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

Department of Obstetrics and Gynecology (T.A.J., D.M.K., A.P.B.), Department of Biochemistry and Molecular Genetics (R.E.S., A.P.B.), and the Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80262

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 PKC 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 PKC from cytosolic to membrane fractions, consistent with enzyme activation. In contrast, other PKCs expressed in GH4T2 cells (, ßI, ßII, and ) did not translocate in response to fibroblast growth factors. The PKC subtype-selective inhibitor, rottlerin, or expression of a dominant negative PKC adenoviral construct also blocked fibroblast growth factor induction of rat PRL promoter activity, confirming a role for the novel PKC isoform. PKC inhibitors selective for the conventional and ß isoforms or dominant negative PKC adenoviral expression constructs had no effect. Induction of the endogenous PRL gene was also blocked by adenoviral dominant negative PKC expression but not by an analogous dominant negative PKC 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 PKC.

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