cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination
cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination
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DOI：
10.1016/j.molcel.2008.05.014
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发表时间：
2008-06-20
期刊：
影响因子：
16
通讯作者：
Barker, Philip A.
中科院分区：
文献类型：
--
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
细胞凋亡抑制因子（IAP）家族蛋白通过尚不确定的机制增强细胞存活。在这份报告中，我们表明，cIAP 1和cIAP 2促进癌细胞的生存作为E3泛素连接酶，保持组成性泛素化的RIP 1衔接蛋白。我们证明，AEG 40730，一个化合物的模型BIR结合四肽，结合到cIAP 1和cIAP 2，促进其autoubiquitination和蛋白体降解，并导致RIP 1泛素化显着减少。我们发现，cIAP 1和cIAP 2直接泛素化RIP 1和诱导组成型RIP 1泛素化的癌细胞，并证明组成型泛素化RIP 1与促生存激酶TAK 1。当通过AEG 40730处理去泛素化时，RIP 1结合caspase-8并诱导细胞凋亡。这些发现提供了对IAP功能的深入了解，并为癌症治疗提供了新的治疗机会。
The inhibitor of apoptosis (IAP) family of proteins enhances cell survival through mechanisms that remain uncertain. In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. When deubiquitinated by AEG40730 treatment, RIP1 binds caspase-8 and induces apoptosis. These findings provide insights into the function of the IAPs and provide new therapeutic opportunities in the treatment of cancer.