Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein
Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein
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DOI：
10.1038/386177a0
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发表时间：
1997-03-13
期刊：
影响因子：
64.8
通讯作者：
Ewen, ME
中科院分区：
文献类型：
--
作者：
Peeper, DS;Upton, TM;Ewen, ME
Ras原癌基因是有丝分裂信号转导通路的核心组成部分，是细胞离开静止状态（G0）和通过细胞周期G1/S转变所必需的（1-6）。然而，Ras信号调控细胞周期进程的机制尚不清楚。在这里，我们报道了视网膜母细胞瘤肿瘤抑制蛋白（Rb）， G1退出的调节因子(7)，在功能上连接通路通过G1期。循环细胞中Ras的失活导致cyclin D1蛋白水平下降，低磷酸化Rb的积累，生长抑制形式和G1停滞。当Rb在基因上或生物化学上被破坏时，细胞在Ras失活后的G1期无法停止。相反，静止细胞中Ras的失活阻止了生长因子诱导的即刻早期基因转录和以rb独立的方式退出G0。这些数据表明Rb是一种重要的g1特异性介质，将ras依赖的有丝分裂信号传导与细胞周期调节联系起来。
The Ras proto-oncogene is a central component of mitogenic signal-transduction pathways, and is essential for cells both to leave a quiescent state (G0) and to pass through the G1/S transition of the cell cycle(1-6). The mechanism by which Ras signalling regulates cell-cycle progression is unclear, however. Here we report that the retinoblastoma tumour-suppressor protein (Rb), a regulator of G1 exit(7), functionally Links pas to passage through the G1 phase. Inactivation of Ras in cycling cells-caused a decline in cyclin D1 protein levels, accumulation of the hypophosphorylated, growth-suppressive form of Rb, and G1 arrest. When Rb was disrupted either genetically or biochemically, cells failed to arrest in G1 following Ras inactivation. In contrast, inactivation of Ras in quiescent cells prevented growth-factor induction of both immediate-early gene transcription and exit from G0 in an Rb-independent manner. These data suggest that Rb is an essential G1-specific mediator that links Ras-dependent mitogenic signalling to cell-cycle regulation.