maps were determined. The overlap of the clones with each other and with FGF1 cosmid and phage clones was characterized. Three of the YAC clones were found to contain the entire FGF1 gene, which spans more than 100 kb. Proximal and distal ends of several of these YAC clones were isolated for further overlap cloning. The proximal ends of both Y2 and Y4 were localized to previously isolated FGF1 DNA by sequence analysis. The distal ends of these two clones also hybridized to a human-hamster hybrid containing chromosome 5 as the only human genetic material. These results suggest that these YAC clones represent colinear DNA around the FGF1 locus. None of the YAC clones were found to contain the CD 14 and GRL genes, the closest known proximal and distal markers (relative to the centromere) to the FGF1 gene, respectively. This contig is useful for the overlap cloning of the 5q31 region and for reverse genetic strategies for the isolation of disease genes in the region. 46 refs., 7 figs., 5 tabs.

  14. Fibroblast growth factor receptors in in vitro and in vivo chondrogenesis: relating tissue engineering using adult mesenchymal stem cells to embryonic development.

    Science.gov (United States)

    Hellingman, Catharine A; Koevoet, Wendy; Kops, Nicole; Farrell, Eric; Jahr, Holger; Liu, Wei; Baatenburg de Jong, Robert J; Frenz, Dorothy A; van Osch, Gerjo J V M

    2010-02-01

    Adult mesenchymal stem cells (MSCs) are considered promising candidate cells for therapeutic cartilage and bone regeneration. Because tissue regeneration and embryonic development may involve similar pathways, understanding common pathways may lead to advances in regenerative medicine. In embryonic limb development, fibroblast growth factor receptors (FGFRs) play a role in chondrogenic differentiation. The aim of this study was to investigate and compare FGFR expression in in vivo embryonic limb development and in vitro chondrogenesis of MSCs. Our study showed that in in vitro chondrogenesis of MSCs three sequential stages can be found, as in embryonic limb development. A mesenchymal condensation (indicated by N-cadherin) is followed by chondrogenic differentiation (indicated by collagen II), and hypertrophy (indicated by collagen X). FGFR1-3 are expressed in a stage-dependent pattern during in vitro differentiation and in vivo embryonic limb development. In both models FGFR2 is clearly expressed by cells in the condensation phase. No FGFR expression was observed in differentiating and mature hyaline chondrocytes, whereas hypertrophic chondrocytes stained strongly for all FGFRs. To evaluate whether stage-specific modulation of chondrogenic differentiation in MSCs is possible with different subtypes of FGF, FGF2 and FGF9 were added to the chondrogenic medium during different stages in the culture process (early or late). FGF2 and FGF9 differentially affected the amount of cartilage formed by MSCs depending on the stage in which they were added. These results will help us understand the role of FGF signaling in chondrogenesis and find new tools to monitor and control chondrogenic differentiation.

  15. Clopidogrel inhibits angiogenesis of gastric ulcer healing via downregulation of vascular endothelial growth factor receptor 2.

    Science.gov (United States)

    Luo, Jiing-Chyuan; Peng, Yen-Ling; Chen, Tseng-Shing; Huo, Teh-Ia; Hou, Ming-Chih; Huang, Hui-Chun; Lin, Han-Chieh; Lee, Fa-Yauh

    2016-09-01

    Although clopidogrel does not cause gastric mucosal injury, it does not prevent peptic ulcer recurrence in high-risk patients. We explored whether clopidogrel delays gastric ulcer healing via inhibiting angiogenesis and to elucidate the possible mechanisms. Gastric ulcers were induced in Sprague Dawley rats, and ulcer healing and angiogenesis of ulcer margin were compared between clopidogrel-treated rats and controls. The expressions of the proangiogenic growth factors and their receptors including basic fibroblast growth factor (bFGF), bFGF receptor (FGFR), vascular endothelial growth factor (VEGF), VEGFR1, VEGFR2, platelet-derived growth factor (PDGF)A, PDGFB, PDGFR A, PDGFR B, and phosphorylated form of mitogenic activated protein kinase pathways over the ulcer margin were compared via western blot and reverse transcription polymerase chain reaction. In vitro, human umbilical vein endothelial cells (HUVECs) were used to elucidate how clopidogrel inhibited growth factors-stimulated HUVEC proliferation. The ulcer sizes were significantly larger and the angiogenesis of ulcer margin was significantly diminished in the clopidogrel (2 and 10 mg/kg/d) treated groups. Ulcer induction markedly increased the expression of phosphorylated form of extracellular signal-regulated kinase (pERK), FGFR2, VEGF, VEGFR2, and PDGFRA when compared with those of normal mucosa. Clopidogrel treatment significantly decreased pERK, FGFR2, VEGF, VEGFR2, and PDGFRA expression at the ulcer margin when compared with those of the respective control group. In vitro, clopidogrel (10(-6)M) inhibited VEGF-stimulated (20 ng/mL) HUVEC proliferation, at least, via downregulation of VEGFR2 and pERK. Clopidogrel inhibits the angiogenesis of gastric ulcer healing at least partially by the inhibition of the VEGF-VEGFR2-ERK signal transduction pathway. Copyright © 2015. Published by Elsevier B.V.

  16. FGF signalling regulates chromatin organisation during neural differentiation via mechanisms that can be uncoupled from transcription.

    Directory of Open Access Journals (Sweden)

    Nishal S Patel

    Full Text Available Changes in higher order chromatin organisation have been linked to transcriptional regulation; however, little is known about how such organisation alters during embryonic development or how it is regulated by extrinsic signals. Here we analyse changes in chromatin organisation as neural differentiation progresses, exploiting the clear spatial separation of the temporal events of differentiation along the elongating body axis of the mouse embryo. Combining fluorescence in situ hybridisation with super-resolution structured illumination microscopy, we show that chromatin around key differentiation gene loci Pax6 and Irx3 undergoes both decompaction and displacement towards the nuclear centre coincident with transcriptional onset. Conversely, down-regulation of Fgf8 as neural differentiation commences correlates with a more peripheral nuclear position of this locus. During normal neural differentiation, fibroblast growth factor (FGF signalling is repressed by retinoic acid, and this vitamin A derivative is further required for transcription of neural genes. We show here that exposure to retinoic acid or inhibition of FGF signalling promotes precocious decompaction and central nuclear positioning of differentiation gene loci. Using the Raldh2 mutant as a model for retinoid deficiency, we further find that such changes in higher order chromatin organisation are dependent on retinoid signalling. In this retinoid deficient condition, FGF signalling persists ectopically in the elongating body, and importantly, we find that inhibiting FGF receptor (FGFR signalling in Raldh2-/- embryos does not rescue differentiation gene transcription, but does elicit both chromatin decompaction and nuclear position change. These findings demonstrate that regulation of higher order chromatin organisation during differentiation in the embryo can be uncoupled from the machinery that promotes transcription and, for the first time, identify FGF as an extrinsic signal that

  17. HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1

    Directory of Open Access Journals (Sweden)

    Gallagher John

    2006-01-01

    Full Text Available Abstract Background Heparin/heparan sulfate (HS proteoglycans are found in the extracellular matrix (ECM and on the cell surface. A considerable body of evidence has established that heparin and heparan sulfate proteoglycans (HSPGs interact with numerous protein ligands including fibroblast growth factors, vascular endothelial growth factor (VEGF, cytokines, and chemokines. These interactions are highly dependent upon the pattern of sulfation modifications within the glycosaminoglycan chains. We previously cloned a cDNA encoding a novel human endosulfatase, HSulf-2, which removes 6-O-sulfate groups on glucosamine from subregions of intact heparin. Here, we have employed both recombinant HSulf-2 and the native enzyme from conditioned medium of the MCF-7-breast carcinoma cell line. To determine whether HSulf-2 modulates the interactions between heparin-binding factors and heparin, we developed an ELISA, in which soluble factors were allowed to bind to immobilized heparin. Results Our results show that the binding of VEGF, FGF-1, and certain chemokines (SDF-1 and SLC to immobilized heparin was abolished or greatly diminished by pre-treating the heparin with HSulf-2. Furthermore, HSulf-2 released these soluble proteins from their association with heparin. Native Sulf-2 from MCF-7 cells reproduced all of these activities. Conclusion Our results validate Sulf-2 as a new tool for deciphering the sulfation requirements in the interaction of protein ligands with heparin/HSPGs and expand the range of potential biological activities of this enzyme.

  18. Fibroblast growth factor receptor-3 is expressed in undifferentiated intestinal epithelial cells during murine crypt morphogenesis.

