Gueven Nuri, Becherel Olivier J, Birrell Geoff, Chen Philip, DelSal Giannino, Carney James P, Grattan-Smith Padraic, Lavin Martin F
Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Cancer Res. 2006 Mar 15;66(6):2907-12. doi: 10.1158/0008-5472.CAN-05-3428.
Ataxia-telangiectasia mutated (ATM), the protein defective in ataxia-telangiectasia, plays a central role in DNA damage response and signaling to cell cycle checkpoints. We describe here a cell line from a patient with an ataxia-telangiectasia-like clinical phenotype defective in the p53 response to radiation but with normal ATM activation and efficient downstream phosphorylation of other ATM substrates. No mutations were detected in ATM cDNA. A normal level of interaction between p53 and peptidyl-prolyl-isomerase Pin1 suggests that posttranslational modification was intact in these cells but operating at reduced level. Defective p53 stabilization was accompanied by defective induction of p53 effector genes and failure to induce apoptosis in response to DNA-damaging agents. Continued association between p53 and murine double minute-2 (Mdm2) occurred in irradiated ATL2ABR cells in response to DNA damage, and incubation with Mdm2 antagonists, nutlins, increased the stabilization of p53 and its transcriptional activity but failed to induce apoptosis. These results suggest that ATM-dependent stabilization of p53 and induction of apoptosis by radiation involve an additional factor(s) that is defective in ATL2ABR cells.
共济失调毛细血管扩张症突变基因（ATM）是共济失调毛细血管扩张症中存在缺陷的蛋白质，在DNA损伤反应及向细胞周期检查点的信号传导中起核心作用。我们在此描述了一个来自患有共济失调毛细血管扩张症样临床表型患者的细胞系，该细胞系对辐射的p53反应存在缺陷，但ATM激活正常且其他ATM底物的下游磷酸化有效。在ATM cDNA中未检测到突变。p53与肽基脯氨酰异构酶Pin1之间的正常相互作用水平表明，这些细胞中的翻译后修饰是完整的，但作用水平降低。p53稳定性缺陷伴随着p53效应基因诱导缺陷以及对DNA损伤剂无诱导凋亡反应。在受辐射的ATL2ABR细胞中，p53与小鼠双微体2（Mdm2）在DNA损伤反应中持续结合，用Mdm2拮抗剂Nutlins孵育可增加p53的稳定性及其转录活性，但未能诱导凋亡。这些结果表明，ATM依赖的p53稳定性及辐射诱导的凋亡涉及ATL2ABR细胞中存在缺陷的其他因素。
