ATM associates with and phosphorylates p53: mapping the region of interaction
ATM associates with and phosphorylates p53: mapping the region of interaction
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DOI：
10.1038/3882
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发表时间：
1998-12-01
期刊：
影响因子：
30.8
通讯作者：
Lavin, MF
中科院分区：
文献类型：
--
作者：
Khanna, KK;Keating, KE;Lavin, MF
人类遗传性疾病共济失调毛细血管扩张症（AT）以免疫缺陷为特征。进行性小脑共济失调。放射敏感性，细胞周期检查点缺陷和癌症易感性(1)。在这种综合征中发生突变的基因ATM （AT突变）编码一种含有磷脂酰肌醇3-激酶（PI-3激酶）样结构域的蛋白质（2,3）。ATM还包含一个富含脯氨酸的区域(4)和一个亮氨酸拉链（2,5），这两个区域都与该蛋白参与信号转导有关。富含脯氨酸的区域已被证明与c-Abl的SH3结构域结合，从而促进其被ATM磷酸化和激活（文献4,6）。先前的研究结果表明，AT细胞在辐射损伤后激活的G1/S检查点存在缺陷，这种缺陷可归因于p53信号转导途径的缺陷（7,8）。我们在这里报道了ATM和p53之间的直接相互作用，涉及ATM的两个区域。一个在氨基端，另一个在羧基端，对应于PI-3激酶结构域。重组ATM蛋白磷酸化p53在N端附近的丝氨酸15。此外，AT细胞中ATM的异位表达恢复了电离辐射（IR）诱导的p53的正常磷酸化，而对照细胞中ATM反义RNA的表达消除了IR诱导的p53在丝氨酸15上的快速磷酸化。这些结果表明，ATM可以直接结合p53，并负责其丝氨酸15磷酸化。从而在红外诱导的DNA损伤反应中促进p53的激活和稳定。
The human genetic disorder ataxia-telangiectasia (AT) is characterized by immunodeficiency. progressive cerebellar ataxia. radiosensitivity, cell cycle checkpoint defects and cancer predisposition(1). The gene mutated in this syndrome, ATM (for AT mutated), encodes a protein containing a phosphatidyl-inositol 3-kinase (PI-3 kinase)-like domain(2,3). ATM also contains a proline-rich region(4) and a leucine zipper(2,5), both of which implicate this protein in signal transduction. The proline-rich region has been shown to bind to the SH3 domain of c-Abl, which facilitates its phosphorylation and activation by ATM (refs 4,6). Previous results have demonstrated that AT cells are defective in the G1/S checkpoint activated after radiation damage and that this defect is attributable to a defective p53 signal transduction pathway(7,8). We report here direct interaction between ATM and p53 involving two regions in ATM. one at the amino terminus and the other at the carboxy terminus, corresponding to the PI-3 kinase domain. Recombinant ATM protein phosphorylates p53 on serine 15 near the N terminus. Furthermore, ectopic expression of ATM in AT cells restores normal ionizing radiation (IR)-induced phosphorylation of p53, whereas expression of ATM antisense RNA in control cells abrogates the rapid IR-induced phosphorylation of p53 on serine 15. These results demonstrate that ATM can bind p53 directly and is responsible for its serine 15 phosphorylation. thereby contributing to the activation and stabilization of p53 during the IR-induced DNA damage response.