TY - JOUR
T1 - Ras- and mitogen-activated protein kinase kinase-dependent and - independent pathways in p21(Cip2/Waf1) induction by fibroblast growth factor- 2, platelet-derived growth factor, and transforming growth factor-β1
AU - Kivinen, Laura
AU - Laiho, Marikki
PY - 1999/9/1
Y1 - 1999/9/1
N2 - p21(Waf1/Cip1) (hereafter referred to as p21) is upregulated in differentiating 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-derived growth factor (PDGF), and transforming growth factor-β1 (TGF-β1) all induce p21 expression in mouse fibroblasts, but with markedly different kinetics. We link their effect on p21 to Ras and mitogen-activated protein kinase kinase-1(/2) [MEK1(/2)]-regulated pathways using either a specific MEK1(/2) inhibitor (PD 098059) or cells expressing conditionally activated Ras or dominant negative Ras. We demonstrate that p21 induction by PDGF and TGF-β1 requires MEK1(/2) and, additionally, that the TGF-β1 effect on p21 depends on Ras, 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 either FGF- 2 or PDGF, suggesting separate signaling pathways for FGF-2 in induction of p21 and in S-phase entry. The results suggest different but partly overlapping signaling pathways in growth factor regulation of p21.
AB - p21(Waf1/Cip1) (hereafter referred to as p21) is upregulated in differentiating 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-derived growth factor (PDGF), and transforming growth factor-β1 (TGF-β1) all induce p21 expression in mouse fibroblasts, but with markedly different kinetics. We link their effect on p21 to Ras and mitogen-activated protein kinase kinase-1(/2) [MEK1(/2)]-regulated pathways using either a specific MEK1(/2) inhibitor (PD 098059) or cells expressing conditionally activated Ras or dominant negative Ras. We demonstrate that p21 induction by PDGF and TGF-β1 requires MEK1(/2) and, additionally, that the TGF-β1 effect on p21 depends on Ras, 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 either FGF- 2 or PDGF, suggesting separate signaling pathways for FGF-2 in induction of p21 and in S-phase entry. The results suggest different but partly overlapping signaling pathways in growth factor regulation of p21.
UR - http://www.scopus.com/inward/record.url?scp=0032880860&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032880860&partnerID=8YFLogxK
M3 - Article
C2 - 10511312
AN - SCOPUS:0032880860
SN - 1541-7786
VL - 10
SP - 621
EP - 628
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
IS - 9
ER -