Caspase-9-induced mitochondrial disruption through cleavage of anti-apoptotic BCL-2 family members
Caspase-9-induced mitochondrial disruption through cleavage of anti-apoptotic BCL-2 family members
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DOI：
10.1074/jbc.m702969200
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发表时间：
2007-11-16
影响因子：
4.8
通讯作者：
Wang, Jin
中科院分区：
文献类型：
--
作者：
Chen, Min;Guerrero, Alan D.;Wang, Jin
凋亡过程中线粒体破坏导致细胞色素c的释放，细胞色素c与Apaf-1和caspase-9形成凋亡小体。凋亡小体中caspase-9的二聚化激活触发caspase信号级联反应。此外，线粒体释放的其他凋亡信号分子，如凋亡诱导因子和内切酶G，也可能诱导caspase-9不依赖的细胞凋亡。为了确定caspase-9诱导的信号事件，我们使用化学诱导的二聚化来特异性激活caspase-9。我们观察到caspase-9二聚化导致线粒体膜电位的丧失和抗凋亡的Bcl-2、Bcl-xL和Mcl-1的分裂。此外，抗切割的Bcl-2、Bcl-xL或Mcl-1能有效抑制caspase-9依赖性的线粒体膜电位丧失和细胞色素c的释放。我们的数据表明，caspase-9信号级联通过切割抗凋亡的Bcl-2、Bcl-xL和Mcl-1诱导线粒体的反馈破坏。
Mitochondrial disruption during apoptosis results in the release of cytochrome c that forms apoptosomes with Apaf-1 and caspase-9. Activation of caspase-9 by dimerization in apoptosomes then triggers a caspase signaling cascade. In addition, other apoptosis signaling molecules released from the mitochondrion, such as apoptosis-inducing factor and endonuclease G, may induce caspase-9-independent apoptosis. To determine the signaling events induced by caspase-9, we used chemically induced dimerization for specific activation of caspase-9. We observed that caspase-9 dimerization resulted in the loss of mitochondrial membrane potential and the cleavage of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1. Moreover, cleavage-resistant Bcl-2, Bcl-xL, or Mcl-1 potently inhibited caspase-9-dependent loss of mitochondrial membrane potential and the release of cytochrome c. Our data suggest that a caspase-9 signaling cascade induces feedback disruption of the mitochondrion through cleavage of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1.