RELEASE FROM G(1) GROWTH ARREST BY TRANSFORMING GROWTH-FACTOR-BETA-1 REQUIRES CELLULAR RAS ACTIVITY

Transforming growth factor beta1 (TGFbeta1) is a potent inhibitor of e pithelial cell growth, although the mechanism of growth inhibition rem ains unknown. We report here a critical relationship between cellular p21ras activity and TGFbeta1 action. Microinjection of oncogenic Ha-ra s protein into TGFbeta1-arrested mink lung epithelial cells overcomes TGFbeta1 growth inhibition and allows progression into S phase. Cells released from TGFbeta1 inhibition following microinjection with anti-p 21ras antibody, on the other hand, remain TGFbeta1-arrested and do not enter S phase, indicating a requirement for p21ras activity. These bi ological data are substantiated biochemically in that TGFbeta1 is show n to decrease the activation state of endogenous p21ras as measured by the level of GTP-bound p21ras. In addition, the phosphorylation and k inase activity of mitogen-activated protein kinase, which depends upon cellular ras activity, is elevated in cells which have been released from growth arrest by TGFbeta1. Together these data demonstrate the in volvement of p21ras activity in TGFbeta1-induced growth inhibition and suggest that the inhibitor controls proliferation by modulating the a ctivity of p21ras.