Post-cytochrome c protection from apoptosis conferred by a MAPK pathway in Xenopus egg extracts
Post-cytochrome c protection from apoptosis conferred by a MAPK pathway in Xenopus egg extracts
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DOI：
10.1091/mbc.01-06-0291
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发表时间：
2002-02-01
影响因子：
3.3
通讯作者：
Kornbluth, S
中科院分区：
文献类型：
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作者：
Tashker, JS;Olson, M;Kornbluth, S
在许多不同的凋亡刺激下，细胞色素c从线粒体的膜间隙释放到细胞质中，在那里它作为激活原天冬氨酸酶9的辅助因子。这一过程的抑制可以通过阻止细胞色素c的释放或通过阻断caspase的激活或活性来实现。非洲爪哇卵无细胞提取物的体外细胞凋亡重建实验表明，滞留在间期的萃取物容易受到导致caspase激活的内源性凋亡程序的影响，而滞留在减数分裂中期的萃取物则不是。我们在此报道，在M期滞留卵细胞中，活跃的MOS/MEK/MAPK通路是导致它们对细胞不能发生凋亡的原因。有趣的是，M相抑制提取物能够释放细胞色素c，但仍然不激活caspase。同时，我们还证明了重组的MOS、MEK和ERK足以在缺乏转录和翻译的纯化非洲爪哇胞浆中阻断细胞色素c依赖的caspase激活。这些数据表明，在缺乏新的mRNA/蛋白质合成的情况下，MAP激酶途径可以靶向并抑制细胞色素c释放后的凋亡事件，这一生化途径是在莱氏X.laevis减数分裂卵液中观察到的细胞凋亡抑制的原因。
In response to many different apoptotic stimuli, cytochrome c is released from the intermembrane space of the mitochondria into the cytoplasm, where it serves as a cofactor in the activation of procaspase 9. Inhibition of this process can occur either by preventing cytochrome c release or by blocking caspase activation or activity. Experiments involving in vitro reconstitution of apoptosis in cell-free extracts of Xenopus laevis eggs have suggested that extracts arrested in interphase are susceptible to an endogenous apoptotic program leading to caspase activation, whereas extracts arrested in meiotic metaphase are not. We report here that Mos/MEK/MAPK pathways active in M phase-arrested eggs are responsible for rendering them refractory to apoptosis. Interestingly, M phase-arrested extracts are competent to release cytochrome c, yet still do not activate caspases. Concomitantly, we have also demonstrated that recombinant Mos, MEK, and ERK are sufficient to block cytochrome c-dependent caspase activation in purified Xenopus cytosol, which lacks both transcription and translation. These data indicate that the MAP kinase pathway can target and inhibit post-cytochrome c release apoptotic events in the absence of new mRNA/protein synthesis and that this biochemical pathway is responsible for the apoptotic inhibition observed in meiotic X. laevis egg extracts.