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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >MAP-1 is a mitochondrial effector of Bax.
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MAP-1 is a mitochondrial effector of Bax.

机译：MAP-1是Bax的线粒体效应子。

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Apoptotic stimuli induce conformational changes in Bax and trigger its translocation from cytosol to mitochondria. Upon assembling into the mitochondrial membrane, Bax initiates a death program through a series of events, culminating in the release of apoptogenic factors such as cytochrome c. Although it is known that Bax is one of the key factors for integrating multiple death signals, the mechanism by which Bax functions in mitochondria remains controversial. We have previously identified modulator of apoptosis-1 (MAP-1) as a Bax-associating protein, but its functional relationship with Bax in contributing to apoptosis regulation remains to be established. In this study, we show that MAP-1 is a critical mitochondrial effector of Bax. MAP-1 is a mitochondria-enriched protein that associates with Bax only upon apoptotic induction, which coincides with the release of cytochrome c from mitochondria. Small interfering RNAs that diminish MAP-1 levels in mammalian cell lines confer selective inhibition of Bax-mediated apoptosis. Mammalian cells with stable expression of MAP-1 small interfering RNAs are resistant to multiple apoptotic stimuli in triggering apoptotic death as well as in inducing conformation change and translocation of Bax. Similar to Bax-deficient cells, MAP-1-deficient cells exhibit aggressive anchorage-independent growth. Remarkably, recombinant Bax- or tBid-mediated release of cytochrome c from isolated mitochondria is significantly compromised in the MAP-1 knockdown cells. We propose that MAP-1 is a direct mitochondrial target of Bax.
机译：凋亡刺激诱导Bax的构象变化，并触发其从胞质溶胶到线粒体的易位。组装到线粒体膜中后，Bax通过一系列事件启动了死亡程序，最终导致了细胞色素c等凋亡因子的释放。尽管已知Bax是整合多个死亡信号的关键因素之一，但Bax在线粒体中发挥作用的机制仍存在争议。我们之前已经确定凋亡调控因子1（MAP-1）作为Bax相关蛋白，但它与Bax在促凋亡调控中的功能关系尚待建立。在这项研究中，我们表明MAP-1是Bax的关键线粒体效应子。 MAP-1是一种富含线粒体的蛋白质，仅在凋亡诱导时才与Bax结合，这与线粒体中细胞色素c的释放相吻合。减少哺乳动物细胞系中MAP-1水平的小分子干扰RNA可选择性抑制Bax介导的细胞凋亡。稳定表达MAP-1小干扰RNA的哺乳动物细胞在触发凋亡死亡以及诱导Bax构象变化和易位时，对多种凋亡刺激具有抗性。与缺乏Bax的细胞相似，缺乏MAP-1的细胞表现出侵袭性的锚定非依赖性生长。值得注意的是，在MAP-1敲低细胞中，重组Bax或tBid介导的细胞色素c从分离的线粒体的释放显着受损。我们建议MAP-1是Bax的直接线粒体靶标。

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