p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase.
p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase.
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DOI：
10.1371/journal.pone.0010486
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发表时间：
2010-05-05
期刊：
影响因子：
3.7
通讯作者：
Walsh MJ
中科院分区：
文献类型：
--
作者：
Li S;Banck M;Mujtaba S;Zhou MM;Sugrue MM;Walsh MJ
p53功能的一个标志是调节转录程序，以响应细胞外和细胞内应激，指导细胞周期阻滞，细胞凋亡和细胞衰老。除了p53在细胞核中的作用外，它的一些抗增殖功能存在于线粒体中。在EJ膀胱癌细胞环境中，p53可以响应线粒体p53抑制细胞生长，在诱导p53表达之前，该环境是p53功能的naïve。TP53可以与内源性核蛋白和线粒体蛋白独立分离，这与p53的衰老能力一致。为了阐明p53在通过线粒体引导细胞衰老中的作用，我们鉴定了SirT3来拯救EJ/p53细胞免受诱导的p53介导的生长停滞。生化和细胞定位分析表明，人类SirT3功能在线粒体中p53表达启动的早期就与p53偶联。我们的证据表明SirT3部分地抑制p53的活性，从而导致生长停滞和衰老。此外，我们发现伴侣蛋白BAG-2可以阻止SirT3靶向p53介导的衰老。这些研究确定了p53、SirT3和伴随因子BAG-2之间的复杂关系，这种关系可能将p53蛋白的挽救和质量保证与细胞命运的控制联系起来，而不依赖于转录活性。
A hallmark of p53 function is to regulate a transcriptional program in response to extracellular and intracellular stress that directs cell cycle arrest, apoptosis, and cellular senescence. Independent of the role of p53 in the nucleus, some of the anti-proliferative functions of p53 reside within the mitochondria. p53 can arrest cell growth in response to mitochondrial p53 in an EJ bladder carcinoma cell environment that is naïve of p53 function until induced to express p53. TP53 can independently partition with endogenous nuclear and mitochondrial proteins consistent with the ability of p53 to enact senescence. In order to address the role of p53 in navigating cellular senescence through the mitochondria, we identified SirT3 to rescue EJ/p53 cells from induced p53-mediated growth arrest. Human SirT3 function appears coupled with p53 early during the initiation of p53 expression in the mitochondria by biochemical and cellular localization analysis. Our evidence suggests that SirT3 partially abrogates p53 activity to enact growth arrest and senescence. Additionally, we identified the chaperone protein BAG-2 in averting SirT3 targeting of p53 -mediated senescence. These studies identify a complex relationship between p53, SirT3, and chaperoning factor BAG-2 that may link the salvaging and quality assurance of the p53 protein for control of cellular fate independent of transcriptional activity.