Release from G1 growth arrest by transforming growth factor beta 1 requires cellular ras activity.

Transforming growth factor beta 1 (TGF beta 1) is a potent inhibitor of epithelial cell growth, although the mechanism of growth inhibition remains unknown. We report here a critical relationship between cellular p21ras activity and TGF beta 1 action. Microinjection of oncogenic Ha-ras protein into TGF beta 1-arrested mink lung epithelial cells overcomes TGF beta 1 growth inhibition and allows progression into S phase. Cells released from TGF beta 1 inhibition following microinjection with anti-p21ras antibody, on the other hand, remain TGF beta 1-arrested and do not enter S phase, indicating a requirement for p21ras activity. These biological data are substantiated biochemically in that TGF beta 1 is shown to decrease the activation state of endogenous p21ras, as measured by the level of GTP-bound p21ras. In addition, the phosphorylation and kinase activity of mitogen-activated protein kinase, which depends upon cellular ras activity, is elevated in cells which have been released from growth arrest by TGF beta 1. Together these data demonstrate the involvement of p21ras activity in TGF beta 1-induced growth inhibition and suggest that the inhibitor controls proliferation by modulating the activity of p21ras.