Mitochondrial p32 is a critical mediator of ARF-induced apoptosis
Mitochondrial p32 is a critical mediator of ARF-induced apoptosis
复制标题
DOI：
10.1016/j.ccr.2008.04.002
复制
发表时间：
2008-06-01
期刊：
影响因子：
50.3
通讯作者：
Zhang, Yanping
中科院分区：
文献类型：
--
作者：
Itahana, Koji;Zhang, Yanping
p14ARF-p16INK4a基因座的共享外显子2在人类癌症中经常发生突变。然而，与外显子1 β编码的ARF n端相比，外显子2编码的ARF c端一半的功能一直是难以捉摸的。在这里，我们报道线粒体蛋白p32/C1QBP与ARF C末端结合。我们发现，p32是ARF定位到线粒体并诱导细胞凋亡所必需的，而ARF突变特异性地破坏p32结合可以损害这两种功能。野生型ARF，而不是p32结合缺陷型ARF突变体，定位于线粒体，降低线粒体膜电位，并使细胞对p53诱导的凋亡敏感。这些发现为针对ARF C末端的频繁人类癌症突变提供了一个潜在的解释。
The shared exon 2 of the p14ARF-p16INK4a locus is frequently mutated in human cancers. However, in contrast to the exon 1 beta-encoded N-terminal half of ARF, the function of the exon 2-encoded C-terminal half of ARF has been elusive. Here, we report that the mitochondrial protein p32/C1QBP binds the ARF C terminus. We show that p32 is required for ARF to localize to mitochondria and induce apoptosis, and that ARF mutations specifically disrupting p32 binding can impair both of these functions. Wild-type ARF, but not a p32-binding-deficient ARF mutant, localizes to mitochondria, reduces mitochondrial membrane potential, and sensitizes cells to p53-induced apoptosis. These findings provide a potential explanation for the frequent human cancer mutations targeting the ARF C terminus.