p53 is cleaved by caspases generating fragments localizing to mitochondria
p53 is cleaved by caspases generating fragments localizing to mitochondria
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DOI：
10.1074/jbc.m512467200
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发表时间：
2006-05-12
影响因子：
4.8
通讯作者：
Cohen, GM
中科院分区：
文献类型：
--
作者：
Sayan, BS;Sayan, AE;Cohen, GM
p53肿瘤抑制蛋白通过转录激活几个促凋亡基因来发挥其大部分抗肿瘤活性。越来越多的证据也表明p53在细胞凋亡过程中的转录非依赖性功能。最近已经表明，当激活时，一部分p53易位到线粒体，引起细胞色素c释放。现在，我们证明了一个半胱天冬酶依赖的切割p53产生的四个片段，其中两个缺乏核定位信号，因此本地化到胞质溶胶。此外，这两个片段易位到线粒体和诱导线粒体膜去极化的转录活性的情况下。p53的这一新特征支持胞质p53在细胞凋亡中发挥主要功能的模型，并且还表明存在正反馈回路，其中激活的半胱天冬酶切割p53以增加线粒体膜去极化。
The p53 tumor suppressor protein exerts most of its anti- tumorigenic activity by transcriptionally activating several pro-apoptotic genes. Accumulating evidence also suggests a transcription-independent function of p53 during apoptosis. It has recently been shown that, when activated, a fraction of p53 translocates to mitochondria, causing cytochrome c release. We now demonstrate a caspase-dependent cleavage of p53 resulting in the generation of four fragments, two of which lack a nuclear localization signal and consequently localize to cytosol. Moreover, these two fragments translocate to mitochondria and induce mitochondrial membrane depolarization in the absence of transcriptional activity. This novel feature of p53 supports the model whereby cytosolic p53 exerts major functions in apoptosis and also suggests the presence of a positive feedback loop in which activated caspases cleave p53 to augment mitochondrial membrane depolarization.