    Science.gov (United States)

    Vidrich, Alda; Buzan, Jenny M; Ilo, Chibuzo; Bradley, Leigh; Skaar, Kirstin; Cohn, Steven M

    2004-05-01

    Prior studies have demonstrated that fibroblast growth factor receptor-3 (FGFR-3) regulates proliferation of undifferentiated intestinal epithelial cells in vitro. However, the function(s) of FGFR-3-mediated signaling during intestinal development and epithelial differentiation in vivo remain unknown. The goal of this study was to define the temporal, regional, and cell-specific patterns of FGFR-3 expression and its ligands during normal intestinal ontogeny and epithelial regeneration. Both the IIIb and IIIc isoforms of FGFR-3 mRNA, which result from differential splicing of the FGFR-3 primary transcript, were detected in mouse small intestine as early as embryonic day 16. FGFR-3 levels peaked in the small intestine from 7 to 21 days after birth and decreased thereafter to reach the low levels observed in adult mice. FGFR-3 IIIb and IIIc mRNA levels were highest in the duodenum and proximal jejunum with lower levels of both seen in the distal jejunum, ileum, and colon. FGFR-3 was expressed in a subset of proliferating undifferentiated crypt epithelial cells located in the intervillous epithelium and in the lower half of nascently forming crypts but not in differentiated epithelial cell types. FGFR-3 IIIb was the dominant isoform expressed in both small intestinal and colonic crypts. Expression of FGF1, FGF2, and FGF9, known ligands of FGFR-3, paralleled patterns of FGFR-3 expression during gut development. These data suggest that signaling through FGFR-3 plays a role in regulating morphogenic events involved in formation of intestinal crypts and/or the fate of epithelial stem cells.

  19. FGF signalling: diverse roles during early vertebrate embryogenesis.

    Science.gov (United States)

    Dorey, Karel; Amaya, Enrique

    2010-11-01

    Fibroblast growth factor (FGF) signalling has been implicated during several phases of early embryogenesis, including the patterning of the embryonic axes, the induction and/or maintenance of several cell lineages and the coordination of morphogenetic movements. Here, we summarise our current understanding of the regulation and roles of FGF signalling during early vertebrate development.

  20. High molecular weight fibroblast growth factor-2 in the human heart is a potential target for prevention of cardiac remodeling.

    Directory of Open Access Journals (Sweden)

    Jon-Jon Santiago

    Full Text Available Fibroblast growth factor 2 (FGF-2 is a multifunctional protein synthesized as high (Hi- and low (Lo- molecular weight isoforms. Studies using rodent models showed that Hi- and Lo-FGF-2 exert distinct biological activities: after myocardial infarction, rat Lo-FGF-2, but not Hi-FGF-2, promoted sustained cardioprotection and angiogenesis, while Hi-FGF-2, but not Lo-FGF-2, promoted myocardial hypertrophy and reduced contractile function. Because there is no information regarding Hi-FGF-2 in human myocardium, we undertook to investigate expression, regulation, secretion and potential tissue remodeling-associated activities of human cardiac (atrial Hi-FGF-2. Human patient-derived atrial tissue extracts, as well as pericardial fluid, contained Hi-FGF-2 isoforms, comprising, respectively, 53%(±20 SD and 68% (±25 SD of total FGF-2, assessed by western blotting. Human atrial tissue-derived primary myofibroblasts (hMFs expressed and secreted predominantly Hi-FGF-2, at about 80% of total. Angiotensin II (Ang II up-regulated Hi-FGF-2 in hMFs, via activation of both type 1 and type 2 Ang II receptors; the ERK pathway; and matrix metalloprotease-2. Treatment of hMFs with neutralizing antibodies selective for human Hi-FGF-2 (neu-AbHi-FGF-2 reduced accumulation of proteins associated with fibroblast-to-myofibroblast conversion and fibrosis, including α-smooth muscle actin, extra-domain A fibronectin, and procollagen. Stimulation of hMFs with recombinant human Hi-FGF-2 was significantly more potent than Lo-FGF-2 in upregulating inflammation-associated proteins such as pro-interleukin-1β and plasminogen-activator-inhibitor-1. Culture media conditioned by hMFs promoted cardiomyocyte hypertrophy, an effect that was prevented by neu-AbHi-FGF-2 in vitro. In conclusion, we have documented that Hi-FGF-2 represents a substantial fraction of FGF-2 in human cardiac (atrial tissue and in pericardial fluid, and have shown that human Hi-FGF-2, unlike Lo-FGF-2, promotes

  1. Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule.

    Directory of Open Access Journals (Sweden)

    Katiuscia Pagano

    Full Text Available Fibroblast growth factors (FGFs are recognized targets for the development of therapies against angiogenesis-driven diseases, including cancer. The formation of a ternary complex with the transmembrane tyrosine kinase receptors (FGFRs, and heparan sulphate proteoglycans (HSPGs is required for FGF2 pro-angiogenic activity. Here by using a combination of techniques including Nuclear Magnetic Resonance, Molecular Dynamics, Surface Plasmon Resonance and cell-based binding assays we clarify the molecular mechanism of inhibition of an angiostatic small molecule, sm27, mimicking the endogenous inhibitor of angiogenesis, thrombospondin-1. NMR and MD data demonstrate that sm27 engages the heparin-binding site of FGF2 and induces long-range dynamics perturbations along FGF2/FGFR1 interface regions. The functional consequence of the inhibitor binding is an impaired FGF2 interaction with both its receptors, as demonstrated by SPR and cell-based binding assays. We propose that sm27 antiangiogenic activity is based on a twofold-direct and allosteric-mechanism, inhibiting FGF2 binding to both its receptors.

  2. Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion.

    Science.gov (United States)

    Knuchel, Sarah; Anderle, Pascale; Werfelli, Patricia; Diamantis, Eva; Rüegg, Curzio

    2015-06-10

    Carcinoma-associated fibroblasts were reported to promote colorectal cancer (CRC) invasion by secreting motility factors and extracellular matrix processing enzymes. Less is known whether fibroblasts may induce CRC cancer cell motility by contact-dependent mechanisms. To address this question we characterized the interaction between fibroblasts and SW620 and HT29 colorectal cancer cells in 2D and 3D co-culture models in vitro. Here we show that fibroblasts induce contact-dependent cancer cell elongation, motility and invasiveness independently of deposited matrix or secreted factors. These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2. Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects. FGFRs activate SRC in cancer cells and inhibition or silencing of SRC in cancer cells, but not in fibroblasts, prevents fibroblasts-mediated effects. Using an RGD-based integrin antagonist and function-blocking antibodies we demonstrate that cancer cell adhesion to fibroblasts requires integrin αvβ5. Taken together, these results demonstrate that fibroblasts induce cell-contact-dependent colorectal cancer cell migration and invasion under 2D and 3D conditions in vitro through fibroblast cell surface-associated FGF-2, FGF receptor-mediated SRC activation and αvβ5 integrin-dependent cancer cell adhesion to fibroblasts. The FGF-2-FGFRs-SRC-αvβ5 integrin loop might be explored as candidate therapeutic target to block colorectal cancer invasion.

  3. Expression profile of critical genes involved in FGF signaling pathway in the developing human primary dentition.

    Science.gov (United States)

    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.

  4. Angiotensin II-induced cardiac hypertrophy and fibrosis are promoted in mice lacking Fgf16

    OpenAIRE

    Matsumoto, Emi; Sasaki, Sayaka; Kinoshita, Hideyuki; Kito, Takuya; Ohta, Hiroya; Konishi, Morichika; Kuwahara, Koichiro; Nakao, Kazuwa; Itoh, Nobuyuki

    2013-01-01

    Fibroblast growth factors (Fgfs) are pleiotropic proteins involved in development, repair and metabolism. Fgf16 is predominantly expressed in the heart. However, as the heart function is essentially normal in Fgf16 knockout mice, its role has remained unclear. To elucidate the pathophysiological role of Fgf16 in the heart, we examined angiotensin II-induced cardiac hypertrophy and fibrosis in Fgf16 knockout mice. Angiotensin II-induced cardiac hypertrophy and fibrosis were significantly promo...

  5. Plasma FGF21 displays a circadian rhythm during a 72-h fast in healthy female volunteers

    DEFF Research Database (Denmark)

    Andersen, Birgitte; Beck-Nielsen, Henning; Højlund, Kurt

    2011-01-01

    Fibroblast growth factor (FGF21) is a potent regulator of glucose and lipid metabolism. In rodents, the hepatic expression of FGF21 is controlled by fasting and a circadian regulation, but the physiological role and regulation of FGF21 in humans is not well established. Therefore, the objective...... of this study was to elucidate the 24-h profiling of plasma FGF21 during a 72-h fast....

