scholarly journals Fibroblast Growth Factors Regulate Prolactin Transcription via an Atypical Rac-Dependent Signaling Pathway

2003 ◽  
Vol 17 (10) ◽  
pp. 1921-1930 ◽  
Author(s):  
Twila A. Jackson ◽  
David M. Koterwas ◽  
Melissa A. Morgan ◽  
Andrew P. Bradford
Keyword(s):  
Gene Expression ◽  
Growth Factors ◽  
Signaling Pathway ◽  
Promoter Activity ◽  
Fibroblast Growth Factors ◽  
Dominant Negative ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
Fibroblast Growth ◽  
Prl Gene

Abstract Fibroblast growth factors (FGFs) play a critical role in pituitary development and in pituitary tumor formation and progression. We have previously characterized FGF signal transduction and regulation of the tissue-specific rat prolactin (rPRL) promoter in GH4 pituitary cells. FGF induction of rPRL transcription is independent of Ras, but mediated by a protein kinase C-δ (PKCδ)-dependent activation of MAPK (ERK). Here we demonstrate a functional role for the Rho family monomeric G protein, Rac1, in FGF regulation of PRL gene expression via an atypical signaling pathway. Expression of dominant negative Rac, but not RhoA or Cdc42, selectively inhibited FGF-induced rPRL promoter activity. Moreover, expression of dominant negative Rac also attenuated FGF-2 and FGF-4 stimulation of MAPK (ERK). However, in contrast to other Rac-dependent signaling pathways, FGF activation of rPRL promoter activity was independent of the c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase/Akt cascades. FGFs failed to activate JNK1 or JNK2, and expression of dominant negative JNK or Akt constructs did not block FGF-induced PRL transcription. Consistent with the role of PKCδ in FGF regulation of PRL gene expression, activation of the rPRL promoter was blocked by an inhibitor of phospholipase Cγ (PLCγ) activity. FGF treatment also induced rapid tyrosine phosphorylation of PLCγ in a Rac-dependent manner. These results suggest that FGF-2 and FGF-4 activate PRL gene expression via a novel Rac1, PLCγ, PKCδ, and ERK cascade, independent of phosphoinositol-3-kinase and JNK.

Fibroblast Growth Factor Activation of the Rat PRL Promoter is Mediated by PKCδ

2001 ◽  
Vol 15 (9) ◽  
pp. 1517-1528
Author(s):  
Twila A. Jackson ◽  
Rebecca E. Schweppe ◽  
David M. Koterwas ◽  
Andrew P. Bradford
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Map Kinase ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factors ◽  
Enzyme Activation ◽  
Dominant Negative ◽  
Pituitary Cells ◽  
Fibroblast Growth ◽  
Pkc Inhibitors

Abstract Fibroblast growth factors play a critical role in cell growth, development, and differentiation and are also implicated in the formation and progression of tumors in a variety of tissues including pituitary. We have previously shown that fibroblast growth factor activation of the rat PRL promoter in GH4T2 pituitary tumor cells is mediated via MAP kinase in a Ras/Raf-1-independent manner. Herein we show using biochemical, molecular, and pharmacological approaches that PKCδ is a critical component of the fibroblast growth factor signaling pathway. PKC inhibitors, or down-regulation of PKC, rendered the rat PRL promoter refractory to subsequent stimulation by fibroblast growth factors, implying a role for PKC in fibroblast growth factor signal transduction. FGFs caused specific translocation of PKCδ from cytosolic to membrane fractions, consistent with enzyme activation. In contrast, other PKCs expressed in GH4T2 cells (α, βI, βII, andε ) did not translocate in response to fibroblast growth factors. The PKCδ subtype-selective inhibitor, rottlerin, or expression of a dominant negative PKCδ adenoviral construct also blocked fibroblast growth factor induction of rat PRL promoter activity, confirming a role for the novel PKCδ isoform. PKC inhibitors selective for the conventional α and β isoforms or dominant negative PKCα adenoviral expression constructs had no effect. Induction of the endogenous PRL gene was also blocked by adenoviral dominant negative PKCδ expression but not by an analogous dominant negative PKCα construct. Finally, rottlerin significantly attenuated FGF-induced MAP kinase phosphorylation. Together, these results indicate that MAP kinase-dependent fibroblast growth factor stimulation of the rat PRL promoter in pituitary cells is mediated by PKCδ.

