Transcriptional blockade induces p53-dependent apoptosis associated with translocation of p53 to mitochondria
Transcriptional blockade induces p53-dependent apoptosis associated with translocation of p53 to mitochondria
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DOI：
10.1074/jbc.m410691200
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发表时间：
2005-05-13
影响因子：
4.8
通讯作者：
Saya, H
中科院分区：
文献类型：
--
作者：
Arima, Y;Nitta, M;Saya, H
肿瘤抑制因子 p53 作为转录激活因子，诱导细胞周期停滞和细胞凋亡以响应 DNA 损伤。尽管 p53 也被证明以独立于其反式激活活性的方式介导细胞凋亡，但触发这种细胞死亡的机制和条件仍然很大程度上未知。我们现在已经证明，通过 α-鹅膏蕈碱或 RNA 干扰抑制 RNA 聚合酶 II 介导的转录可诱导 p53 依赖性细胞凋亡。 pol II 介导的转录抑制导致 p21(Cip1) 下调，这是由转录抑制和蛋白质降解共同引起的，尽管会引起 p53 积累，从而使细胞进入 S 期，然后发生凋亡。这种细胞死亡不需要 p53 靶基因的转录，并且在积累的 p53 易位到线粒体之前发生。因此，我们的数据表明，阻断 pol II 介导的转录会诱导 p53 在线粒体中积累，并且是引发 p53 依赖但不依赖于转录的细胞凋亡的关键因素。
The tumor suppressor p53 functions as a transcriptional activator to induce cell cycle arrest and apoptosis in response to DNA damage. Although p53 was also shown to mediate apoptosis in a manner independent of its transactivation activity, the mechanism and conditions that trigger such cell death have remained largely unknown. We have now shown that inhibition of RNA polymerase II-mediated transcription by alpha-amanitin or RNA interference induced p53-dependent apoptosis. Inhibition of pol II-mediated transcription resulted in down-regulation of p21(Cip1), which was caused by both transcriptional suppression and protein degradation, despite eliciting p53 accumulation, allowing the cells to progress into S phase and then to undergo apoptosis. This cell death did not require the transcription of p53 target genes and was preceded by translocation of the accumulated p53 to mitochondria. Our data thus suggested that blockade of pol II-mediated transcription induced p53 accumulation in mitochondria and was the critical factor for eliciting p53-dependent but transcription-independent apoptosis.