  6. Fibroblast Growth Factor 2 in the Dorsomedial Striatum Is a Novel Positive Regulator of Alcohol Consumption.

    Science.gov (United States)

    Even-Chen, Oren; Sadot-Sogrin, Yossi; Shaham, Ohad; Barak, Segev

    2017-09-06

    Repeated alcohol intake leads to mesostriatal neuroadaptations, resulting in drinking escalation and addiction phenotypes. Fibroblast growth factor 2 (FGF2) has been shown to interact with the mesostriatal dopaminergic system, and has been implicated in the actions of psychostimulants in the brain, and in several psychiatric disorders. Here, we report on a positive regulatory feedback loop of alcohol and FGF2 in rodent models. Specifically, we found that acute alcohol exposure (2.5 g/kg, i.p.) increased the mRNA expression of Fgf2 in the dorsal hippocampus, nucleus accumbens, and dorsal striatum. Longer alcohol exposure (7 d × 2.5 g/kg, i.p.) restricted these increases to the dorsal striatum, and the latter effect was blocked by the dopamine D2-like receptor antagonist haloperidol. Voluntary prolonged and excessive alcohol consumption in a 2-bottle choice procedure increased Fgf2 expression selectively in dorsomedial striatum (DMS) of both mice and rats. Importantly, we found that systemic administration of recombinant FGF2 (rFGF2) in mice, or rFGF2 infusion into the dorsal striatum or DMS of rats, increased alcohol consumption and preference, with no similar effects on saccharin or sucrose consumption. Finally, we found that inhibition of the endogenous FGF2 function in the DMS, by an anti-FGF2 neutralizing antibody, suppressed alcohol consumption and preference. Together, our results suggest that alcohol consumption increases the expression of Fgf2 in the DMS, and that striatal FGF2 promotes alcohol consumption, suggesting that FGF2 in the DMS is a positive regulator of alcohol drinking.SIGNIFICANCE STATEMENT Long-term alcohol intake may lead to neuroadaptations in the mesostriatal reward system, resulting in addiction phenotypes. Fibroblast growth factor 2 (FGF2) is crucial for the development and maintenance of the mesostriatal dopaminergic system. Here, we provide evidence for the involvement of FGF2 in alcohol-drinking behaviors. We show that alcohol

  7. Phosphate enhances Fgf23 expression through reactive oxygen species in UMR-106 cells.

    Science.gov (United States)

    Hori, Michiko; Kinoshita, Yuka; Taguchi, Manabu; Fukumoto, Seiji

    2016-03-01

    Fibroblast growth factor 23 (FGF23) has been shown to work as a phosphotropic hormone. Although FGF23 reduces the serum phosphate level, it has not been established that phosphate directly regulates FGF23 production. In this study, we investigated whether phosphate can enhance Fgf23 expression using the rat osteoblastic cell line UMR-106, which has been shown to express Fgf23 in response to 1,25-dihydroxyvitamin D [1,25(OH)2D]. Phosphate increased Fgf23 expression in a dose- and time-dependent manner in the presence of 1,25(OH)2D. Phosphate also increased Fgf23 promoter activity, but showed no effect on the half-life of Fgf23 messenger RNA. Phosphonoformic acid and PD98059, an inhibitor of MEK, inhibited the effects of phosphate on Fgf23 expression and promoter activity. In addition, phosphate enhanced production of reactive oxygen species (ROS) in UMR-106 cells, and hydrogen peroxide enhanced FGF23 production in a dose- and time-dependent manner. Hydrogen peroxide also enhanced Elk1 reporter activity, a target of the MEK-extracellular-signal-regulated kinase (ERK) pathway. Furthermore, the effect of phosphate on ROS production and Fgf23 expression was inhibited by apocynin, an inhibitor of NADPH oxidase. These results indicate that phosphate directly enhances Fgf23 transcription without affecting the stability of Fgf23 messenger RNA by stimulating NADPH-induced ROS production and the MEK-ERK pathway in UMR-106 cells.

  8. Phosphorylation and lipid raft association of fibroblast growth factor receptor-2 in oligodendrocytes.

    Science.gov (United States)

    Bryant, M R; Marta, C B; Kim, F S; Bansal, R

    2009-07-01

    Fibroblast growth factors (FGFs) and their receptors (FGFRs) initiate diverse cellular responses that contribute to the regulation of oligodendrocyte (OL) function. To understand the mechanisms by which FGFRs elicit these cellular responses, we investigated the phosphorylation of signal transduction proteins and the role of cholesterol-glycosphingolipid-enriched "lipid raft" microdomains in differentiated OLs. Surprisingly, we found that the most abundant tyrosine-phosphorylated protein in OLs was the 120-kd isoform of FGFR2 and that it was phosphorylated even in the absence of FGF2, suggesting a potential ligand-independent function for this receptor. Furthermore, FGFR2, but not FGFR1, was associated with lipid raft microdomains in OLs and myelin (but not in astrocytes). This provides the first evidence for the association of FGFR with TX-100-insoluble lipid raft fractions. FGFR2 phosphorylated the key downstream target, FRS2 in OLs. Raft disruption resulted in loss of phosphorylated FRS2 from lipid rafts, coupled with the loss of Akt but not of Mek or Erk phosphorylation. This suggests that FGFR2-FRS2 signaling in lipid rafts operates via the PI3-Kinase/Akt pathway rather than the Ras/Mek/Erk pathway, emphasizing the importance of microenvironments within the cell membrane. Also present in lipid rafts in OLs and myelin, but not in astrocytes, was a novel 52-kd isoform of FGFR2 that lacked the extracellular ligand-binding region. These results demonstrate that FGFR2 in OLs and myelin possess unique characteristics that are specific both to receptor type and to OLs and provide a novel mechanism to elicit distinct cellular responses that mediate both FGF-dependent and -independent functions.

  9. Evaluation of Value for Curative Effect of Serum 25-OH-D,FGF23 Factors Glucocorticoid Therapy in Patients with Osteoporosis%血清中25-OH-D、FGF23因子对骨质疏松患者糖皮质激素治疗疗效的评估价值分析

    Institute of Scientific and Technical Information of China (English)

    潘英; 陈东; 李娜

    2016-01-01

    Objective:To discuss the evaluation of value for curative effect of serum 25-OH-D,FGF23 factors glucocorticoid therapy in patients with osteoporosis.Method:A total of 120 patients with osteoporosis were selected for retrospective analysis from August 2014 to June 2015 glucocorticoid treatment, therapy for half a year, before treatment adopt bone mineral density,bone mineral density detector to detect the bone mineral density T value in -1.0- -2.5 s,according to their bone mineral density all patients were divided into group A(T=+2.5--1.0 s),group B(T=-1.0--2.5 s) and group C(T0.05).In the respect of after treatment serum 25-OH-D,FGF23 factor levels,group A>group B>group C(P0.05);治疗后血清中25-OH-D、FGF23因子水平方面,A组>B组>C组,差异均有统计学意义(P<0.05);ROC曲线分析结果显示,25-OH-D评估骨质疏松治疗后疗效的特异度为71.34%、灵敏度为83.45%、准确度为86.71%,FGF23评估骨质疏松治疗后疗效的特异度为79.64%、灵敏度为88.57%、准确度为91.22%。结论:血清中25-OH-D、FGF23因子与骨质疏松患者的病情密切相关,在早期诊断评估治疗后疗效方面具有更为良好的特异度、敏感度、准确度,利于指导临床治疗,值得临床进一步推广。

  10. Repair of large osteochondral defects in rabbits using porous hydroxyapatite/collagen (HAp/Col) and fibroblast growth factor-2 (FGF-2).

    Science.gov (United States)

    Maehara, Hidetsugu; Sotome, Shinichi; Yoshii, Toshitaka; Torigoe, Ichiro; Kawasaki, Yuichi; Sugata, Yumi; Yuasa, Masato; Hirano, Masahiro; Mochizuki, Naomi; Kikuchi, Masanori; Shinomiya, Kenichi; Okawa, Atsushi

    2010-05-01

    Articular cartilage has a limited capacity for self-renewal. This article reports the development of a porous hydroxyapatite/collagen (HAp/Col) scaffold as a bone void filler and a vehicle for drug administration. The scaffold consists of HAp nanocrystals and type I atelocollagen. The purpose of this study was to investigate the efficacy of porous HAp/Col impregnated with FGF-2 to repair large osteochondral defects in a rabbit model. Ninety-six cylindrical osteochondral defects 5 mm in diameter and 5 mm in depth were created in the femoral trochlear groove of the right knee. Animals were assigned to one of four treatment groups: porous HAp/Col impregnated with 50 microl of FGF-2 at a concentration of 10 or 100 microg/ml (FGF10 or FGF100 group); porous HAp/Col with 50 microl of PBS (HAp/Col group); and no implantation (defect group). The defect areas were examined grossly and histologically. Subchondral bone regeneration was quantified 3, 6, 12, and 24 weeks after surgery. Abundant bone formation was observed in the HAp/Col implanted groups as compared to the defect group. The FGF10 group displayed not only the most abundant bone regeneration but also the most satisfactory cartilage regeneration, with cartilage presenting a hyaline-like appearance. These findings suggest that porous HAp/Col with FGF-2 augments the cartilage repair process.

  11. Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21

    Science.gov (United States)

    Cornu, Marion; Oppliger, Wolfgang; Albert, Verena; Robitaille, Aaron M.; Trapani, Francesca; Quagliata, Luca; Fuhrer, Tobias; Sauer, Uwe; Terracciano, Luigi; Hall, Michael N.