scholarly journals Role of fibroblast growth factors in pancreatic cancer

2016 ◽  
Vol 62 (6) ◽  
pp. 622-629 ◽  
Author(s):  
D.A. Gnatenko ◽  
E.P. Kopantsev ◽  
E.D. Sverdlov
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factors ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Fibroblast Growth Factors ◽  
Specific Marker ◽  
Fibroblast Growth ◽  
Complex Process ◽  
Wide Range ◽  
Fgfr Signaling

Fibroblast growth factors belong to a family of growth factors that are involved in various processes in organism and have a wide range of biological functions. Specifically for pancreas, FGFs are important during both organogenesis and carcinogenesis. One of the main characteristic of pancreatic cancer, is it close interaction between cancer and stromal cells via different factors, including FGF. Pathological changes in FGF/FGFR signaling pathway is a complex process. The remodeling effects and stimulation of tumor growth are mostly depend not only on types of receptors, but also from their isoforms. FGF/FGFR signaling pathway is a perspective specific marker for cancer progression, and a potential drug target, which can be used for treatment of pancreatic cancer.

Fibroblast Growth Factor: Promising Target for Schizophrenia

2020 ◽  
Vol 21 (13) ◽  
pp. 1344-1353
Author(s):  
Ali Talaei ◽  
Tahereh Farkhondeh ◽  
Fatemeh Forouzanfar
Keyword(s):  
Gene Expression ◽  
Growth Factors ◽  
Drug Targets ◽  
Web Of Science ◽  
Fibroblast Growth Factors ◽  
Fibroblast Growth ◽  
Open Access Journals ◽  
Promising Target ◽  
The World

Schizophrenia is one of the most debilitating mental disorders around the world. It is characterized by neuroanatomical or biochemical changes. The role of the fibroblast growth factors (FGFs) system in schizophrenia has received considerable attention in recent years. Various changes in the gene expression and/or level of FGFs have been implicated in the etiology, symptoms and progression of schizophrenia. For example, studies have substantiated an interaction between FGFs and the signaling pathway of dopamine receptors. To understand the role of this system in schizophrenia, the databases of Open Access Journals, Web of Science, PubMed (NLM), LISTA (EBSCO), and Google Scholar with keywords including fibroblast growth factors, dopamine, schizophrenia, psychosis, along with neurotrophic were searched. In conclusion, the FGF family represent molecular candidates as new drug targets and treatment targets for schizophrenia.

scholarly journals Heme Oxygenase-1 Gene Activation by the NAD(P)H Oxidase Inhibitor 4-(2-Aminoethyl) Benzenesulfonyl Fluoride via a Protein Kinase B, p38-dependent Signaling Pathway in Monocytes

2005 ◽  
Vol 280 (23) ◽  
pp. 21820-21829 ◽  
Author(s):  
Nastiti Wijayanti ◽  
Thomas Kietzmann ◽  
Stephan Immenschuh
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Heme Oxygenase ◽  
Promoter Activity ◽  
Protein Kinase B ◽  
Oxidase Inhibitor ◽  
Luciferase Assay ◽  
Heme Oxygenase 1 ◽  
Dependent Manner

Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation and modulates the inflammatory immune response. Because HO-1 is up-regulated by NAD(P)H oxidase activators such as lipopolysaccharide and 12-O-tetradecanoylphorbol-13-acetate in monocytic cells, we investigated the gene regulation of HO-1 by the chemical NAD(P)H oxidase inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF). Unexpectedly, AEBSF induced endogenous gene expression and promoter activity of HO-1 in cell cultures of human and mouse monocytes. Inhibition of the phosphatidylinositol 3-kinase/protein kinase B (PKB) pathway by pharmacological inhibitors and cotransfection of an expression vector for a dominant negative mutant of PKB reduced the AEBSF-dependent induction of HO-1 gene transcription. Accordingly, overexpressed constitutively active PKB markedly up-regulated HO-1 promoter activity. AEBSF activated the mitogen-activated protein kinases (MAPK) JNK and p38. Inhibition of p38α and p38β, but not that of JNK or p38γ and p38δ, prevented the induction of HO-1 gene expression by AEBSF. p38 was stimulated by AEBSF in a PKB-dependent manner as demonstrated by a luciferase assay with a Gal4-CHOP fusion protein. Finally, AEBSF- and PKB-dependent induction of HO-1 promoter activity was reduced by simultaneous mutation of an E-box motif (–47/–42) and a cAMP response element/AP-1 element (–664/–657) of the proximal HO-1 gene promoter. Overexpression of the basic helix-loop-helix transcription factor USF2 and coactivator p300 enhanced the AEBSF-dependent response of the HO-1 promoter. The data suggest that the transcriptional induction of HO-1 gene expression by AEBSF is mediated via activation of a PKB, p38 MAPK signaling pathway.

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