Small GTPases act as molecular switches in intracellular signal-transd
uction pathways(1). In the case of the Ras family of GTPases, one of t
heir most important roles is as regulators of cell proliferation, and
the mitogenic response to a variety of growth factors and oncogenes ca
n 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 trigge
r 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, constituti
vely active Ras induces the cyclin-dependent-kinase inhibitor p2I(Waf1
/Cip1) and entry into the DNA-synthesis phase of the cell cycle is blo
cked. When Rho is active, induction of p21(Waf1/Cip1) by Ras is suppre
ssed and Ras induces DNA synthesis. Cells that lack p21(Watl/Cip1) do
not require Rho signalling for the induction of DNA synthesis by activ
ated Ras, indicating that, once Ras has become activated, the primary
requirement for Rho signalling is the suppression of p21(Waf1/Cip1) in
duction.