Weak p53 permits senescence during cell cycle arrest
Weak p53 permits senescence during cell cycle arrest
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DOI：
10.4161/cc.9.21.13584
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发表时间：
2010-11-01
期刊：
影响因子：
4.3
通讯作者：
Blagosklonny, Mikhail V.
中科院分区：
文献类型：
--
作者：
Leontieva, Olga V.;Gudkov, Andrei V.;Blagosklonny, Mikhail V.
细胞周期停滞与过度活跃的mTO R结合导致细胞衰老。在阻止细胞周期的同时，高水平的p53可以抑制mTO R（在一些细胞系中），从而引起可逆的静止而不是衰老。Nutlin-3a诱导的p53抑制mTO R，从而引起WI-38细胞的静止。相反，DNA损伤药物阿霉素（DOX）在阻滞细胞周期的同时，不抑制mTO R并引起衰老。通过nutlin-3a或高浓度DOX（高DOX）对p53的超诱导防止了低DOX诱导的衰老，将其转化为静止。这就解释了为什么为了引起衰老，必须使用低浓度的DNA损伤药物，这些药物阻止细胞周期，但不会诱导p53达到足以抑制mTO R的水平。值得注意的是，用nutlin-3a非常长时间的治疗也引起可由雷帕霉素预防的衰老。在RPE细胞中，低浓度的nutlin-3a引起半衰老形态。较高浓度的nutlin-3a抑制mTO R并引起静止形态。我们的结论是，低水平的p53在细胞周期停滞延长往往会导致衰老，而高水平的p53往往会导致静止或细胞死亡。
Cell cycle arrest coupled with hyper-active mTO R leads to cellular senescence. While arresting cell cycle, high levels of p53 can inhibit mTO R (in some cell lines), thus causing reversible quiescence instead of senescence. Nutlin-3a-induced p53 inhibited mTO R and thus caused quiescence in WI-38 cells. In contrast, while arresting cell cycle, the DNA-damaging drug doxorubicin (DOX) did not inhibit mTO R and caused senescence. Super-induction of p53 by either nutlin-3a or high concentrations of DOX (high-DOX) prevented low-DOX-induced senescence, converting it into quiescence. This explains why in order to cause senescence, DNA damaging drugs must be used at low concentrations, which arrest cell cycle but do not induce p53 at levels sufficient to suppress mTO R. Noteworthy, very prolonged treatment with nutlin-3a also caused senescence preventable by rapamycin. In RPE cells, low concentrations of nutlin-3a caused a semi-senescent morphology. Higher concentrations of nutlin-3a inhibited mTO R and caused quiescent morphology. We conclude that low p53 levels during prolonged cell cycle arrest tend to cause senescence, whereas high levels of p53 tend to cause either quiescence or cell death.