Saelens Xavier, Festjens Nele, Vande Walle Lieselotte, van Gurp Maria, van Loo Geert, Vandenabeele Peter
Department for Molecular Biomedical Research, VIB and Ghent University, Fiers-Shell-Van Montagu Building, Ghent B9052, Belgium.
Oncogene. 2004 Apr 12;23(16):2861-74. doi: 10.1038/sj.onc.1207523.
A plethora of apoptotic stimuli converge on the mitochondria and affect their membrane integrity. As a consequence, multiple death-promoting factors residing in the mitochondrial intermembrane space are liberated in the cytosol. Pro- and antiapoptotic Bcl-2 family proteins control the release of these mitochondrial proteins by inducing or preventing permeabilization of the outer mitochondrial membrane. Once released into the cytosol, these mitochondrial proteins activate both caspase-dependent and -independent cell death pathways. Cytochrome c was the first protein shown to be released from the mitochondria into the cytosol, where it induces apoptosome formation. Other released mitochondrial proteins include apoptosis-inducing factor (AIF) and endonuclease G, both of which contribute to apoptotic nuclear DNA damage in a caspase-independent way. Other examples are Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP-binding protein with low PI) and the serine protease HtrA2/OMI (high-temperature requirement protein A2), which both promote caspase activation and instigate caspase-independent cytotoxicity. The precise mode of action and importance of cytochrome c in apoptosis in mammalian cells has become clear through biochemical, structural and genetic studies. More recently identified factors, for example HtrA2/OMI and Smac/DIABLO, are still being studied intensively in order to delineate their functions in apoptosis. A better understanding of these functions may help to develop new strategies to treat cancer.
大量凋亡刺激因素作用于线粒体并影响其膜完整性。结果，位于线粒体外膜间隙的多种促死亡因子被释放到细胞质中。促凋亡和抗凋亡的Bcl-2家族蛋白通过诱导或阻止线粒体外膜通透性来控制这些线粒体蛋白的释放。一旦释放到细胞质中，这些线粒体蛋白就会激活半胱天冬酶依赖性和非依赖性细胞死亡途径。细胞色素c是第一个被证明从线粒体释放到细胞质中的蛋白，在细胞质中它会诱导凋亡小体的形成。其他释放的线粒体蛋白包括凋亡诱导因子（AIF）和核酸内切酶G，它们都以半胱天冬酶非依赖性方式导致凋亡性核DNA损伤。其他例子还有Smac/DIABLO（第二个线粒体衍生的半胱天冬酶激活剂/低PI值直接IAP结合蛋白）和丝氨酸蛋白酶HtrA2/OMI（高温需求蛋白A2），它们都促进半胱天冬酶激活并引发半胱天冬酶非依赖性细胞毒性。通过生化、结构和遗传学研究，细胞色素c在哺乳动物细胞凋亡中的精确作用方式和重要性已变得清晰。最近发现的因子，例如HtrA2/OMI和Smac/DIABLO，仍在深入研究中，以阐明它们在凋亡中的功能。更好地理解这些功能可能有助于开发治疗癌症的新策略。