    2014-01-01

    The liver is a key metabolic organ that controls whole-body physiology in response to nutrient availability. Mammalian target of rapamycin (mTOR) is a nutrient-activated kinase and central controller of growth and metabolism that is negatively regulated by the tumor suppressor tuberous sclerosis complex 1 (TSC1). To investigate the role of hepatic mTOR complex 1 (mTORC1) in whole-body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice. L-Tsc1 KO mice displayed reduced locomotor activity, body temperature, and hepatic triglyceride content in a rapamycin-sensitive manner. Ectopic activation of mTORC1 also caused depletion of hepatic and plasma glutamine, leading to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α)–dependent fibroblast growth factor 21 (FGF21) expression in the liver. Injection of glutamine or knockdown of PGC-1α or FGF21 in the liver suppressed the behavioral and metabolic defects due to mTORC1 activation. Thus, mTORC1 in the liver controls whole-body physiology through PGC-1α and FGF21. Finally, mTORC1 signaling correlated with FGF21 expression in human liver tumors, suggesting that treatment of glutamine-addicted cancers with mTOR inhibitors might have beneficial effects at both the tumor and whole-body level. PMID:25082895

  12. Heart-specific expression of FGF-16 and a potential role in postnatal cardioprotection.

    Science.gov (United States)

    Wang, Jie; Sontag, David; Cattini, Peter A

    2015-02-01

    Fibroblast growth factor 16 (FGF-16) was originally cloned from rat heart. Subsequent investigation of mouse FGF-16, including generation of null mice, revealed a specific pattern of expression in the endocardium and epicardium, and role for FGF-16 during embryonic heart development. FGF-16 is expressed mainly in brown adipose tissue during rat embryonic development, but is expressed mainly in the murine heart after birth. There is also an apparent switch from limited endocardial and epicardial expression in the embryo to the myocardium in the perinatal period. The FGF-16 gene and its location on the X chromosome are conserved between human and murine species, and no other member of the FGF family shows this pattern of spatial and temporal expression. The human and murine FGF-16 gene promoter regions also share an equivalent location for TATA sequences, as well as adjacent putative binding sites for transcription factors linked to cardiac expression and response to stress. Recent evidence has implicated nonsense mutation of FGF-16 with increased cardiovascular risk, and FGF-16 supplementation with cardioprotection. Here we review the important role of FGF-16 in embryonic heart development, its gene regulation, and evidence for FGF-16 as an endogenous and exogenous cardiac-specific and protective factor in the postnatal heart. Moreover, given the conservation of the FGF-16 gene and its chromosomal location between species, the question of support for a cardiac role in the human population is also considered.

  13. Direct effects of FGF21 on glucose uptake in human skeletal muscle

    DEFF Research Database (Denmark)

    Mashili, Fredirick L; Austin, Reginald L; Deshmukh, Atul S

    2011-01-01

    BACKGROUND: Fibroblast growth factor (FGF) 21, a novel member of the FGF family, plays a role in a variety of endocrine functions, including regulation of glucose and lipid metabolism. The role of FGF21 in skeletal muscle is currently not known. METHODS: Serum levels and skeletal muscle mRNA of FGF...... phosphorylation of Akt or AMP-activated protein kinase. CONCLUSIONS: Plasma FGF21 is increased in T2D patients, and positively correlated with fasting insulin and BMI. However, FGF21 has direct effects in enhancing skeletal muscle glucose uptake, providing additional points of regulation that may contribute......21 were determined in normal glucose tolerant (n = 40) and type 2 diabetic (T2D; n = 40) subjects. We determined whether FGF21 has direct effects on glucose metabolism in cultured myotubes (n = 8) and extensor digitorum longus skeletal muscle. RESULTS: Serum FGF21 levels increased 20% in T2D versus...

  14. Circulating FGF23 levels in response to acute changes in plasma Ca(2+)

    DEFF Research Database (Denmark)

    Gravesen, E; Mace, M.L.; Hofman-Bang, J.

    2014-01-01

    The regulation of fibroblast growth factor 23 (FGF23) synthesis and secretion is still incompletely understood. FGF23 is an important regulator of renal phosphate excretion and has regulatory effects on the calciotropic hormones calcitriol and parathyroid hormone (PTH). Calcium (Ca) and phosphate...... homeostasis are closely interrelated, and it is therefore likely that Ca is involved in FGF23 regulation. It has recently been reported that dietary Ca influenced FGF23 levels, with high Ca increasing FGF23. The mechanism remains to be clarified. It remains unknown whether acute changes in plasma Ca influence...... FGF23 levels and whether a close relationship, similar that known for Ca and PTH, exists between Ca and FGF23. Thus, the aim of the present study was to examine whether acute hypercalcemia and hypocalcemia regulate FGF23 levels in the rat. Acute hypercalcemia was induced by an intravenous Ca infusion...

  15. FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations.

    Science.gov (United States)

    Hébert, J M; Rosenquist, T; Götz, J; Martin, G R

    1994-09-23

    Fibroblast growth factor 5 (FGF5) is a secreted signaling protein. Mice homozygous for a predicted null allele of the Fgf5 gene, fgf5neo, produced by gene targeting in embryonic stem cells, have abnormally long hair. This phenotype appears identical to that of mice homozygous for the spontaneous mutation angora (go). The fgf5neo and go mutations fail to complement one another, and exon 1 of Fgf5 is deleted in DNA from go homozygotes, demonstrating that go is a mutant allele of Fgf5. Expression of Fgf5 is detected in hair follicles from wild-type mice and is localized to the outer root sheath during the anagen VI phase of the hair growth cycle. These findings provide evidence that FGF5 functions as an inhibitor of hair elongation, thus identifying a molecule whose normal function is apparently to regulate one step in the progression of the follicle through the hair growth cycle.

  16. FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis.

    Science.gov (United States)

    Naiche, L A; Holder, Nakisha; Lewandoski, Mark

    2011-03-08

    Somites form along the embryonic axis by sequential segmentation from the presomitic mesoderm (PSM) and differentiate into the segmented vertebral column as well as other unsegmented tissues. Somites are thought to form via the intersection of two activities known as the clock and the wavefront. Previous work has suggested that fibroblast growth factor (FGF) activity may be the wavefront signal, which maintains the PSM in an undifferentiated state. However, it is unclear which (if any) of the FGFs expressed in the PSM comprise this activity, as removal of any one gene is insufficient to disrupt early somitogenesis. Here we show that when both Fgf4 and Fgf8 are deleted in the PSM, expression of most PSM genes is absent, including cycling genes, WNT pathway genes, and markers of undifferentiated PSM. Significantly, markers of nascent somite cell fate expand throughout the PSM, demonstrating the premature differentiation of this entire tissue, a highly unusual phenotype indicative of the loss of wavefront activity. When WNT signaling is restored in mutants, PSM progenitor markers are partially restored but premature differentiation of the PSM still occurs, demonstrating that FGF signaling operates independently of WNT signaling. This study provides genetic evidence that FGFs are the wavefront signal and identifies the specific FGF ligands that encode this activity. Furthermore, these data show that FGF action maintains WNT signaling, and that both signaling pathways are required in parallel to maintain PSM progenitor tissue.

  17. 成纤维细胞生长因子受体的结构与功能%Structure and Function of Fibroblast Gro wth Factor Receptor

    Institute of Scientific and Technical Information of China (English)

    叶展; 赵涵芳; 钱关祥

    2003-01-01

    @@ 目前已发现的成纤维细胞生长因子(fibroblast growth factor, FGF)家族至少有19个成员(FGF1-19)[1],它们在发育、血管生成、创伤愈合中有重要作用.而它们的功能是通过与成纤维细胞生长因子受体(fibroblast growth factor receptor, FGFR)结合后,经过信号传递系统,激活相应的基因而实现的.本文主要介绍FGFR结构和功能的基础知识与研究近况.

  18. FGF2 — EDRN Public Portal

    Science.gov (United States)

    From NCBI Gene: The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members bind heparin and possess broad mitogenic and angiogenic activities. This protein has been implicated in diverse biological processes, such as limb and nervous system development, wound healing, and tumor growth. The mRNA for this gene contains multiple polyadenylation sites, and is alternatively translated from non-AUG (CUG) and AUG initiation codons, resulting in five different isoforms with distinct properties. The CUG-initiated isoforms are localized in the nucleus and are responsible for the intracrine effect, whereas, the AUG-initiated form is mostly cytosolic and is responsible for the paracrine and autocrine effects of this FGF. [provided by RefSeq, Jul 2008

  19. PKCε ACTIVATION PROMOTES FGF-2 EXOCYTOSIS AND INDUCES ENDOTHELIAL CELL PROLIFERATION AND SPROUTING

    Science.gov (United States)

    Monti, Martina; Donnini, Sandra; Morbidelli, Lucia; Giachetti, Antonio; Mochly-Rosen, Daria; Mignatti, Paolo; Ziche, Marina

    2013-01-01

    Protein kinase C epsilon (PKCε) activation controls fibroblast growth factor-2 (FGF-2) angiogenic signaling. Here, we examined the effect of activating PKCε on FGF-2 dependent vascular growth and endothelial activation. ψεRACK, a selective PKCε agonist induces pro-angiogenic responses in endothelial cells, including formation of capillary like structures and cell growth. These effects are mediated by FGF-2 export to the cell membrane, as documented by biotinylation and immunofluorescence, and FGF-2/FGFR1 signaling activation, as attested by ERK1/2-STAT-3 phosphorylation and de novo FGF-2 synthesis. Similarly, vascular endothelial growth factor (VEGF) activates PKCε in endothelial cells, and promotes FGF-2 export and FGF-2/FGFR1 signaling activation. ψεRACK fails to elicit responses in FGF-2−/− endothelial cells, and in cells pretreated with methylamine (MeNH2), an exocytosis inhibitor, indicating that both intracellular FGF-2 and its export toward the membrane are required for the ψεRACK activity. In vivo ψεRACK does not induce angiogenesis in the rabbit cornea. However, ψεRACK promotes VEGF angiogenic responses, an effect sustained by endothelial FGF-2 release and synthesis, since anti-FGF-2 antibody strongly attenuates VEGF responses. The results demonstrate that PKCε stimulation promotes angiogenesis and modulates VEGF activity, by inducing FGF-2 release and autocrine signaling. PMID:23880610

  20. Dimerization capacities of FGF2 purified with or without heparin-affinity chromatography.

    Directory of Open Access Journals (Sweden)

    Natalia Platonova

    Full Text Available Fibroblast growth factor-2 (FGF2 is a pleiotropic growth factor exhibiting a variety of biological activities. In this article, we studied the capacity of FGF2 purified with or without heparin affinity chromatography to self-associate. Analyzing the NMR HSQC spectra for different FGF2 concentrations, heparin-affinity purified FGF2 showed perturbations that indicate dimerization and are a higher-order oligomerization state. HSQC perturbation observed with different FGF2 concentrations revealed a heparin-binding site and two dimer interfaces. Thus, with increasing protein concentrations, FGF2 monomers make contacts with each other and form dimers or higher order oligomers. On the contrary, FGF2 purified with ion-exchange chromatography did not show similar perturbation indicating that self-association of FGF2 is eliminated if purification is done without heparin-affinity chromatography. The HSQC spectra of heparin-affinity purified FGF2 can be reproduced to some extent by adding heparin tetra-saccharide to ion exchange chromatography purified FGF2. Heparin-affinity purified FGF2 bound to acceptor and donor beads in a tagged form using His-tagged or GST-tagged proteins, also dimerized in the AlphaScreen™ assay. This assay was further validated using different experimental conditions and competitors. The assay constitutes an interesting tool to study dimerization of other FGF forms as well.

