A chemical inhibitor of Apaf-1 exerts mitochondrioprotective functions and interferes with the intra-S-phase DNA damage checkpoint
A chemical inhibitor of Apaf-1 exerts mitochondrioprotective functions and interferes with the intra-S-phase DNA damage checkpoint
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DOI：
10.1007/s10495-008-0310-x
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发表时间：
2009-02-01
期刊：
影响因子：
7.2
通讯作者：
Kroemer, Guido
中科院分区：
文献类型：
--
作者：
Mondragon, Laura;Galluzzi, Lorenzo;Kroemer, Guido
QM 31代表一类新的细胞保护剂，其抑制由Apaf-1、细胞色素c、dATP和半胱天冬酶-9组成的半胱天冬酶活化复合物-半胱天冬酶体的形成。在这里，我们分析了QM 31的细胞效应，与原型半胱天冬酶抑制剂Z-VAD-favor相比。QM 31在抑制半胱天冬酶-3活化方面与Z-VAD-fastin一样有效，并赋予类似的细胞保护作用。与Z-VAD-fetamine相反，QM 31抑制细胞色素c从线粒体的释放，这是一种不可预见的性质，可能有助于其显著的细胞保护活性。此外，QM 31抑制Apaf-1依赖的S期内DNA损伤检查点。这些结果表明，QM 31可以干扰Apaf-1的两个已知功能，即线粒体组装/激活和S期内细胞周期阻滞。此外，QM 31可以抑制线粒体外膜透化，这种作用独立于其对Apaf-1的作用。
QM31 represents a new class of cytoprotective agents that inhibit the formation of the apoptosome, the caspase activation complex composed by Apaf-1, cytochrome c, dATP and caspase-9. Here, we analyzed the cellular effects of QM31, as compared to the prototypic caspase inhibitor Z-VAD-fmk. QM31 was as efficient as Z-VAD-fmk in suppressing caspase-3 activation, and conferred a similar cytoprotective effect. In contrast to Z-VAD-fmk, QM31 inhibited the release of cytochrome c from mitochondria, an unforeseen property that may contribute to its pronounced cytoprotective activity. Moreover, QM31 suppressed the Apaf-1-dependent intra-S-phase DNA damage checkpoint. These results suggest that QM31 can interfere with the two known functions of Apaf-1, namely apoptosome assembly/activation and intra-S-phase cell cycle arrest. Moreover, QM31 can inhibit mitochondrial outer membrane permeabilization, an effect that is independent from its action on Apaf-1.