117 FIBROBLAST GROWTH FACTOR RECEPTOR-1c, -2c, -3c, and -4 mRNA ABUNDANCE IN GRANULOSA CELLS DURING FOLLICULAR GROWTH IN CATTLE

2017 ◽  
Vol 29 (1) ◽  
pp. 167
Author(s):  
L. F. Schütz ◽  
L. Zhang ◽  
B. C. Morrell ◽  
N. B. Schreiber ◽  
C. Cortinovis ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Granulosa Cells ◽  
Growth Factor Receptor ◽  
Mrna Abundance ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors ◽  
Genes Encoding ◽  
Mrna Extraction ◽  
Domain Iii

Fibroblast growth factors (FGF) regulate folliculogenesis of several species, including cattle. The cellular responses to a particular FGF are influenced by the diversity of high affinity fibroblast growth factor receptors (FGFR). There are 4 distinct genes encoding FGFR in vertebrates and the occurrence of mRNA splicing in the immunoglobulin-like domain III generates a diversity of sequences, and results in various isoforms of FGFR1, FGFR2, and FGFR3 (but not of FGFR4). Because FGFR have different ligand specificities, the presence of FGFR in bovine antral follicles is of fundamental importance for the FGF to exert their effects in the ovary. Hence, the objective of this study was to determine if FGFR1c, FGFR2c, FGFR3c, and FGFR4 mRNA abundance in granulosa cells (GC) change according to follicular size, steroidogenic status, and days post-ovulation during growth of first-wave dominant follicles in cattle. Oestrous cycles of non-lactating dairy cattle were synchronized and ovaries were collected on either Day 3–4 (n = 8) or Day 5–6 (n = 8) post-ovulation (as assessed by rectal ultrasonography). Follicular fluid (FFL) was aspirated from small (1–5 mm), medium (5.1–8 mm), or large (8.1–18 mm) follicles for measurement of oestradiol (E2) and progesterone (P4) levels by radioimmunoassay, and GC were collected for mRNA extraction. Relative quantity of target gene mRNA was expressed as 2−ΔΔCt using the comparative threshold cycle (Ct) method. Data were transformed to natural log (x + 1), to correct for heterogeneity of variance, and analysed via factorial ANOVA with the general linear model procedure of SAS and are reported as least squares means ± s.e.M. Follicle group (based on steroidogenic status and size of follicles), but not days post-ovulation or their interaction, significantly affected FGFR1c, FGFR2c, and FGFR3c mRNA abundance, whereas FGFR4 mRNA abundance was not affected by follicle group or days post-ovulation. FGFR1c mRNA abundance was greater (P < 0.01) in large (44.8 ± 11.3; n = 29), medium (63.8 ± 7.6; n = 64), and small (44.6 ± 11.2; n = 29) E2-inactive (FFL E2/P4 ratio < 1) than in large E2-active (FFL E2/P4 ratio > 1) follicles (10.5 ± 15.5; n = 16) and greater (P < 0.05) in medium E2-inactive than in large and small E2-inactive follicles. FGFR2c mRNA abundance was greater (P < 0.01) in large (423.9 ± 131.9), medium (585.8 ± 97.0), and small (273.6 ± 143.2) E2-inactive than in large E2-active (56.2 ± 195.6) follicles. The FGFR3c mRNA abundance was greater (P < 0.05) in large (143.4 ± 40.2) and medium (160.2 ± 29.3) E2-inactive than in large E2-active (43.2 ± 58.6) follicles and tended to be greater (P = 0.06) in small E2-inactive (101.9 ± 42.9) than in large E2-active follicles. Taken together, the findings that FGFR1c, FGFR2c, and FGFR3c mRNA abundance is lower in GC of E2-active follicles during growth of the first dominant follicle support an anti-differentiation role for these FGFR as well as support the idea that some FGF may regulate the selection of dominant follicles in cattle.

scholarly journals Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer

Cells ◽  
2018 ◽  
Vol 7 (7) ◽  
pp. 76 ◽  
Author(s):  
Navid Sobhani ◽  
Anna Ianza ◽  
Alberto D’Angelo ◽  
Giandomenico Roviello ◽  
Fabiola Giudici ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Tumor Formation ◽  
Current Status ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.

scholarly journals Regulation and action of fibroblast growth factor 17 in bovine follicles

2009 ◽  
Vol 202 (3) ◽  
pp. 347-353 ◽  
Author(s):  
M F Machado ◽  
V M Portela ◽  
C A Price ◽  
I B Costa ◽  
P Ripamonte ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Granulosa Cells ◽  
Cumulus Cells ◽  
Mrna Abundance ◽  
Fibroblast Growth ◽  
Theca Cells ◽  
Progesterone Secretion ◽  
Igf I

