BCL-2、BCL-X(L)隔离仅含BH3结构域的分子，从而阻止BAX和BAK介导的线粒体凋亡。
BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis.
作者信息
Cheng E H, Wei M C, Weiler S, Flavell R A, Mak T W, Lindsten T, Korsmeyer S J
机构信息
Howard Hughes Medical Institute, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
出版信息
Mol Cell. 2001 Sep;8(3):705-11. doi: 10.1016/s1097-2765(01)00320-3.
Critical issues in apoptosis include the importance of caspases versus organelle dysfunction, dominance of anti- versus proapoptotic BCL-2 members, and whether commitment occurs upstream or downstream of mitochondria. Here, we show cells deficient for the downstream effectors Apaf-1, Caspase-9, or Caspase-3 display only transient protection from "BH3 domain-only" molecules and die a caspase-independent death by mitochondrial dysfunction. Cells with an upstream defect, lacking "multidomain" BAX, BAK demonstrate long-term resistance to all BH3 domain-only members, including BAD, BIM, and NOXA. Comparison of wild-type versus mutant BCL-2, BCL-X(L) indicates these antiapoptotics sequester BH3 domain-only molecules in stable mitochondrial complexes, preventing the activation of BAX, BAK. Thus, in mammals, BH3 domain-only molecules activate multidomain proapoptotic members to trigger a mitochondrial pathway, which both releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction.
细胞凋亡中的关键问题包括半胱天冬酶与细胞器功能障碍的重要性、抗凋亡与促凋亡BCL-2成员的主导作用，以及细胞凋亡的决定是发生在线粒体的上游还是下游。在此，我们发现，下游效应分子Apaf-1、半胱天冬酶-9或半胱天冬酶-3缺陷的细胞仅对“仅含BH3结构域”的分子表现出短暂的保护作用，并通过线粒体功能障碍以一种不依赖半胱天冬酶的方式死亡。具有上游缺陷且缺乏“多结构域”BAX和BAK的细胞，对所有仅含BH3结构域的成员，包括BAD、BIM和NOXA，表现出长期抗性。野生型与突变型BCL-2、BCL-X(L)的比较表明，这些抗凋亡蛋白将仅含BH3结构域的分子隔离在稳定的线粒体复合物中，从而阻止BAX和BAK的激活。因此在哺乳动物中，仅含BH3结构域的分子激活多结构域促凋亡成员以触发线粒体途径，该途径既能释放细胞色素c以激活半胱天冬酶，又能引发不依赖半胱天冬酶的线粒体功能障碍。
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