Regulation of Mitochondrial Apoptotic Events by p53-mediated Disruption of Complexes between Antiapoptotic Bcl-2 Members and Bim
Regulation of Mitochondrial Apoptotic Events by p53-mediated Disruption of Complexes between Antiapoptotic Bcl-2 Members and Bim
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DOI：
10.1074/jbc.m109.081042
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发表时间：
2010-07-16
影响因子：
4.8
通讯作者：
Rabinowich, Hannah
中科院分区：
文献类型：
--
作者：
Han, Jie;Goldstein, Leslie A.;Rabinowich, Hannah
p53的线粒体功能有多种机制，它们依赖于或不依赖于其转录活性。然而，这些机制都不涉及Bim在p53线粒体易位下游的功能。利用一个p53核定位信号突变体，其核进口是完全废除，我们表明，其在线粒体外膜，其中涉及Bax和巴克的构象变化，凋亡活性介导的Bim。我们进一步证明了p53和Bim与Mcl-1的结合水平之间的负相关性。因此，p53与Mcl-1的结合增强涉及Mcl-1和Bim之间现有复合物的破坏。我们认为，线粒体p53作为Bim去抑制剂的功能，释放Bim螯合复合物与Mcl-1，Bcl-2，Bcl-XL，并允许其参与巴克/Bax激活。
Multiple mechanisms have been proposed for the mitochondrial function of p53 that are either dependent on or independent of its transcriptional activity. However, none of these mechanisms involves Bim functioning downstream of p53 mitochondrial translocation. Utilizing a p53 nuclear localization signal mutant, whose nuclear import is completely abrogated, we demonstrate that its apoptotic activity at the outer mitochondrial membrane, which involves conformational changes in Bax and Bak, is mediated by Bim. We further demonstrate an inverse correlation between the binding levels of p53 and Bim to Mcl-1. Thus, enhanced binding of p53 to Mcl-1 involves the disruption of existing complexes between Mcl-1 and Bim. We propose that mitochondrial p53 functions as a Bim derepressor by releasing Bim from sequestrating complexes with Mcl-1, Bcl-2, and Bcl-XL, and allowing its engagement in Bak/Bax activation.