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

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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 pharmacologi- cal approaches that PKC is a critical component of the fibroblast growth factor signaling pathway. PKC inhibitors, or down-regulation of PKC, ren- dered the rat PRL promoter refractory to subse- quent stimulation by fibroblast growth factors, im- plying a role for PKC in fibroblast growth factor signal transduction. FGFs caused specific translo- cation of PKC from cytosolic to membrane frac- tions, consistent with enzyme activation. In con- trast, other PKCs expressed in GH4T2 cells (, I, II, and ) did not translocate in response to fibro- blast 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 pro- moter activity, confirming a role for the novel PKC isoform. PKC inhibitors selective for the conven- tional and 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 ex- pression but not by an analogous dominant nega- tive PKC construct. Finally, rottlerin significantly attenuated FGF-induced MAP kinase phosphoryla- tion. Together, these results indicate that MAP ki- nase-dependent fibroblast growth factor stimula- tion of the rat PRL promoter in pituitary cells is mediated by PKC .( Molecular Endocrinology 15: 1517-1528, 2001)

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