Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53
Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53
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DOI：
10.1038/cddis.2015.117
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发表时间：
2015-05-01
影响因子：
9
通讯作者：
Fanciulli, M.
中科院分区：
文献类型：
--
作者：
Desantis, A.;Bruno, T.;Fanciulli, M.
抑癌基因p53主要参与大量生长停滞和凋亡相关基因的转录调控。然而，清楚地了解哪些因素影响这两个相反的p53依赖性结果之间的选择仍然很难。我们以前描述过，在DNA损伤的反应中，RNA聚合酶II结合蛋白Che-1/AATF转录激活p53。在这里，我们发现Che-1直接与p53结合。这种相互作用基本上发生在DNA损伤的最初几个小时，而当细胞因转录后修饰而发生凋亡时，这种相互作用就会消失。此外，Che-1与p53和抑癌基因Brca 1形成三元复合物。因此，我们对p53全基因组染色质占有率的分析表明，p53/Che 1相互作用导致生长停滞p53靶基因优先反式激活，而不是其促凋亡靶基因。值得注意的是，与WT小鼠相比，Che-1（+/-）小鼠暴露于电离辐射导致胸腺细胞凋亡增加。这些结果证实了Che-1作为p53活性的重要调节剂，并表明Che-1是一个有前途但有吸引力的癌症治疗药物靶点。
The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest-and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53-dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II-binding protein Che-1/AATF transcriptionally activates p53. Here, we show that Che-1 binds directly to p53. This interaction essentially occurs in the first hours of DNA damage, whereas it is lost when cells undergo apoptosis in response to posttranscriptional modifications. Moreover, Che-1 sits in a ternary complex with p53 and the oncosuppressor Brca1. Accordingly, our analysis of genome-wide chromatin occupancy by p53 revealed that p53/Che1 interaction results in preferential transactivation of growth arrest p53 target genes over its pro-apoptotic target genes. Notably, exposure of Che-1(+/-) mice to ionizing radiations resulted in enhanced apoptosis of thymocytes, compared with WT mice. These results confirm Che-1 as an important regulator of p53 activity and suggest Che-1 to be a promising yet attractive drug target for cancer therapy.