  1. Effects of estrogen receptor antagonist on biological behavior and expression of growth factors in the prolactinoma MMQ cell line.

    Science.gov (United States)

    Lv, Hongtao; Li, Chuzhong; Gui, Songbai; Sun, Meizhen; Li, Dan; Zhang, Yazhuo

    2011-04-01

    The relationship between estrogen and pituitary prolactinoma is well documented. The biological effects of estrogen are mainly mediated by estrogen receptor α (ERα). Several lines of evidence demonstrate that growth factors such as pituitary tumor transforming gene (PTTG), basic fibroblast growth factor (bFGF), transforming growth factor β1 (TGFβ1), transforming growth factor β3 (TGFβ3), and transforming growth factor β receptor type II (TGFβRII) play an important role in prolactinoma pathogenesis induced by estrogen, but the relationship between ERα and such growth factors is still unclear. The aims of this study are to investigate the functional role of ERα in proliferation, prolactin (PRL) secretion, and expression of the above-mentioned growth factors in MMQ cells in the absence of estrogen and to discuss the feasibility of using an estrogen receptor antagonist to treat prolactinoma. Fulvestrant, a "pure" antiestrogen without any estrogen-like activity, was used to block expression of ERα in the MMQ cell line. Proliferation and PRL secretion of MMQ cells were measured using CellTiter 96(®) AQueous One Solution Cell Proliferation Assay (MTS) and the enzyme-linked immunosorbent assay (ELISA) method. Levels of ERα, PTTG, bFGF, TGFβ1, TGFβ3, and TGFβRII were analyzed by real-time polymerase chain reaction (PCR) and Western blot. Fulvestrant significantly inhibited cell proliferation (up to 60.80%) and PRL secretion (up to 77.95%), and changed expression of TGFβ3 and TGFβRII in the absence of estrogen. In conclusion, ERα plays an important functional role in proliferation and PRL secretion of pituitary prolactinomas and also can change expression of some growth factors even under the condition of no estrogen. Fulvestrant could potentially be an effective therapy for treating such tumors.

  2. Heparin modulates the mitogenic activity of fibroblast growth factor by inducing dimerization of its receptor. a 3D view by using NMR.

    Science.gov (United States)

    Nieto, Lidia; Canales, Ángeles; Fernández, Israel S; Santillana, Elena; González-Corrochano, Rocío; Redondo-Horcajo, Mariano; Cañada, F Javier; Nieto, Pedro; Martín-Lomas, Manuel; Giménez-Gallego, Guillermo; Jiménez-Barbero, Jesús

    2013-09-23

    In vitro mitogenesis assays have shown that sulfated glycosaminoglycans (GAGs; heparin and heparan sulfate) cause an enhancement of the mitogenic activity of fibroblast growth factors (FGFs). Herein, we report that the simultaneous presence of FGF and the GAG is not an essential requisite for this event to take place. Indeed, preincubation with heparin (just before FGF addition) of cells lacking heparan sulfate produced an enhancing effect equivalent to that observed when the GAG and the protein are simultaneously added. A first structural characterization of this effect by analytical ultracentrifugation of a soluble preparation of the heparin-binding domain of fibroblast growth factor receptor 2 (FGFR2) and a low molecular weight (3 kDa) heparin showed that the GAG induces dimerization of FGFR2. To derive a high resolution structural picture of this molecular recognition process, the interactions of a soluble heparin-binding domain of FGFR2 with two different homogeneous, synthetic, and mitogenically active sulfated GAGs were analyzed by NMR spectroscopy. These studies, assisted by docking protocols and molecular dynamics simulations, have demonstrated that the interactions of these GAGs with the soluble heparin-binding domain of FGFR induces formation of an FGFR dimer; its architecture is equivalent to that in one of the two distinct crystallographic structures of FGFR in complex with both heparin and FGF1. This preformation of the FGFR dimer (with similar topology to that of the signaling complex) should favor incorporation of the FGF component to form the final assemblage of the signaling complex, without major entropy penalty. This cascade of events is probably at the heart of the observed activating effect of heparin in FGF-driven mitogenesis.

  3. SREBP-2 negatively regulates FXR-dependent transcription of FGF19 in human intestinal cells.

    Science.gov (United States)

    Miyata, Masaaki; Hata, Tatsuya; Yamazoe, Yasushi; Yoshinari, Kouichi

    2014-01-10

    Sterol regulatory element-binding protein-2 (SREBP-2) is a basic helix-loop-helix-leucine zipper transcription factor that positively regulates transcription of target genes involved in cholesterol metabolism. In the present study, we have investigated a possible involvement of SREBP-2 in human intestinal expression of fibroblast growth factor (FGF)19, which is an endocrine hormone involved in the regulation of lipid and glucose metabolism. Overexpression of constitutively active SREBP-2 decreased FGF19 mRNA levels in human colon-derived LS174T cells. In reporter assays, active SREBP-2 overexpression suppressed GW4064/FXR-mediated increase in reporter activities in regions containing the IR-1 motif (+848 to +5200) in the FGF19 gene. The suppressive effect disappeared in reporter activities in the region containing the IR-1 motif when the mutation was introduced into the IR-1 motif. In electrophoretic mobility shift assays, binding of the FXR/retinoid X receptor α heterodimer to the IR-1 motif was attenuated by adding active SREBP-2, but SREBP-2 binding to the IR-1 motif was not observed. In chromatin immunoprecipitation assays, specific binding of FXR to the IR-1-containing region of the FGF19 gene (+3214 to +3404) was increased in LS174T cells by treatment with cholesterol and 25-hydroxycholesterol. Specific binding of SREBP-2 to FXR was observed in glutathione-S-transferase (GST) pull-down assays. These results suggest that SREBP-2 negatively regulates the FXR-mediated transcriptional activation of the FGF19 gene in human intestinal cells.

  4. Fgf19 expression patterns in the developing chick inner ear.

    Science.gov (United States)

    Sánchez-Calderón, Hortensia; Francisco-Morcillo, Javier; Martín-Partido, Gervasio; Hidalgo-Sánchez, Matías

    2007-01-01

    The inner ear is a complex sensorial structure with hearing and balance functions. A key aim of developmental biology is to understand the molecular and cellular mechanisms involved in the induction, patterning and innervation of the vertebrate inner ear. These developmental events could be mediated by the expression of regulating genes, such as the members of the family of Fibroblast Growth Factors (Fgfs). This work reports the detailed spatial and temporal patterns of Fgf19 expression in the developing inner ear from otic cup (stage 14) to 8 embryonic days (stage 34). In the earliest stages, Fgf19 and Fgf8 expressions determine two subdomains within the Fgf10-positive proneural-sensory territory. We show that, from the earliest stages, the Fgf19 expression was detected in the acoustic-vestibular ganglion and the macula utriculi. The Fgf19 gene was also strongly, but transiently, expressed in the macula lagena, whereas the macula neglecta never expressed this gene in the period analysed. The Fgf19 expression was also clearly observed in some borders of various sensory elements. These results could be useful from further investigations into the role of FGF19 in otic patterning.

