Potentiality of DNA-dependent protein kinase to phosphorylate Ser46 of human p53
Potentiality of DNA-dependent protein kinase to phosphorylate Ser46 of human p53
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DOI：
10.1016/j.bbrc.2004.08.161
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发表时间：
2004-10-22
影响因子：
3.1
通讯作者：
Suzuki, N
中科院分区：
文献类型：
--
作者：
Komiyama, S;Taniguchi, S;Suzuki, N
DNA 损伤通过各种翻译后修饰诱导 p53 的积累和激活。其中，多项证据表明 Ser46 磷酸化是 DNA 损伤诱导细胞凋亡的重要介质，但负责的激酶仍有待澄清，特别是在电离辐射 (IR) 的情况下。在这里，我们表明，除了报道的磷酸化位点 Ser15 和 Ser37 之外，DNA 依赖性蛋白激酶 (DNA-PK) 还可以磷酸化 p53 的 Ser46。然而，即使在 M059J（一种缺乏 DNA-PKcs 的人神经胶质瘤细胞系）中也观察到了 IR 诱导的 Ser46 磷酸化，而且最多仅比对照 M059K 稍少一些。另一方面，相关激酶共济失调毛细血管扩张突变 (ATM) 被证明是 IR 诱导的 Ser46 磷酸化所必需的，但它本身不能很好地磷酸化 Ser46。这些结果共同表明 IR 诱导的 Ser46 磷酸化有两种途径，即通过 DNA-PK 直接磷酸化和通过 ATM 间接磷酸化。 (C) 2004 Elsevier Inc. 保留所有权利。
DNA damage induces accumulation and activation of p53 via various posttranslational modifications. Among them, several lines of evidence indicated the phosphorylation of Ser46 as an important mediator of DNA damage-induced apoptosis but the responsible kinase remains to be clarified, especially in the case of ionizing radiation (IR). Here we showed that DNA-dependent protein kinase (DNA-PK) could phosphorylate Ser46 of p53 in addition to reported phosphorylation sites Ser15 and Ser37. However, IR-induced phosphorylation of Ser46 was seen even in M059J, a human glioma cell line lacking DNA-PKcs, and it was, at most, only slightly less than in control M059K. On the other hand, a related kinase ataxia-telangiectasia mutated (ATM), which was shown to be essential for IR-induced phosphorylation of Ser46, could poorly phosphorylate Ser46 by itself. These results collectively suggested two pathways for IR-induced phosphorylation of Ser46, i.e., direct phosphorylation by DNA-PK and indirect phosphorylation via ATM. (C) 2004 Elsevier Inc. All rights reserved.