Fibroblast growth factor 17 (FGF17) is a member of the FGF8 subfamily that appears to be relevant to folliculogenesis and oogenesis, as the prototype member FGF8 is an oocyte-derived protein that signals to cumulus cells. FGF8 has structural and receptor-binding similarities to FGF17, whose expression in the ovary has not been reported. In this study, we demonstrate localization of FGF17 protein to the oocyte of preantral follicles, and to the oocyte and granulosa cells of antral follicles. Real-time PCR demonstrated the presence of mRNA in oocytes and, to a lesser extent, in granulosa and theca cells. FGF17 mRNA abundance was low in granulosa and theca cells from healthy follicles and increased significantly in atretic follicles. Addition of FSH or IGF-I to granulosa cells in vitro decreased FGF17 mRNA abundance, and treatment with FGF17 inhibited estradiol and progesterone secretion from granulosa cells in relation to control cultures without these additives. We conclude that FGF17 is a potential mediator of granulosa cell differentiation.

scholarly journals Current Status of Fibroblast Growth Factor Receptors Targeted Therapies in Breast Cancer

2018 ◽  
Author(s):  
Navid Sobhani ◽  
Anna Ianza ◽  
Alberto D'Angelo ◽  
Giandomenico Roviello ◽  
Fabiola Giudici ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Current Knowledge ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Current Status ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors ◽  
Molecular Aberrations

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, the metastatic breast cancer leaves a poor prognosis. In an era of personalized medicine, there is an urgent need for a better knowledge of the biology leading to the disease, which can lead to the design of always more accurate drugs against patients&rsquo; specific molecular aberrations. Among one of the actionable targets is the Fibroblast Growth Factor Receptor (FGFR) pathway, triggered by specific ligands. The FGFRs/FGFs axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of the FGFRs mutations leading to tumour formation and summarizes the state-of-the-art of therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.

scholarly journals Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction

Development ◽  
1998 ◽  
Vol 125 (4) ◽  
pp. 753-765 ◽  
Author(s):  
X. Xu ◽  
M. Weinstein ◽  
C. Li ◽  
M. Naski ◽  
R.I. Cohen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptor ◽  
Limb Bud ◽  
Fibroblast Growth ◽  
Reciprocal Regulation ◽  
Fusion Junction ◽  
High Affinity Receptor ◽  
Membrane Spanning ◽  
Domain Iii

FGFR2 is a membrane-spanning tyrosine kinase that serves as a high affinity receptor for several members of the fibroblast growth factor (FGF) family. To explore functions of FGF/FGFR2 signals in development, we have mutated FGFR2 by deleting the entire immunoglobin-like domain III of the receptor. We showed that murine FGFR2 is essential for chorioallantoic fusion and placenta trophoblast cell proliferation. Fgfr2(DeltaIgIII/DeltaIgIII) embryos displayed two distinct defects that resulted in failures in formation of a functional placenta. About one third of the mutants failed to form the chorioallantoic fusion junction and the remaining mutants did not have the labyrinthine portion of the placenta. Consequently, all mutants died at 10–11 days of gestation. Interestingly, Fgfr2(DeltaIgIII/DeltaIgIII) embryos do not form limb buds. Consistent with this defect, the expression of Fgf8, an apical ectodermal factor, is absent in the mutant presumptive limb ectoderm, and the expression of Fgf10, a mesenchymally expressed limb bud initiator, is down regulated in the underlying mesoderm. These findings provide direct genetic evidence that FGF/FGFR2 signals are absolutely required for vertebrate limb induction and that an FGFR2 signal is essential for the reciprocal regulation loop between FGF8 and FGF10 during limb induction.

scholarly journals Therapeutic Targeting of Fibroblast Growth Factor Receptors in Gastric Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Mikito Inokuchi ◽  
Yoshitaka Fujimori ◽  
Sho Otsuki ◽  
Yuya Sato ◽  
Masatoshi Nakagawa ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptor ◽  
Growth Factor Receptors ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors ◽  
Genomic Amplification

Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 (HER2) have become standard therapy for HER2-positive GC. An inhibitor of vascular endothelial growth factor receptor 2 or MET has also produced promising results in patients with GC. Fibroblast growth factor receptors (FGFR) play key roles in tumor growth via activated signaling pathways in GC. Genomic amplification of FGFR2 leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical relevance of FGFR in GC and examines FGFR as a potential therapeutic target in patients with GC. Preclinical studies in animal models suggest that multitargeted tyrosine kinase inhibitors (TKIs), including FGFR inhibitor, suppress tumor cell proliferation and delay tumor progression. Several TKIs are now being evaluated in clinical trials as treatment for metastatic or unresectable GC harboring FGFR2 amplification.

scholarly journals Role of fibroblast growth factor receptor signaling in kidney development

2011 ◽  
Vol 301 (2) ◽  
pp. F245-F251 ◽  
Author(s):  
Carlton M. Bates
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kidney Development ◽  
Growth Factor Receptor ◽  
Conditional Knockout ◽  
Fibroblast Growth ◽  
Metanephric Mesenchyme ◽  
Fibroblast Growth Factor Receptors ◽  
Conditional Deletion ◽  
Developing Kidney

