Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1

Small GTPases act as molecular switches in intracellular signal-transduction pathways(1). In the case of the Ras family of GTPases, one of their most important roles is as regulators of cell proliferation, and the mitogenic response to a variety of growth factors and oncogenes can be blocked by inhibiting Ras function(23). But in certain situations, activation of Ras signalling pathways arrests the cell cycle rather than causing cell proliferation(4-6). Extracellular signals may trigger different cellular responses by activating Ras-dependent signalling pathways to varying degrees(7-9). Other signalling pathways could also influence the consequences of Ras signalling. Here we show that when signalling through the Ras-related GTPase Rho is inhibited, constitutively active Ras induces the cyclin-dependent-kinase inhibitor p2I(Waf1/Cip1) and entry into the DNA-synthesis phase of the cell cycle is blocked. When Rho is active, induction of p21(Waf1/Cip1) by Ras is suppressed and Ras induces DNA synthesis. Cells that lack p21(Watl/Cip1) do not require Rho signalling for the induction of DNA synthesis by activated Ras, indicating that, once Ras has become activated, the primary requirement for Rho signalling is the suppression of p21(Waf1/Cip1) induction.