The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death
The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death
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DOI：
10.1074/jbc.m308785200
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发表时间：
2003-11-28
影响因子：
4.8
通讯作者：
Kim, TH
中科院分区：
文献类型：
--
作者：
Seo, YW;Shin, JN;Kim, TH
基因毒性应激稳定p53肿瘤抑制蛋白，其反过来反式激活靶基因以引起细胞凋亡。虽然Noxa是Bcl-2家族的“仅BH 3”成员，被证明是p53介导的反式激活的靶点，并通过线粒体功能障碍作为p53依赖性凋亡的介导者，但Noxa引起线粒体功能障碍的分子机制在很大程度上是未知的。在这里，我们表明，在Noxa的两个结构域（BH 3结构域和线粒体靶向结构域）是必不可少的细胞色素c从线粒体的释放。Noxa诱导的细胞色素c释放被渗透性转换孔抑制剂如CsA或MgCl 2抑制，并且Noxa诱导线粒体的超微结构变化，产生“肿胀”线粒体，这与tBid诱导的变化不同。这表明，Noxa可能激活通透性转换相关孔，将细胞色素c从线粒体释放到胞质溶胶中。此外，Bak-oligomerization，这是一个必不可少的事件tBid诱导的细胞色素c释放的外在死亡信号通路，是不相关的Noxa诱导的细胞色素c释放。这一发现表明，Noxa诱导的线粒体功能障碍的途径不同于TBID诱导的线粒体功能障碍的途径。因此，我们提出，至少有两种不同的线粒体功能障碍的途径，一个介导的通过Noxa在响应于遗传毒性应激和其他通过tBid在响应于死亡配体。
Genotoxic stresses stabilize the p53 tumor suppressor protein which, in turn, transactivates target genes to cause apoptosis. Although Noxa, a "BH3-only" member of the Bcl-2 family, was shown to be a target of p53-mediated transactivation and to function as a mediator of p53-dependent apoptosis through mitochondrial dysfunction, the molecular mechanism by which Noxa causes mitochondrial dysfunction is largely unknown. Here we show that two domains (BH3 domain and mitochondrial targeting domain) in Noxa are essential for the release of cytochrome c from mitochondria. Noxa-induced cytochrome c release is inhibited by permeability transition pore inhibitors such as CsA or MgCl2, and Noxa induces an ultra-structural change of mitochondria yielding "swollen" mitochondria that are unlike changes induced by tBid. This indicates that Noxa may activate the permeability transition-related pore to release cytochrome c from mitochondria into cytosol. Moreover, Bak-oligomerization, which is an essential event for tBid-induced cytochrome c release in the extrinsic death signaling pathway, is not associated with Noxa-induced cytochrome c release. This finding suggests that the pathway of Noxa-induced mitochondrial dysfunction is distinct from the one of tBid-induced mitochondrial dysfunction. Thus, we propose that there are at least two different pathways of mitochondrial dysfunction; one mediated through Noxa in response to genotoxic stresses and the other through tBid in response to death ligands.