Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death
Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death
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DOI：
10.1126/science.1059108
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发表时间：
2001-04-27
期刊：
影响因子：
56.9
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Wei, MC;Zong, WX;Korsmeyer, SJ
多种死亡信号在线粒体凋亡过程中影响线粒体，但体内线粒体功能障碍的关键启动事件尚不清楚。TbID是BH3结构域BCL-2家族成员的半胱氨酸酶激活形式，它触发多结构域保守的促凋亡家族成员BAK或Bax的同源齐聚，导致细胞色素c从线粒体中释放。我们发现，缺乏Bax和Bak的细胞，而不是缺乏其中一种成分的细胞，完全抵抗TBID诱导的细胞色素c的释放和凋亡。此外，双缺陷细胞对多种通过破坏线粒体功能而起作用的凋亡刺激具有抵抗力：星形孢子素、紫外线辐射、生长因子剥夺、依托泊苷以及内质网应激刺激thapsigargin和衣霉素。因此，一个“多结构域”促凋亡成员Bax或BAK的激活似乎是导致细胞在不同刺激下死亡所需的线粒体功能障碍的重要途径。
Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a "BH3-domain-only" BCL-2 family member, triggers the homooligomerization of "multidomain" conserved proapoptotic family members BAK or BAX, resulting in the release of cytochrome c from mitochondria. We find that cells lacking both Bax and Bak, but not cells lacking only one of these components, are completely resistant to tBID-induced cytochrome c release and apoptosis. Moreover, doubly deficient cells are resistant to multiple apoptotic stimuli that act through disruption of mitochondrial function: staurosporine, ultraviolet radiation, growth factor deprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsigargin and tunicamycin. Thus, activation of a "multidomain" proapoptotic member, BAX or BAK, appears to be an essential gateway to mitochondrial dysfunction required for cell death in response to diverse stimuli.