Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage
Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage
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DOI：
10.1073/pnas.96.24.13777
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发表时间：
1999-11-23
影响因子：
11.1
通讯作者：
Halazonetis, TD
中科院分区：
文献类型：
--
作者：
Chehab, NH;Malikzay, A;Halazonetis, TD
p53对DNA损伤的稳定性是由其与Mdm 2的解离引起的，Mdm 2是一种靶向p53在蛋白酶体中降解的蛋白质。DNA损伤诱导的p53翻译后修饰可能导致p53与Mdm 2的解离。ATM和ATR激酶分别响应于电离辐射（IR）和UV光而活化，是p53稳定化所需的，它们直接磷酸化Ser-15上的p53。然而，Ser-15的磷酸化对于p53的凋亡活性是关键的，而不是对于p53的稳定性。因此，是否有任何p53修饰，以及哪些修饰是DNA损伤后p53-Mdm 2复合物破坏的基础，仍有待确定。我们分析了IR和UV光诱导的p53蛋白的稳定性，已知在DNA损伤后被后修饰的Ser取代。Ser-20的取代足以消除p53响应于IR和UV光的稳定性。此外，IR和UV光诱导Ser-20上的p53磷酸化，这涉及大部分核p53蛋白，并减弱p53与Mdm 2的相互作用。ATM和ATR不能磷酸化Ser-20上的p53。因此，我们认为ATM和ATR激活了一种尚未鉴定的激酶，该激酶通过使p53在Ser-20上磷酸化来稳定p53。
Stabilization of p53 in response to DNA damage is caused by its dissociation from Mdm2, a protein that targets p53 for degradation in the proteasome. Dissociation of p53 from Mdm2 could be caused by DNA damage-induced p53 posttranslational modifications. The ATM and ATR kinases, whose activation in response to ionizing radiation (IR) and UV light, respectively, is required for p53 stabilization, directly phosphorylate p53 on Ser-15. However, phosphorylation of Ser-15 is critical for the apoptotic activity of p53 and not for p53 stabilization. Thus, whether any p53 modifications, and which, underlie disruption of the p53-Mdm2 complex after DNA damage remains to be determined. We analyzed the IR- and UV light-induced stabilization of p53 proteins with substitutions of Ser known to be posttranslationally modified after DNA damage. Substitution of Ser-20 was sufficient to abrogate p53 stabilization in response to both IR and UV light. Furthermore, both IR and UV light induced phosphorylation of p53 on Ser-20, which involved the majority of nuclear p53 protein and weakened the interaction of p53 with Mdm2 in vitro. ATM and ATR cannot phosphorylate p53 on Ser-20. We therefore propose that ATM and ATR activate an, as yet unidentified, kinase that stabilizes p53 by phosphorylating it on Ser-20.