ATM regulates cell fate choice upon p53 activation by modulating mitochondrial turnover and ROS levels.
ATM regulates cell fate choice upon p53 activation by modulating mitochondrial turnover and ROS levels.
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DOI：
10.4161/15384101.2014.973330
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Espinosa JM
中科院分区：
文献类型：
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作者：
Sullivan KD;Palaniappan VV;Espinosa JM
尽管进行了广泛的研究，但细胞命运选择对P53激活的机制仍然知之甚少。通过全基因组shRNA筛选，我们最近发现ATM激酶与Nutlin-3合成致死，Nutlin-3是一种MDM2抑制剂，导致非遗传毒性的P53激活。在这里，我们证明，虽然这种合成的致命相互作用依赖于内在和外在的凋亡途径(例如，Bax和Bid)的成分，但这并不是由于ATM对p53靶基因表达的显著影响。相反，ATM活性的丧失会导致线粒体和活性氧物种增加，从而推动细胞凋亡。最后，我们提供了证据表明，药物抑制ATM阻止自噬与激活这一过程的P53直接对立，并且当与Nutlin-3结合时，抑制自噬足以引发凋亡反应。
Despite extensive study, the mechanisms of cell fate choice upon p53 activation remain poorly understood. Using genome-wide shRNA screening, we recently identified the ATM kinase as synthetic lethal with Nutlin-3, an MDM2 inhibitor that leads to non-genotoxic p53 activation. Here, we demonstrate that while this synthetic lethal interaction relies upon components of both the intrinsic and extrinsic apoptotic pathways (e.g., BAX and BID), it is not due to significant ATM effects on the expression of p53 target genes. Instead, loss of ATM activity results in increased mitochondria and reactive oxygen species that drive apoptosis. Finally, we provide evidence that pharmacologic inhibition of ATM blocks autophagy in direct opposition to p53, which activates this process, and that inhibition of autophagy is sufficient to elicit an apoptotic response when combined with Nutlin-3.