Mediation of basic fibroblast growth factor-induced lactotropic cell proliferation by Src-Ras-mitogen-activated protein kinase p44/42 signaling

Basic fibroblast growth factor ( bFGF), which is secreted from folliculostellate cells in the anterior pituitary, is known to be involved in the communication between folliculostellate cells and lactotropes during estradiol- induced lactotropic cell proliferation. We studied the role of MAPK p44/ 42 in bFGF- regulated cell proliferation using enriched lactotropes and the lactotrope- derived PR1 cell line. In cell cultures, bFGF increased cell proliferation of PR1 cells and enriched lactotropes. In both of these cell populations, bFGF also increased phosphorylation of MAPK p44/ 42. U0126, an inhibitor of MAPK p44/ 42, blocked the bFGF- induced activation of MAPK p44/ 42 as well as the bFGF- induced cell proliferation of enriched lactotropes and PR1 cells. Treatment of PR1 cells with bFGF increased the activity of Ras p21, whereas overexpression of a dominant negative mutant of Ras p21 abrogated the bFGF-induced activation of MAPK p44/ 42 in these cells. Furthermore, the Src kinase inhibitor PP1 suppressed bFGF- induced activation of MAPK p44/ 42 in both enriched lactotropes and PR1 cells. The Src kinase inhibitor PP1 also reduced bFGF activation of Ras p21 and cell proliferation in PR1 cells. On the other hand, the bFGF- induced activation of MAPK p44/ 42 in enriched lactotropes and PR1 cells was not affected by protein kinase C inhibitors. These data suggest that bFGF induction of lactotropic cell proliferation is possibly mediated by activation of Src kinase, Ras p21, and MAPK p44/ 42.