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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mechanism Of Apoptosis Induction By Inhibition Of The Anti-apoptotic Bcl-2 Proteins
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Mechanism Of Apoptosis Induction By Inhibition Of The Anti-apoptotic Bcl-2 Proteins

机译：抑制抗凋亡Bcl-2蛋白诱导细胞凋亡的机制

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摘要

Normal cellular lifespan is contingent upon preserving outer mi-tochondrial membrane (OMM) integrity, as permeabilization promotes apoptosis. BCL-2 family proteins control mitochondrial outer membrane permeabilization (MOMP) by regulating the activation of the pro-apoptotic BCL-2 effector molecules, BAX and BAK. Sustainable cellular stress induces proteins (e.g., BID, BIM, and cytosolic p53) capable of directly activating BAX and/or BAK, but these direct activators are sequestered by the anti-apoptotic BCL-2 proteins (e.g., BCL-2, BCL-xL, and MCL-1). In the event of accumulated or marked cellular stress, a coordinated effort between previously sequestered and nascent BH3-only proteins inhibits the anti-apoptotic BCL-2 repertoire to promote direct activator protein-mediated MOMP. We examined the effect of ABT-737, a BCL-2 antagonist, and PUMA, a BH3-only protein that inhibits the entire anti-apoptotic BCL-2 repertoire, with cells and mitochondria that sequestered direct activator proteins. ABT-737 and PUMA cooperated with sequestered direct activator proteins to promote MOMP and apoptosis, which in the absence of ABT-737 or PUMA did not influence OMM integrity or cellular survival. Our data show that the induction of apoptosis by inhibition of the anti-apoptotic BCL-2 repertoire requires "covert" levels of direct activators of BAX and BAK at the OMM.
机译：正常的细胞寿命取决于保持外部线粒体膜（OMM）的完整性，因为通透性会促进细胞凋亡。 BCL-2家族蛋白通过调节促凋亡BCL-2效应分子BAX和BAK的激活来控制线粒体外膜通透性（MOMP）。持续的细胞应激诱导能够直接激活BAX和/或BAK的蛋白质（例如BID，BIM和胞质p53），但是这些直接激活剂被抗凋亡的BCL-2蛋白（例如BCL-2，BCL- xL和MCL-1）。在累积或明显的细胞应激情况下，先前螯合的和新生的仅BH3的蛋白质之间的协调努力会抑制抗凋亡的BCL-2分子库，从而促进直接激活蛋白介导的MOMP。我们检查了ABT-737（一种BCL-2拮抗剂）和PUMA（一种仅BH3蛋白质）的作用，该蛋白质可抑制整个抗凋亡的BCL-2组成部分，而细胞和线粒体则隔离了直接激活蛋白。 ABT-737和PUMA与螯合的直接激活蛋白协同作用以促进MOMP和细胞凋亡，而在没有ABT-737或PUMA的情况下，它们不会影响OMM完整性或细胞存活。我们的数据表明，通过抑制抗凋亡BCL-2分子库来诱导凋亡需要在OMM处“隐蔽”水平的BAX和BAK直接激活剂。

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