Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage
Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage
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DOI：
10.1073/pnas.96.26.14973
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发表时间：
1999-12-21
影响因子：
11.1
通讯作者：
Shkedy, D
中科院分区：
文献类型：
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作者：
Khosravi, R;Maya, R;Shkedy, D
p53肿瘤抑制蛋白是细胞对遗传毒性应激反应的关键调节因子，在DNA损伤后被稳定和激活。这一过程与p53的翻译后修饰有关，其中一些修饰是由ATM蛋白激酶介导的。p53 ′ 5的稳定性和活性受癌蛋白MDM 2负调节，其基因由p53激活。可以想象，p53功能也可以通过MDM 2的修饰来调节。我们发现，在用电离辐射或拟辐射化学物质而不是紫外线辐射处理细胞后，MDM 2以ATM依赖的方式迅速磷酸化，这种磷酸化不依赖于p53和DNA依赖性蛋白激酶。此外，MDM 2在体外被ATM直接磷酸化。这些发现表明，在响应DNA链断裂时，ATM可能通过介导p53-MDM 2自动调节反馈环的两个伙伴的同时磷酸化来促进p53活性和稳定性。
The p53 tumor-suppressor protein, a key regulator of cellular responses to genotoxic stress, is stabilized and activated after DNA damage, This process is associated with posttranslational modifications of p53, some of which are mediated by the ATM protein kinase, However, these modifications alone may not account in full for p53 stabilization. p53'5 stability and activity are negatively regulated by the oncoprotein MDM2, whose gene is activated by p53. Conceivably, p53 function may be modulated by modifications of MDM2 as well. We show here that after treatment of cells with ionizing radiation or a radiomimetic chemical, but not UV radiation, MDM2 is phosphorylated rapidly in an ATM-dependent manner, This phosphorylation is independent of p53 and the DNA-dependent protein kinase, Furthermore, MDM2 is directly phosphorylated by ATM in vitro, These findings suggest that in response to DNA strand breaks, ATM may promote p53 activity and stability by mediating simultaneous phosphorylation of both partners of the p53-MDM2 autoregulatory feedback loop.