Involvement of protein kinase C-dependent mitogen-activated protein kinase p44/42 signaling pathway for cross-talk between estradiol and transforming growth factor-beta3 in increasing basic fibroblast growth factor in folliculostellate cells.

Abstract

We have recently shown that TGF-beta3, in the presence of estradiol, increases the release of basic fibroblast growth factor (bFGF) from folliculostellate (FS) cells in the pituitary. We determined the interactive effects of TGF-beta3 and estradiol on bFGF production and release from FS cells, and the role of the MAPK pathway in TGF-beta3 and estradiol interaction. We found that TGF-beta3 and estradiol alone moderately increased cell content and release of bFGF from FS cells; but together, they markedly increased the peptide. Estradiol and TGF-beta3 alone moderately activated MAPK p44/42; together they produced marked activation of MAPK p44/42. Pretreatment of FS cells with an MAPK kinase 1/2 inhibitor or with protein kinase C inhibitors suppressed the activation of MAPK p44/42, bFGF release, and protein level increases, all of which were induced by TGF-beta3 and estradiol. Estradiol and TGF-beta3, either alone or in combination, increased the levels of active Ras. Furthermore, bFGF induction by TGF-beta3 and estradiol was blocked by overexpression of Ras N17, a dominant negative mutant of Ras p21. Estrogen receptor blocker ICI 182,780 failed to prevent estrogen's and TGF-beta3's effects on bFGF. These data suggest that an estradiol receptor-independent protein kinase C- activated Ras-dependent MAPK pathway is involved in the cross-talk between TGF-beta3 and estradiol to increase bFGF production and/or release from FS cells.