Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1
Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1
复制标题
DOI：
10.1038/emboj.2011.434
复制
发表时间：
2012-02-01
期刊：
影响因子：
11.4
通讯作者：
Dai, Mu-Shui
中科院分区：
文献类型：
--
作者：
Sun, Xiao-Xin;Challagundla, Kishore B.;Dai, Mu-Shui
泛素（ubiquitin，Ub）-蛋白酶体系统在调节p53蛋白的稳定性和活性中起着关键作用。p53被MDM 2和其他几种Ub E3泛素化和去稳定化，而它被Ub特异性蛋白酶（USP）7和USP 10去泛素化和稳定化。在这里，我们表明，卵巢肿瘤结构域含有Ub受体结合蛋白1（Otub 1）是一种新的p53调节剂。Otub 1在细胞和体外直接抑制MDM 2介导的p53泛素化。过度表达的Otub 1急剧稳定和激活p53，导致细胞凋亡和显着抑制细胞增殖的p53依赖性的方式。这些作用与其催化活性无关，但需要残基Asp 88。Asp 88突变为Ala（Otub 1（D88 A））消除了Otub 1抑制p53泛素化的活性。此外，野生型Otub 1及其催化突变体（Otub 1（C91 S）），而不是Otub 1（D88 A），与MDM 2同源物E2，UbcH 5结合，并在体外抑制其Ub缀合活性。过度表达Otub 1（D88 A）或通过siRNA消融内源性Otub 1显著损害了p53对DNA损伤的稳定性和活化。总之，这些结果揭示了Otub 1在调节p53稳定性和活性方面的新功能。The EMBO Journal（2012）31，576-592. doi：10.1038/daj.2011.434; 2011年11月29日在线发布
The ubiquitin (Ub)-proteasome system plays a pivotal role in the regulation of p53 protein stability and activity. p53 is ubiquitinated and destabilized by MDM2 and several other Ub E3s, whereas it is deubiquitinated and stabilized by Ub-specific protease (USP) 7 and USP10. Here we show that the ovarian tumour domain-containing Ub aldehyde-binding protein 1 (Otub1) is a novel p53 regulator. Otub1 directly suppresses MDM2-mediated p53 ubiquitination in cells and in vitro. Overexpression of Otub1 drastically stabilizes and activates p53, leading to apoptosis and marked inhibition of cell proliferation in a p53-dependent manner. These effects are independent of its catalytic activity but require residue Asp88. Mutation of Asp88 to Ala (Otub1(D88A)) abolishes activity of Otub1 to suppress p53 ubiquitination. Further, wild-type Otub1 and its catalytic mutant (Otub1(C91S)), but not Otub1(D88A), bind to the MDM2 cognate E2, UbcH5, and suppress its Ub-conjugating activity in vitro. Overexpression of Otub1(D88A) or ablation of endogenous Otub1 by siRNA markedly impaired p53 stabilization and activation in response to DNA damage. Together, these results reveal a novel function for Otub1 in regulating p53 stability and activity. The EMBO Journal (2012) 31, 576-592. doi:10.1038/emboj.2011.434; Published online 29 November 2011