  5. Molecular mechanisms of the synergy between cysteinyl-leukotrienes and receptor tyrosine kinase growth factors on human bronchial fibroblast proliferation

    Directory of Open Access Journals (Sweden)

    Hajime Yoshisue

    2006-12-01

    Full Text Available We have reported that cysteinyl-leukotrienes (cys-LTs synergise not only with epidermal growth factor (EGF but also with platelet-derived growth factor (PDGF and fibroblast growth factor (FGF to induce mitogenesis in human bronchial fibroblasts. We now describe the molecular mechanisms underlying this synergism. Mitogenesis was assessed by incorporation of [3H]thymidine into DNA and changes in protein phosphorylation by Western blotting. Surprisingly, no CysLT receptor antagonists (MK-571, montelukast, BAY u9773 prevented the synergistic mitogenesis. LTD4 did not cause phosphorylation of EGFR nor did it augment EGF-induced phosphorylation of EGFR, and the synergy between LTD4 and EGF was not blocked by the metalloproteinase inhibitor GM6001 or by an HB-EGF neutralising antibody. The EGFR-selective kinase inhibitor, AG1478, suppressed the synergy by LTD4 and EGF, but had no effect on the synergy with PDGF and FGF. While inhibitors of mitogen-activated protein kinase, phosphatidylinositol 3-kinase and protein kinase C (PKC prevented the synergy, these drugs also inhibited mitogenesis elicited by EGF alone. In contrast, pertussis toxin (PTX efficiently inhibited the potentiating effect of LTD4 on EGF-induced mitogenesis, as well as that provoked by PDGF or FGF, but had no effect on mitogenesis elicited by the growth factors alone. Whereas LTD4 alone did not augment phosphorylation of extracellular signal-regulated kinase (Erk-1/2 and Akt, it increased phosphorylation of PKC in a Gi-dependent manner. Addition of LTD4 prolonged the duration of EGF-induced phosphorylation of Erk-1/2 and Akt, both of which were sensitive to PTX. The effect of cys-LTs involves a PTX-sensitive and PKC-mediated intracellular pathway leading to sustained growth factor-dependent phosphorylation of Erk-1/2 and Akt.

  6. Endothelial proteoglycans inhibit bFGF binding and mitogenesis.

    Science.gov (United States)

    Forsten, K E; Courant, N A; Nugent, M A

    1997-08-01

    Basic fibroblast growth factor (bFGF) is a known mitogen for vascular smooth muscle cells and has been implicated as having a role in a number of proliferative vascular disorders. Binding of bFGF to heparin or heparan sulfate has been demonstrated to both stimulate and inhibit growth factor activity. The activity, towards bFGF, of heparan sulfate proteoglycans present within the vascular system is likely related to the chemical characteristics of the glycosaminoglycan as well as the structure and pericellular location of the intact proteoglycans. We have previously shown that endothelial conditioned medium inhibits both bFGF binding to vascular smooth muscle cells and bFGF stimulated cell proliferation in vitro. In the present study, we have isolated proteoglycans from endothelial cell conditioned medium and demonstrated that they are responsible for the bFGF inhibitory activity. We further separated endothelial secreted proteoglycans into two fractions, PG-A and PG-B. The large sized fraction (PG-A) had greater inhibitory activity than did PG-B for both bFGF binding and bFGF stimulation of vascular smooth muscle cell proliferation. The increased relative activity of PG-A was attributed, in part, to larger heparan sulfate chains which were more potent inhibitors of bFGF binding than the smaller heparan sulfate chains on PG-B. Both proteoglycan fractions contained perlecan-like core proteins; however, PG-A contained an additional core protein (approximately 190 kDa) that was not observed in PG-B. Both proteoglycan fractions bound bFGF directly, and PG-A bound a significantly greater relative amount of bFGF than did PG-B. Thus the ability of endothelial heparan sulfate proteoglycans to bind bFGF and prevent its association with vascular smooth muscle cells appears essential for inhibition of bFGF-induced mitogenesis. The production of potent bFGF inhibitory heparan sulfate proteoglycans by endothelial cells might contribute to the maintenance of vascular homeostasis.

  7. Short hairpin RNA screen indicates that Klotho beta/FGF19 protein overcomes stasis in human colonic epithelial cells.

    Science.gov (United States)

    Kim, Jinyong; Eskiocak, Ugur; Stadler, Guido; Lou, Zhenjun; Kuro-o, Makoto; Shay, Jerry W; Wright, Woodring E

    2011-12-16

    Normal human colonic epithelial cells (HCECs) are not immortalized by telomerase alone but also require CDK4. Some human cell types growth-arrest due to stress- or aberrant signaling-induced senescence (stasis). Stasis represents the consequences of growth conditions culture that are inadequate to maintain long-term proliferation. Overexpressed CDK4 titers out p16 and allows cells to ignore the growth arrest signals produced by stasis. To identify factors contributing to the inadequate culture environment, we used a 62,000-member shRNA library to knock down factors cooperating with human telomerase reverse transcriptase (hTERT) in the immortalization of HCECs. Knockdown of Klotho gamma (KLG; also known as KLPH and LCTL) allowed hTERT to immortalize HCECs. KLG is one isoform of the Klotho family of factors that coordinate interaction between different FGF ligands and the FGF receptor. We also found that knockdown of KLG induced another member of the Klotho family, Klotho beta (KLB). Induction of KLB was maintained and could activate ERK1/2 in immortalized cells. Supplementation of the culture medium with the KLB ligand FGF19 had a similar effect on hTERT-expressing HCECs as knockdown of KLG regarding both immortalization and down-regulation of the tumor suppressor Klotho alpha. Together, these data suggest that KLB is an important regulator in the immortalization of HCECs by facilitating FGF19 growth factor signaling.

  8. FGF-23 and cognitive performance in hemodialysis patients.

    Science.gov (United States)

    Drew, David A; Tighiouart, Hocine; Scott, Tammy M; Lou, Kristina V; Fan, Li; Shaffi, Kamran; Weiner, Daniel E; Sarnak, Mark J

    2014-01-01

    Although cognitive impairment is common in hemodialysis patients, the etiology of and risk factors for its development remain unclear. Fibroblast growth factor 23 (FGF-23) levels are elevated in hemodialysis patients and are associated with increased mortality and left ventricular hypertrophy. Despite FGF-23 being found within the brain, there are no prior studies assessing whether FGF-23 levels are associated with cognitive performance. We measured FGF-23 in 263 prevalent hemodialysis patients in whom comprehensive neurocognitive testing was also performed. The cross-sectional association between patient characteristics and FGF-23 levels was assessed. Principal factor analysis was used to derive two factors from cognitive test scores, representing memory and executive function, which carried a mean of 0 and a standard deviation of 1. Multivariable linear regression adjusting for age, sex, education status, and other relevant covariates was used to explore the relationship between FGF-23 and each factor. Mean age was 63 years, 46% were women and 22% were African American. The median FGF-23 level was 3098 RU/mL. Younger age, lower prevalence of diabetes, longer dialysis vintage, and higher calcium and phosphorus were independently associated with higher FGF-23 levels. Higher FGF-23 was independently associated with a lower memory score (per doubling of FGF-23, β = -0.08 SD [95% confidence interval, CI: -0.16, -0.01]) and highest quartile vs. lowest quartile (β = -0.42 SD [-0.82, -0.02]). There was no definite association of FGF 23 with executive function when examined as a continuous variable (β = -0.03 SD [-0.10, 0.04]); however, there was a trend in the quartile analysis (β = -0.28 SD [-0.63, 0.07], P = 0.13, for 4th quartile vs. 1st quartile). FGF-23 was associated with worse performance on a composite memory score, including after adjustment for measures of mineral metabolism. High FGF-23 levels in hemodialysis patients may contribute to

  9. FGF21 as a Stress Hormone: The Roles of FGF21 in Stress Adaptation and the Treatment of Metabolic Diseases

    Directory of Open Access Journals (Sweden)

    Kook Hwan Kim

    2014-08-01

    Full Text Available Fibroblast growth factor 21 (FGF21 is an endocrine hormone that is primarily expressed in the liver and exerts beneficial effects on obesity and related metabolic diseases. In addition to its remarkable pharmacologic actions, the physiological roles of FGF21 include the maintenance of energy homeostasis in the body in conditions of metabolic or environmental stress. The expression of FGF21 is induced in multiple organs in response to diverse physiological or pathological stressors, such as starvation, nutrient excess, autophagy deficiency, mitochondrial stress, exercise, and cold exposure. Thus, the FGF21 induction caused by stress plays an important role in adaptive response to these stimuli. Here, we highlight our current understanding of the functional importance of the induction of FGF21 by diverse stressors as a feedback mechanism that prevents excessive stress.

  10. FGF signalling regulates bone growth through autophagy.

    Science.gov (United States)

    Cinque, Laura; Forrester, Alison; Bartolomeo, Rosa; Svelto, Maria; Venditti, Rossella; Montefusco, Sandro; Polishchuk, Elena; Nusco, Edoardo; Rossi, Antonio; Medina, Diego L; Polishchuk, Roman; De Matteis, Maria Antonietta; Settembre, Carmine

    2015-12-10

    Skeletal growth relies on both biosynthetic and catabolic processes. While the role of the former is clearly established, how the latter contributes to growth-promoting pathways is less understood. Macroautophagy, hereafter referred to as autophagy, is a catabolic process that plays a fundamental part in tissue homeostasis. We investigated the role of autophagy during bone growth, which is mediated by chondrocyte rate of proliferation, hypertrophic differentiation and extracellular matrix (ECM) deposition in growth plates. Here we show that autophagy is induced in growth-plate chondrocytes during post-natal development and regulates the secretion of type II collagen (Col2), the major component of cartilage ECM. Mice lacking the autophagy related gene 7 (Atg7) in chondrocytes experience endoplasmic reticulum storage of type II procollagen (PC2) and defective formation of the Col2 fibrillary network in the ECM. Surprisingly, post-natal induction of chondrocyte autophagy is mediated by the growth factor FGF18 through FGFR4 and JNK-dependent activation of the autophagy initiation complex VPS34-beclin-1. Autophagy is completely suppressed in growth plates from Fgf18(-/-) embryos, while Fgf18(+/-) heterozygous and Fgfr4(-/-) mice fail to induce autophagy during post-natal development and show decreased Col2 levels in the growth plate. Strikingly, the Fgf18(+/-) and Fgfr4(-/-) phenotypes can be rescued in vivo by pharmacological activation of autophagy, pointing to autophagy as a novel effector of FGF signalling in bone. These data demonstrate that autophagy is a developmentally regulated process necessary for bone growth, and identify FGF signalling as a crucial regulator of autophagy in chondrocytes.

