Olson M F, Paterson H F, Marshall C J
CRC Centre for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, London, UK.
Nature. 1998 Jul 16;394(6690):295-9. doi: 10.1038/28425.
Small GTPases act as molecular switches in intracellular signal-transduction pathways. 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. But in certain situations, activation of Ras signalling pathways arrests the cell cycle rather than causing cell proliferation. Extracellular signals may trigger different cellular responses by activating Ras-dependent signalling pathways to varying degrees. 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 p21Waf1/Cip1 and entry into the DNA-synthesis phase of the cell cycle is blocked. When Rho is active, induction of p21Waf1/Cip1 by Ras is suppressed and Ras induces DNA synthesis. Cells that lack p21Waf1/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 p21Waf1/Cip1 induction.
小GTP酶在细胞内信号转导途径中充当分子开关。就GTP酶的Ras家族而言，其最重要的作用之一是作为细胞增殖的调节因子，并且通过抑制Ras功能可以阻断对多种生长因子和癌基因的促有丝分裂反应。但在某些情况下，Ras信号通路的激活会使细胞周期停滞，而不是导致细胞增殖。细胞外信号可能通过不同程度地激活Ras依赖性信号通路来触发不同的细胞反应。其他信号通路也可能影响Ras信号的后果。在此我们表明，当通过Ras相关GTP酶Rho的信号传导受到抑制时，组成型激活的Ras会诱导细胞周期蛋白依赖性激酶抑制剂p21Waf1/Cip1，并且细胞周期进入DNA合成期会被阻断。当Rho活跃时，Ras对p21Waf1/Cip1的诱导会受到抑制，并且Ras会诱导DNA合成。缺乏p21Waf1/Cip1的细胞在激活的Ras诱导DNA合成时不需要Rho信号传导，这表明，一旦Ras被激活，Rho信号传导的主要需求是抑制p21Waf1/Cip1的诱导。
