Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16(INK4a)
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16(INK4a)
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DOI：
10.1016/s0092-8674(00)81902-9
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发表时间：
1997-03-07
期刊：
影响因子：
64.5
通讯作者：
Lowe, SW
中科院分区：
文献类型：
--
作者：
Serrano, M;Lin, AW;Lowe, SW
致癌的ras可以将大多数不朽的啮齿动物细胞转化为致瘤状态。然而，ras对原代细胞的转化需要一个协同的癌基因或灭活抑癌基因，如p53或p16。在这里，我们发现原代人类或啮齿动物细胞中ras的表达导致永久性的G1期停滞。ras诱导的停滞伴随着p53和p16的积聚，并且与细胞衰老没有明显的区别。P53或p16的失活可以阻止ras诱导的啮齿动物细胞停滞，而E1a在人类细胞中也达到了类似的效果。这些观察表明，细胞衰老的开始并不是简单地反映细胞分裂的积累，而是可以对致癌刺激做出反应而过早激活。抑制ras诱导的衰老可能与肿瘤的多步发生有关。
Oncogenic ras can transform most immortal rodent cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Here we show that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence. Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells. These observations suggest that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. Negation of ras-induced senescence may be relevant during multistep tumorigenesis.