Chen Min, Guerrero Alan D, Huang Li, Shabier Zainuer, Pan Michael, Tan Tse-Hua, Wang Jin
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030.
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030.
J Biol Chem. 2007 Nov 16;282(46):33888-33895. doi: 10.1074/jbc.M702969200. Epub 2007 Sep 24.
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.
细胞凋亡过程中的线粒体破坏会导致细胞色素c释放，细胞色素c与凋亡蛋白酶激活因子-1（Apaf-1）和半胱天冬酶-9形成凋亡小体。凋亡小体中二聚化激活半胱天冬酶-9，进而触发半胱天冬酶信号级联反应。此外，从线粒体释放的其他凋亡信号分子，如凋亡诱导因子和核酸内切酶G，可能诱导不依赖半胱天冬酶-9的细胞凋亡。为了确定由半胱天冬酶-9诱导的信号事件，我们使用化学诱导二聚化来特异性激活半胱天冬酶-9。我们观察到半胱天冬酶-9二聚化导致线粒体膜电位丧失以及抗凋亡蛋白Bcl-2、Bcl-xL和Mcl-1的裂解。此外，抗裂解的Bcl-2、Bcl-xL或Mcl-1能有效抑制半胱天冬酶-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，半胱天冬酶-9信号级联反应通过裂解抗凋亡蛋白Bcl-2、Bcl-xL和Mcl-1诱导线粒体的反馈性破坏。
