MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation
MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation
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DOI：
10.1093/emboj/cdf616
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发表时间：
2002-11-15
期刊：
影响因子：
11.4
通讯作者：
Yao, TP
中科院分区：
文献类型：
--
作者：
Ito, A;Kawaguchi, Y;Yao, TP
肿瘤抑制因子p53通过翻译后修饰（包括乙酰化）对细胞应激作出反应而被稳定和激活。p300/CBP介导的p53乙酰化受MDM 2负调控。在这里，我们表明，MDM 2可以促进p53去乙酰化招募含有HDAC 1的复合物。HDAC 1复合物以p53非依赖性方式结合MDM 2，并在体内所有已知的乙酰化赖氨酸处使p53脱乙酰化。显性阴性HDAC 1突变体的异位表达在MDM 2存在下恢复p53乙酰化，而野生型HDAC 1和MDM 2协同地使p53去乙酰化。成纤维细胞过度表达显性负HDAC 1突变显示增强DNA损伤诱导的p53乙酰化，增加p53水平和更明显的诱导p21和MDM 2。这些结果表明乙酰化促进p53稳定性和功能。由于乙酰化的p53赖氨酸残基与泛素化的残基重叠，我们的研究结果表明，p53乙酰化的一个主要功能是通过阻止MDM 2依赖的泛素化来促进p53稳定性，而MDM 2对HDAC 1的招募通过去除这些乙酰基促进p53降解。
The tumor suppressor p53 is stabilized and activated in response to cellular stress through post-translational modifications including acetylation. p300/CBP-mediated acetylation of p53 is negatively regulated by MDM2. Here we show that MDM2 can promote p53 deacetylation by recruiting a complex containing HDAC1. The HDAC1 complex binds MDM2 in a p53-independent manner and deacetylates p53 at all known acetylated lysines in vivo. Ectopic expression of a dominant-negative HDAC1 mutant restores p53 acetylation in the presence of MDM2, whereas wildtype HDAC1 and MDM2 deacetylate p53 synergistically. Fibroblasts overexpressing a dominant negative HDAC1 mutant display enhanced DNA damage-induced p53 acetylation, increased levels of p53 and a more pronounced induction of p21 and MDM2. These results indicate that acetylation promotes p53 stability and function. As the acetylated p53 lysine residues overlap with those that are ubiquitylated, our results suggest that one major function of p53 acetylation is to promote p53 stability by preventing MDM2-dependent ubiquitylation, while recruitment of HDAC1 by MDM2 promotes p53 degradation by removing these acetyl groups.