Cooperation between p21 and Akt is required for p53-dependent cellular senescence.
Cooperation between p21 and Akt is required for p53-dependent cellular senescence.
复制标题
P53依赖的细胞衰老需要p21和Akt的协同作用。
作者：
Kim YY;Jee HJ;Um JH;Kim YM;Bae SS;Yun J
细胞衰老与正常衰老、组织动态平衡和肿瘤抑制有关。虽然P53已被证明是细胞衰老的中心调节因子，但它诱导衰老的信号通路仍不完全清楚。在这项研究中，我们已经证明Akt和p21都是诱导细胞衰老所必需的，以响应P53的表达。在P53诱导的衰老模型中，我们发现Akt激活是诱导细胞衰老表型所必需的。令人惊讶的是，Akt抑制并没有取消P53诱导的细胞周期停滞，但它抑制了细胞内活性氧(ROS)水平的增加。细胞周期和形态分析的结果表明，在Akt抑制之后，P53诱导了细胞的静止，而不是衰老。相反，抑制p21诱导可消除细胞周期停滞，但不影响P53诱导的ROS水平的增加。此外，在H-RAS诱导的人正常成纤维细胞衰老过程中，p21和Akt分别控制细胞周期停滞和ROS水平。机制分析表明，AKT通过NOX4诱导ROS水平升高，而依赖AKT的NF-κB与NOX4启动子结合增加是NOX4诱导P53表达的原因。我们进一步证明Akt对P53表达的激活是由哺乳动物靶点雷帕霉素复合体2介导的。此外，P53介导的IL6和IL8的诱导被Akt抑制而被取消，这表明Akt的激活对于衰老相关的分泌表型也是必需的。综上所述，这些结果表明，p53通过p21和Akt同时控制多条诱导细胞衰老的途径。
Cellular senescence has been implicated in normal aging, tissue homeostasis, and tumor suppression. Although p53 has been shown to be a central mediator of cellular senescence, the signaling pathway by which it induces senescence remains incompletely understood. In this study, we have shown that both Akt and p21 are required to induce cellular senescence in response to p53 expression. In a p53‐induced senescence model, we found that Akt activation was essential for inducing a cellular senescence phenotype. Surprisingly, Akt inhibition did not abolish p53‐induced cell cycle arrest, but it suppressed the increase in intracellular reactive oxygen species (ROS) levels. The results of the cell cycle and morphological analysis suggest that p53 induced quiescence, not senescence, following Akt inhibition. Conversely, the inhibition of p21 induction abolished cell cycle arrest but did not affect the p53‐induced increase in ROS levels. Additionally, p21 and Akt separately controlled cell cycle arrest and ROS levels, respectively, during H‐Ras‐induced senescence in human normal fibroblasts. The mechanistic analysis revealed that Akt increased ROS levels through NOX4 induction, and increased Akt‐dependent NF‐κB binding to the NOX4 promoter is responsible for NOX4 induction upon p53 expression. We further showed that Akt activation upon p53 expression is mediated by mammalian target of rapamycin complex 2. In addition, p53‐mediated IL6 and IL8 induction was abrogated by Akt inhibition, suggesting that Akt activation is also required for the senescence‐associated secretory phenotype. Collectively, these results suggest that p53 simultaneously controls multiple pathways to induce cellular senescence through p21 and Akt.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
5.3
作者：
Kang, S;Jung, MS;Shin, DY
通讯作者：
Shin, DY
影响因子：
4.8
作者：
Jung, MS;Jin, DH;Shin, DY
通讯作者：
Shin, DY
DOI：
10.18632/aging.100160
发表时间：
2010-06
期刊：
Aging
影响因子：
--
作者：
Korotchkina LG;Leontieva OV;Bukreeva EI;Demidenko ZN;Gudkov AV;Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
5.3
作者：
Ferbeyre, G;de Stanchina, E;Lowe, SW
通讯作者：
Lowe, SW