  11. FGF19-A New Metabolic Regulator%FGF19——新的代谢调节因子

    Institute of Scientific and Technical Information of China (English)

    宋倩倩

    2012-01-01

    Fibroblast growth factor 19( FGF19 ),a newly found metabolic regulator, is secreted and expressed when stimulated by bile acid secretion into the intestine. Human FGF19 and mouse FGF15 are homologous. Secreted intestinal FGF19 can go into the liver along with the circulation to combine with FGFR4 to function , which is hormone-like, playing an important role in metabolic regulation: such as the regulation of bile acid metabolism and filling of the gallbladder, improving the energy metabolism to reduce body weight, and improving blood glucose and so on.%成纤维细胞生长因子19(FGF19)是新近发现的一种代谢调节因子,由胆汁酸分泌进入肠道后刺激肠道分泌和表达.人类的FGF19与小鼠的FGF15同源.FGF19经肠道分泌后可随循环进入肝脏并与肝脏中的FGFR4结合起作用,它具有激素样作用,发挥着重要的代谢调节作用,如调节胆汁酸代谢、调节胆囊的充盈、提高能量代谢降低体质量、改善血糖等.

  12. The MAPK-dependent regulation of the Jagged/Notch gene expression by VEGF, bFGF or PPAR gamma mediated angiogenesis in HUVEC

    DEFF Research Database (Denmark)

    Kiec-Wilk, B; Grzybowska-Galuszka, J; Polus, A

    2010-01-01

    The Jagged-Notch signalling, plays a crucial role in cell differentiation. Angiogenesis, is regulated by VEGF, bFGF as well as by the free fatty acid metabolites , which are regulators of transcription factors such as peroxisome proliferation activating receptors (PPARs). The study analyzed...... the signalling pathways involved in the regulation of Jagged-1/Notch-4 expression in endothelial cells (HUVECs) in response to VEGF, bFGF and PPAR-gamma exogenous activator - ciglitazone. HUVECs were incubated with investigated substances for 24 hours, with or without the presence of the MAP-kinases inhibitors...

  13. Circulating FGF23 levels in response to acute changes in plasma Ca(2+).

    Science.gov (United States)

    Gravesen, Eva; Mace, Maria L; Hofman-Bang, Jacob; Olgaard, Klaus; Lewin, Ewa

    2014-07-01

    The regulation of fibroblast growth factor 23 (FGF23) synthesis and secretion is still incompletely understood. FGF23 is an important regulator of renal phosphate excretion and has regulatory effects on the calciotropic hormones calcitriol and parathyroid hormone (PTH). Calcium (Ca) and phosphate homeostasis are closely interrelated, and it is therefore likely that Ca is involved in FGF23 regulation. It has recently been reported that dietary Ca influenced FGF23 levels, with high Ca increasing FGF23. The mechanism remains to be clarified. It remains unknown whether acute changes in plasma Ca influence FGF23 levels and whether a close relationship, similar that known for Ca and PTH, exists between Ca and FGF23. Thus, the aim of the present study was to examine whether acute hypercalcemia and hypocalcemia regulate FGF23 levels in the rat. Acute hypercalcemia was induced by an intravenous Ca infusion and hypocalcemia by infusion of ethylene glycol tetraacetic acid (EGTA) in normal and acutely parathyroidectomized rats. Intact plasma FGF23 and intact plasma PTH and plasma Ca(2+) and phosphate were measured. Acute hypercalcemia and hypocalcemia resulted as expected in adequate PTH secretory responses. Plasma FGF23 levels remained stable at all plasma Ca(2+) levels; acute parathyroidectomy did not affect FGF23 secretion. In conclusion, Ca is not a regulator of acute changes in FGF23 secretion.

  14. Establishment of canine hemangiosarcoma xenograft models expressing endothelial growth factors, their receptors, and angiogenesis-associated homeobox genes

    Directory of Open Access Journals (Sweden)

    Maruo Kouji

    2009-10-01

    Full Text Available Abstract Background Human hemangiosarcoma (HSA tends to have a poor prognosis; its tumorigenesis has not been elucidated, as there is a dearth of HSA clinical specimens and no experimental model for HSA. However, the incidence of spontaneous HSA is relatively high in canines; therefore, canine HSA has been useful in the study of human HSA. Recently, the production of angiogenic growth factors and their receptors in human and canine HSA has been reported. Moreover, the growth-factor environment of HSA is very similar to that of pathophysiological angiogenesis, which some homeobox genes regulate in the transcription of angiogenic molecules. In the present study, we established 6 xenograft canine HSA tumors and detected the expression of growth factors, their receptors, and angiogenic homeobox genes. Methods Six primary canine HSAs were xenografted to nude mice subcutaneously and serially transplanted. Subsequently, the expressions of vascular endothelial growth factor (VEGF-A, basic fibroblast growth factors (bFGF, flt-1 and flk-1 (receptors of VEGF-A, FGFR-1, and angiogenic homeobox genes HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 were investigated in original and xenograft tumors by histopathology, immunostaining, and reverse transcription polymerase chain reaction (RT-PCR, using canine-specific primer sets. Results Histopathologically, xenograft tumors comprised a proliferation of neoplastic cells that were varied in shape, from spindle-shaped and polygonal to ovoid; some vascular-like structures and vascular clefts of channels were observed, similar to those in the original tumors. The expression of endothelial markers (CD31 and vWF was detected in xenograft tumors by immunohistochemistry and RT-PCR. Moreover, the expression of VEGF-A, bFGF, flt-1, flk-1, FGFR-1, HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 was detected in xenograft tumors. Interestingly, expressions of bFGF tended to be higher in 3 of the xenograft HSA tumors than in the

  15. Decline in Proliferation and Immature Neuron Markers in the Human Subependymal Zone during Aging: Relationship to EGF- and FGF-related Transcripts

    Directory of Open Access Journals (Sweden)

    Christin Weissleder

    2016-11-01

    Full Text Available Neuroblasts exist within the human subependymal zone (SEZ; however, it is debated to what extent neurogenesis changes during normal aging. It is also unknown how precursor proliferation may correlate with the generation of neuronal and glial cells or how expression of growth factors and receptors may change throughout the adult lifespan. We provided evidence of dividing cells in the human SEZ in conjunction with a dramatic age-related decline (n=50; 21-103 years of mRNAs indicative of proliferating cells (Ki67 and immature neurons (doublecortin. Microglia mRNA (ionized calcium-binding adapter molecule 1 increased during aging, whereas transcript levels of stem/precursor cells (glial fibrillary acidic protein delta and achaete-scute homolog 1, astrocytes (vimentin and glial fibrillary acidic protein and oligodendrocytes (oligodendrocyte lineage transcription factor 2 remained stable. Epidermal growth factor receptor (EGFR and fibroblast growth factor 2 (FGF2 mRNAs increased throughout adulthood, while transforming growth factor alpha (TGFα, EGF, Erb-B2 receptor tyrosine kinase 4 (ErbB4 and FGF receptor 1 (FGFR1 mRNAs were unchanged across adulthood. Cell proliferation mRNA positively correlated with FGFR1 transcripts. Immature neuron and oligodendrocyte expression positively correlated with TGFα and ErbB4 mRNAs, whilst astrocyte transcripts positively correlated with EGF, FGF2 and FGFR1 mRNAs. Microglia mRNA positively correlated with EGF and FGF2 expression. Our findings indicate that neurogenesis in the human SEZ continues well into adulthood, although proliferation and neuronal differentiation may decline across adulthood. We suggest that mRNA expression of EGF- and FGF-related family members do not become limited during aging and may modulate neuronal and glial fate determination in the SEZ throughout human life.

  16. Epidermal Growth Factor Receptor in Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira-Cunha, Melissa, E-mail: melissacunha@doctors.org.uk [Hepatobiliary Surgery Unit, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL (United Kingdom); Newman, William G. [Genetic Medicine, MAHSC, University of Manchester, St Mary' s Hospital, Oxford Road, Manchester, M13 9WL (United Kingdom); Siriwardena, Ajith K. [Hepatobiliary Surgery Unit, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL (United Kingdom)

    2011-03-24

    Pancreatic cancer is the fourth leading cause of cancer related death. The difficulty in detecting pancreatic cancer at an early stage, aggressiveness and the lack of effective therapy all contribute to the high mortality. Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein, which is expressed in normal human tissues. It is a member of the tyrosine kinase family of growth factors receptors and is encoded by proto-oncogenes. Several studies have demonstrated that EGFR is over-expressed in pancreatic cancer. Over-expression correlates with more advanced disease, poor survival and the presence of metastases. Therefore, inhibition of the EGFR signaling pathway is an attractive therapeutic target. Although several combinations of EGFR inhibitors with chemotherapy demonstrate inhibition of tumor-induced angiogenesis, tumor cell apoptosis and regression in xenograft models, these benefits remain to be confirmed. Multimodality treatment incorporating EGFR-inhibition is emerging as a novel strategy in the treatment of pancreatic cancer.