Fibroblast growth factor receptors (Fgfrs) consist of four signaling family members and one nonsignaling “decoy” receptor, Fgfr-like 1 (Fgfrl1), all of which are expressed in the developing kidney. Several studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB) in cultured tissues. Transgenic and conditional knockout approaches in whole animals have shown that Fgfr1 and Fgfr2 (predominantly the IIIc isoform) in kidney mesenchyme are critical for early MM and UB formation. Conditional deletion of the ligand, Fgf8, in nephron precursors or global deletion of Fgfrl1 interrupts nephron formation. Fgfr2 (likely the IIIb isoform signaling downstream of Fgf7 and Fgf10) is critical for ureteric morphogenesis. Moreover, Fgfr2 appears to act independently of Frs2α (the major signaling adapter for Fgfrs) in regulating UB branching. Loss of Fgfr2 in the MM leads to many kidney and urinary tract anomalies, including vesicoureteral reflux. Thus Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development.

scholarly journals Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 4111-4119 ◽  
Author(s):  
Linlin Wang ◽  
Thomas C. Schulz ◽  
Eric S. Sherrer ◽  
Derek S. Dauphin ◽  
Soojung Shin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Embryonic Stem ◽  
Growth Factor Receptor ◽  
Insulin Like Growth Factor ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors ◽  
Self Renewal

Abstract Despite progress in developing defined conditions for human embryonic stem cell (hESC) cultures, little is known about the cell-surface receptors that are activated under conditions supportive of hESC self-renewal. A simultaneous interrogation of 42 receptor tyrosine kinases (RTKs) in hESCs following stimulation with mouse embryonic fibroblast (MEF) conditioned medium (CM) revealed rapid and prominent tyrosine phosphorylation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R); less prominent tyrosine phosphorylation of epidermal growth factor receptor (EGFR) family members, including ERBB2 and ERBB3; and trace phosphorylation of fibroblast growth factor receptors. Intense IGF1R and IR phosphorylation occurred in the absence of MEF conditioning (NCM) and was attributable to high concentrations of insulin in the proprietary KnockOut Serum Replacer (KSR). Inhibition of IGF1R using a blocking antibody or lentivirus-delivered shRNA reduced hESC self-renewal and promoted differentiation, while disruption of ERBB2 signaling with the selective inhibitor AG825 severely inhibited hESC proliferation and promoted apoptosis. A simple defined medium containing an IGF1 analog, heregulin-1β (a ligand for ERBB2/ERBB3), fibroblast growth factor-2 (FGF2), and activin A supported long-term growth of multiple hESC lines. These studies identify previously unappreciated RTKs that support hESC proliferation and self-renewal, and provide a rationally designed medium for the growth and maintenance of pluripotent hESCs.

scholarly journals Apoptosis of Granulosa Cells and Female Infertility in Achondroplastic Mice Expressing Mutant Fibroblast Growth Factor Receptor 3G374R

2001 ◽  
Vol 15 (9) ◽  
pp. 1610-1623 ◽  
Author(s):  
Abraham Amsterdam ◽  
Karuppiah Kannan ◽  
David Givol ◽  
Yoshio Yoshida ◽  
Kimihisa Tajima ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Granulosa Cells ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Female Infertility ◽  
Fibroblast Growth

scholarly journals Uptake and Intracellular Transport of Acidic Fibroblast Growth Factor: Evidence for Free and Cytoskeleton-anchored Fibroblast Growth Factor Receptors

1999 ◽  
Vol 10 (11) ◽  
pp. 3835-3848 ◽  
Author(s):  
Lucı́a Citores ◽  
Jørgen Wesche ◽  
Elona Kolpakova ◽  
Sjur Olsnes
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Intracellular Transport ◽  
Growth Factor Receptor ◽  
Endocytic Pathway ◽  
Fibroblast Growth ◽  
Acidic Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptors ◽  
Coated Pits ◽  
Recycling Endosome

Endocytic uptake and intracellular transport of acidic FGF was studied in cells transfected with FGF receptor 4 (FGFR4). Acidification of the cytosol to block endocytic uptake from coated pits did not inhibit endocytosis of the growth factor in COS cells transfected with FGFR4, indicating that it is to a large extent taken up by an alternative endocytic pathway. Fractionation of the cells demonstrated that part of the growth factor receptor was present in a low-density, caveolin-containing fraction, but we were unable to demonstrate binding to caveolin in immunoprecipitation studies. Upon treatment of the cells with acidic FGF, the activated receptor, together with the growth factor, moved to a juxtanuclear compartment, which was identified as the recycling endosome compartment. When the cells were lysed with Triton X-100, 3-([3-chloramidopropyl]dimethylammonio)-2-hydroxy-1-propanesulfonate, or 2-octyl glucoside, almost all surface-exposed and endocytosed FGFR4 was solubilized, but only a minor fraction of the total FGFR4 in the cells was found in the soluble fraction. The data indicate that the major part of FGFR4 is anchored to detergent-insoluble structures, presumably cytoskeletal elements associated with the recycling endosome compartment.

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