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

Section of Basic Reproductive Science (T.A.J., D.M.K., A.P.B.), Department of Obstetrics & Gynecology and Department of Biochemistry & Molecular Genetics (M.A.M., A.P.B.), University of Colorado Health Sciences Center, Denver, Colorado 80262

Address all correspondence and requests for reprints to: Dr. Andrew P. Bradford, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, B-198, 4200 East Ninth Avenue, Denver, Colorado 80262. E-mail: Andy.Bradford{at}uchsc.edu.

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- (PKC)-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 PKC in FGF regulation of PRL gene expression, activation of the rPRL promoter was blocked by an inhibitor of phospholipase C (PLC) activity. FGF treatment also induced rapid tyrosine phosphorylation of PLC in a Rac-dependent manner. These results suggest that FGF-2 and FGF-4 activate PRL gene expression via a novel Rac1, PLC, PKC, and ERK cascade, independent of phosphoinositol-3-kinase and JNK.

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