The anaphase-promoting complex/cyclosome is an E3 ubiquitin ligase for Mdm2
The anaphase-promoting complex/cyclosome is an E3 ubiquitin ligase for Mdm2
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DOI：
10.4161/cc.29106
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发表时间：
2014-07-01
期刊：
影响因子：
4.3
通讯作者：
Zhang, Yanping
中科院分区：
文献类型：
--
作者：
He, Yizhou;Tollini, Laura;Zhang, Yanping
Mdm 2原癌蛋白是p53的主要负调节因子。虽然认为Mdm 2降解是通过其自身的E3泛素连接酶活性调节的，但最近开发的敲入小鼠模型表明Mdm 2 E3连接酶功能对于体内自降解是不可缺少的。在这里，我们表明，后期促进复合物/环体（APCC）是一个E3泛素连接酶MDM2降解。我们证明APCC的支架亚基APC2与Mdm 2结合，并且是Mdm 2多聚泛素化和蛋白酶体降解所必需的。通过RNAi下调APC 2导致Mdm 2的非转录依赖性积累和应激诱导的p53稳定性的减弱，从而导致衰老减少和细胞存活增加。此外，APC 2表达在人类癌症中经常下调;在肿瘤细胞系中，APC 2下调与Mdm 2过表达相关。我们的研究表明，Mdm 2的E3泛素连接酶APCC的调节，并与Mdm 2过表达的肿瘤具有重要的治疗意义。
The Mdm2 proto-oncoprotein is the primary negative regulator for p53. While it is believed that Mdm2 degradation is regulated via its own E3 ubiquitin ligase activity, recent development of knock-in mouse models demonstrates that Mdm2 E3 ligase function is dispensable for self-degradation in vivo. Here, we show that the anaphase-promoting complex/cyclosome (APCC) is an E3 ubiquitin ligase for Mdm2 degradation. We demonstrate that APC2, a scaffold subunit of APCC, binds to Mdm2 and is required for Mdm2 polyubiquitination and proteasomal degradation. Downregulation of APC2 by RNAi results in transcription-independent accumulation of Mdm2 and attenuation of stress-induced p53 stabilization, leading to decreased senescence and increased cell survival. Furthermore, APC2 expression is frequently downregulated in human cancers; in tumor cell lines, APC2 downregulation correlates with Mdm2 overexpression. Our study shows the regulation of Mdm2 by the E3 ubiquitin ligase APCC and has important therapeutic implications for tumors with Mdm2 overexpression.