  17. FGF8一FGF家族的新成员

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@ 成纤维细胞生长因子(fibroblast growth factor FGF)家族是能够紧密结合肝素,并在核酸序列上具有一定同源性的一组蛋白,在各种不同的生理、病理过程中起着重要的作用.包括:胚胎发育、细胞生长、形态发生、组织修复、血管发生、肿瘤生长和浸润等.FGF家族目前共有19个成员,其中FGF18是FGF家族新发现的的一个. 1998年,Mickey等人最先用全长的小鼠FGF--18作为探针筛选人心脏λTripEx cDNA文库,获得了几个阳性的克隆,这几个噬菌体克隆的cDNA的插入片段插入到pTripEx质粒载体中,然后进行序列测定和分析,结果发现一种新的FGF因子,遂命名为FGF18.人FGF-18cDNA序列的结果被收入在Genbank中,编号为AFO75292.人FGF-18 cDNA序列全长621个核苷酸,N端的前26个氨基酸为信号肽,有2个糖基化位点,有2个半胱氨酸(不包括信号肽部分),迄今为止还不知这2个半胱氨酸是否参与二硫键的形成.将人FGF-18氨基酸序列与人FGF-17、人FGF-8、小鼠FGF-18进行比较发现,人FGF18与小鼠FGF18的氨甘酸序列有99%相同;与人FGF-8有60%相同;与人FGF-17有58%相同;在某种程度上,人FGF18与其他FGF家庭的成员也有一定的同源性.

  18. Sphingosine-1-phosphate induces VEGF-C expression through a MMP-2/FGF-1/FGFR-1-dependent pathway in endothelial cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Chi-hao CHANG; Yuan-li HUANG; Ming-kwang SHYU; Shee-uan CHEN; Chih-hsin LIN; Tsai-kai JU; JenHer LU

    2013-01-01

    Aim:To investigate whether sphingosine-1-phosphate (S1P),a potent angiogenic factor,induced vascular endothelial growth factor-C (VEGF-C) expression in endothelial cells in vitro and to examine its underlying mechanisms.Methods:Human umbilical vein endothelial cells (HUVECs) were examined.VEGF-C mRNA expression in the cells was assessed using real-time PCR.VEGF-C protein and FGFR-1 phosphorylation in the cells were measured with ELISA.RNA interference was used to downregulate the expression of matrix metalloproteinase-2 (MMP-2),fibroblast growth factor-1(FGF-1) and FGF receptor-1 (FGFR-1).Results:Incubation of HUVECs with S1P (1,5,and 10 μmol/L) significantly increased VEGF-C expression.The effect was blocked by pretreatment with the MMP inhibitor GM6001 or the FGFR inhibitor SU5402,but not the EGFR inhibitor AG1478.The effect was also blocked in HUVECs that were transfected with FGFR-1 or MMP-2 siRNA.Furthermore,incubation of HUVECs with S1P (5 μmol/L) significantly increased FGFR-1 phosphorylation,which was blocked by GM6001.Moreover,knockdown of FGF-1,not FGF-2,in HUVECs with siRNAs,blocked S1P-induced VEGF-C expression.Conclusion:S1P induces VEGF-C expression through a MMP-2/FGF-1/FGFR-1-dependent pathway in HUVECs.

  19. Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice.

    Science.gov (United States)

    Rusli, Fenni; Deelen, Joris; Andriyani, Evi; Boekschoten, Mark V; Lute, Carolien; van den Akker, Erik B; Müller, Michael; Beekman, Marian; Steegenga, Wilma T

    2016-07-29

    Fibroblast growth factor 21 (Fgf21) has emerged as a potential plasma marker to diagnose non-alcoholic fatty liver disease (NAFLD). To study the molecular processes underlying the association of plasma Fgf21 with NAFLD, we explored the liver transcriptome data of a mild NAFLD model of aging C57BL/6J mice at 12, 24, and 28 months of age. The plasma Fgf21 level significantly correlated with intrahepatic triglyceride content. At the molecular level, elevated plasma Fgf21 levels were associated with dysregulated metabolic and cancer-related pathways. The up-regulated Fgf21 levels in NAFLD were implied to be a protective response against the NAFLD-induced adverse effects, e.g. lipotoxicity, oxidative stress and endoplasmic reticulum stress. An in vivo PPARα challenge demonstrated the dysregulation of PPARα signalling in the presence of NAFLD, which resulted in a stochastically increasing hepatic expression of Fgf21. Notably, elevated plasma Fgf21 was associated with declining expression of Klb, Fgf21's crucial co-receptor, which suggests a resistance to Fgf21. Therefore, although liver fat accumulation is a benign stage of NAFLD, the elevated plasma Fgf21 likely indicated vulnerability to metabolic stressors that may contribute towards progression to end-stage NAFLD. In conclusion, plasma levels of Fgf21 reflect liver fat accumulation and dysregulation of metabolic pathways in the liver.

  20. Effect of FGF-BP on angiogenesis in squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    李为民; 陈文彬

    2004-01-01

    @@ Angiogenesis, the formation of new blood vessels, is a critical cellular process for cancer growth and metastasis.Ribozyme targeting studies on overexpression and reduced expression of fibroblast growth factors binding protein (FGF-BP) have indicated that this protein plays a direct role in angiogenesis during tumor development. 1 To explore the effect of FGF-BP on neovascularization of squamous cell carcinoma, we investigated FGF-BP mRNA expression using in situ hybridization on squamous cell carcinoma. To further define the potential role of FGF-BP in individual stages of metastasis, we studied the association of FGF-BP with vascularity.

  1. Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice.

    Science.gov (United States)

    Wu, Xinle; Ge, Hongfei; Lemon, Bryan; Weiszmann, Jennifer; Gupte, Jamila; Hawkins, Nessa; Li, Xiaofan; Tang, Jie; Lindberg, Richard; Li, Yang

    2009-08-25

    FGF19 is a hormone that regulates bile acid and glucose homeostasis. Progress has been made in identifying cofactors for receptor activation. However, several functions of FGF19 have not yet been fully defined, including the actions of FGF19 on target tissues, its FGF receptor specificity, and the contributions of other cofactors, such as heparin. Here, we explore the requirements for FGF19-FGFR/co-receptor interactions and signaling in detail. We show that betaKlotho was essential for FGF19 interaction with FGFRs 1c, 2c, and 3c, but FGF19 was able to interact directly with FGFR4 in the absence of betaKlotho in a heparin-dependent manner. Further, FGF19 activated FGFR4 signaling in the presence or absence of betaKlotho, but activation of FGFRs 1c, 2c, or 3c was completely betaKlotho dependent. We then generated an FGF19 molecule, FGF19dCTD, which has a deletion of the C-terminal region responsible for betaKlotho interaction. We determined that betaKlotho-dependent FGFR1c, 2c, and 3c interactions and activation were abolished, and betaKlotho-independent FGFR4 activation was preserved; therefore, FGF19dCTD is an FGFR4-specific activator. This unique FGF19 molecule specifically activated FGFR4-dependent signaling in liver and suppressed CYP7A1 expression in vivo, but was unable to activate signaling in adipose where FGFR4 expression is very low. Interestingly, unlike FGF19, treatment of ob/ob mice with FGF19dCTD failed to improve glucose levels and insulin sensitivity. These results suggest that FGF19-regulated liver bile acid metabolism could be independent of its glucose-lowering effect, and direct FGFR activation in adipose tissue may play an important role in the regulation of glucose homeostasis.

  2. Fibroblast growth factor 2 and DNA repair involvement in the keratinocyte stem cells response to ionizing radiation; Implication du FGF2 (fibroblast growth factor 2) et la reparation de l'ADN dans la reponse des keratinocytes souches aux irradiations

    Energy Technology Data Exchange (ETDEWEB)

    Harfouche, L' Emira Ghida

    2010-02-15

    Keratinocyte stem cells (KSCs) from the human inter follicular epidermis are regarded as the major target to radiation during radiotherapy. We found herein that KSCs are more resistant to ionizing radiation than their direct progeny, and presented more rapid DNA damage repair kinetics than the progenitors. Furthermore, we provided evidence describing the effect of fibroblast growth factor 2 (FGF2) signaling on the ability of KSCs and progenitors to repair damaged DNA. Despite our knowledge of the fact, that FGF is an anti-apoptotic factor in multiple cell types, the direct link between DNA repair and FGF2 signaling has rarely been shown. Existence of such link is an important issue with implications not only to stem cell field but also to cancer therapy. (author)

  3. Preparation and in vitro activity of controlled release microspheres incorporating bFGF

    Institute of Scientific and Technical Information of China (English)

    SHEN Bin; PEI Fu-xing; DUAN Hong; CHEN Jian; MU Jian-xiong

    2008-01-01

    Objective: To study the preparative method of controlled release microspheres incorporating basic fibroblast growth factor (bFGF) and the bioactivities of bFGF, which were released from bFGF microspheres, on the cultured Schwann cells.Methods: bFGF was microcapsulated with the multiple emulsion encapsulative method using polylactic-coglycolic acid (PLGA) as coating material. Its morphology, particle size distribution, drug loading, enveloping rate and in vitro release property were studied. The cultured Schwann cells were grouped acco