ARF Tumor Suppressor Induces Mitochondria-dependent Apoptosis by Modulation of Mitochondrial Bcl-2 Family Proteins*
ARF Tumor Suppressor Induces Mitochondria-dependent Apoptosis by Modulation of Mitochondrial Bcl-2 Family Proteins*
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DOI：
10.1074/jbc.m300510200
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发表时间：
2003-07
影响因子：
4.8
通讯作者：
Y. Nakazawa;T. Kamijo;K. Koike;T. Noda
中科院分区：
文献类型：
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作者：
Y. Nakazawa;T. Kamijo;K. Koike;T. Noda
肿瘤抑制基因产物ARF在适当的附带信号存在下使细胞对凋亡敏感。在这项研究中，我们分析了ARF依赖性细胞凋亡的机制，并证明ARF诱导p53野生型，ARF/p16-null细胞中的细胞凋亡。我们还发现，ARF引起细胞色素c从线粒体释放，降低线粒体膜电位，并激活caspase-9前体诱导细胞凋亡。我们的研究结果表明，这种凋亡细胞的调制是由上调促凋亡Bcl-2家族蛋白Bax和Bim和下调线粒体组分中的抗凋亡Bcl-2。此外，ARF似乎以p53依赖的方式下调Bcl-2，同时通过p53非依赖性途径上调Bax/Bim。
A tumor suppressor gene product, ARF, sensitizes cells to apoptosis in the presence of appropriate collateral signals. In this study, we analyzed the mechanism of ARF-dependent apoptosis and demonstrated that ARF induces mitochondria-dependent apoptosis in p53 wild-type, ARF/p16-null cells. We also found that ARF evokes cytochrome c release from mitochondria, decreases mitochondrial membrane potential, and activates pro-caspase-9 to induce apoptosis. Our findings suggest that this apoptotic cellular modulation is brought about by up-regulation of the proapoptotic Bcl-2 family proteins Bax and Bim and down-regulation of antiapoptotic Bcl-2 in mitochondrial fractions. Additionally, ARF seems to down-regulate Bcl-2 in a p53-dependent manner while up-regulating Bax/Bim via a p53-independent pathway.