Ras- and mitogen-activated protein kinase kinase-dependent and -independent pathways in p21(Cip1/Waf1) induction by fibroblast growth factor2, platelet-derived growth factor, and transforming growth factor-beta 1

p21(Waf1/Cip1) (hereafter referred to as p21) is upregulated in differentia ting and DNA-damaged cells, but it is also up-regulated by serum and growth factors. We show here that fibroblast growth factor-2 (FGF-2), platelet-de rived growth factor (PDGF), and transforming growth factor-beta 1 (TGF-beta 1) all induce p21 expression in mouse fibroblasts, but with markedly diffe rent kinetics. We link their effect on p21 to Pas and mitogen-activated pro tein kinase kinase-1(/2) [MEK1(/2)]-regulated pathways using either a speci fic MEK1(/2) inhibitor (PD 098059) or cells expressing conditionally activa ted Pas or dominant negative Pas. We demonstrate that p21 induction by PDGF and TGF-beta 1 requires MEK1(/2) and, additionally, that the TGF-beta 1 ef fect on p21 depends on pas, whereas the PDGF effect does not. In contrast, FGF-2 regulation of p21 is largely independent of MEK and Ras, However, PD 098059 efficiently inhibited S-phase entry of quiescent cells induced by ei ther FGF-2 or PDGF, suggesting separate signaling pathways for FGF-2 in ind uction of p21 and in S-phase entry, The results suggest different but partl y overlapping signaling pathways in growth factor regulation of p21.