Bcr-Abl-mediated protection from apoptosis downstream of mitochondrial cytochrome c release
Bcr-Abl-mediated protection from apoptosis downstream of mitochondrial cytochrome c release
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DOI：
10.1128/mcb.24.23.10289-10299.2004
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发表时间：
2004-12-01
影响因子：
5.3
通讯作者：
Kornbluth, S
中科院分区：
文献类型：
--
作者：
Deming, PB;Schafer, ZT;Kornbluth, S
Bcr-Abl在慢性粒细胞白血病中被激活，是一种有效的细胞死亡抑制剂。以前的报道表明，Bcr-Abl通过抑制线粒体细胞色素c的释放来防止细胞凋亡。我们在这里报告，Bcr-Abl也抑制细胞色素c释放后的半胱天冬酶激活。Bcr-Abl抑制caspase激活细胞色素c加入到无细胞裂解液，并防止细胞色素c被微量注射到完整的细胞凋亡。Bcr-Abl的行为posteruptionally防止细胞色素c诱导的Apaf-1的结合，以procaspase 9。虽然Bcr-Abl阻止了内源性Apaf-1与caspase 9的重组前结构域的相互作用，但它并不影响内源性caspase 9与分离的Apaf-1 caspase募集结构域（CARD）或缺乏WD-40重复的Apaf-1的结合。这些数据表明，在Bcr-Abl存在下，Apaf-1对caspase 9的募集是错误的，并且细胞色素c/dATP诱导的Apaf-1 CARD暴露可能是有缺陷的。这些数据提供了一个新的基因座Bcr-Abl抗凋亡作用，并提出了一个独特的机制，aptosomal抑制。
Bcr-Abl, activated in chronic myelogenous leukemias, is a potent cell death inhibitor. Previous reports have shown that Bcr-Abl prevents apoptosis through inhibition of mitochondrial cytochrome c release. We report here that Bcr-Abl also inhibits caspase activation after the release of cytochrome c. Bcr-Abl inhibited caspase activation by cytochrome c added to cell-free lysates and prevented apoptosis when cytochrome c was micro-injected into intact cells. Bcr-Abl acted posttranslationally to prevent the cytochrome c-induced binding of Apaf-1 to procaspase 9. Although Bcr-Abl prevented interaction of endogenous Apaf-1 with the recombinant prodomain of caspase 9, it did not affect the association of endogenous caspase 9 with the isolated Apaf-1 caspase recruitment domain (CARD) or Apaf-1 lacking WD-40 repeats. These data suggest that Apaf-1 recruitment of caspase 9 is faulty in the presence of Bcr-Abl and that cytochrome c/dATP-induced exposure of the Apaf-1 CARD is likely defective. These data provide a novel locus of Bcr-Abl antiapoptotic action and suggest a distinct mechanism of apoptosomal inhibition.