The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress.
The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress.
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DOI：
10.1038/emboj.2012.122
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发表时间：
2012-06-29
期刊：
影响因子：
11.4
通讯作者：
Posas, Francesc
中科院分区：
文献类型：
--
作者：
Joaquin, Manel;Gubern, Albert;Gonzalez-Nunez, Daniel;Josue Ruiz, E.;Ferreiro, Isabel;de Nadal, Eulalia;Nebreda, Angel R.;Posas, Francesc
p57Kip2细胞周期蛋白依赖性激酶抑制剂（CDKi）与胚胎发生、干细胞衰老和病理学有关，但其在细胞周期调控中的作用知之甚少。在这里，我们表明，p57Kip2的p38应激激活蛋白激酶（SAPK）的目标。p57 Kip2在T143处被p38磷酸化增强了其与Cdk2的关联和抑制，这导致应激时细胞周期延迟。SAPK或CDKi的遗传失活消除了细胞周期延迟，并导致细胞活力降低。氧化应激和离子霉素也诱导p38介导的p57磷酸化，缺乏p38或p57的细胞对这些应激表现出活力降低。因此，细胞对各种应激的存活取决于p57被抑制CDK活性的p38磷酸化。总之，这些发现提供了一种新的分子机制，通过这种机制，细胞可以延迟细胞周期进程，以最大限度地提高细胞在压力下的存活率。
The p57Kip2 cyclin-dependent kinase inhibitor (CDKi) has been implicated in embryogenesis, stem-cell senescence and pathologies, but little is known of its role in cell cycle control. Here, we show that p57Kip2 is targeted by the p38 stress-activated protein kinase (SAPK). Phosphorylation of p57Kip2 at T143 by p38 enhances its association with and inhibition of Cdk2, which results in cell-cycle delay upon stress. Genetic inactivation of the SAPK or the CDKi abolishes cell-cycle delay upon osmostress and results in decreased cell viability. Oxidative stress and ionomycin also induce p38-mediated phosphorylation of p57 and cells lacking p38 or p57 display reduced viability to these stresses. Therefore, cell survival to various stresses depends on p57 phosphorylation by p38 that inhibits CDK activity. Together, these findings provide a novel molecular mechanism by which cells can delay cell cycle progression to maximize cell survival upon stress.
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