Deubiquitinating enzyme regulation of the p53 pathway: A lesson from Otub1.
Deubiquitinating enzyme regulation of the p53 pathway: A lesson from Otub1.
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DOI：
10.4331/wjbc.v5.i2.75
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发表时间：
2014-05
期刊：
影响因子：
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通讯作者：
Xiao-Xin Sun;M. Dai
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文献类型：
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作者：
Xiao-Xin Sun;M. Dai
去泛素化已成为p53调控的重要机制。来自泛素特异性蛋白酶家族的许多去泛素化酶（DUBs）已被证明可以调节p53-MDM2-MDMX网络。我们最近报道了Otub1，一个来自otu结构域蛋白酶家族的DUB，是一种新的p53调节因子。有趣的是，Otub1可以消除p53的泛素化，并独立于其去泛素化酶的活性来稳定和激活细胞中的p53。相反，它是通过抑制MDM2同源的泛素结合酶（E2） UbcH5来实现的。Otub1还通过这种非规范机制调节其他生物信号，抑制E2，包括抑制dna损伤诱导的染色质泛素化。因此，Otub1进化为一种独特的DUB，主要抑制E2来调节底物。本文综述了DUBs对p53肿瘤抑制通路的复杂调控、Otub1的生物学功能（包括其对p53的正调控）以及Otub1抑制E2的机制方面的研究进展。
Deubiquitination has emerged as an important mechanism of p53 regulation. A number of deubiquitinating enzymes (DUBs) from the ubiquitin-specific protease family have been shown to regulate the p53-MDM2-MDMX networks. We recently reported that Otub1, a DUB from the OTU-domain containing protease family, is a novel p53 regulator. Interestingly, Otub1 abrogates p53 ubiquitination and stabilizes and activates p53 in cells independently of its deubiquitinating enzyme activity. Instead, it does so by inhibiting the MDM2 cognate ubiquitin-conjugating enzyme (E2) UbcH5. Otub1 also regulates other biological signaling through this non-canonical mechanism, suppression of E2, including the inhibition of DNA-damage-induced chromatin ubiquitination. Thus, Otub1 evolves as a unique DUB that mainly suppresses E2 to regulate substrates. Here we review the current progress made towards the understanding of the complex regulation of the p53 tumor suppressor pathway by DUBs, the biological function of Otub1 including its positive regulation of p53, and the mechanistic insights into how Otub1 suppresses E2.