Radiation Sensitivity and Tumor Susceptibility in ATM Phospho-Mutant ATF2 Mice.
Radiation Sensitivity and Tumor Susceptibility in ATM Phospho-Mutant ATF2 Mice.
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DOI：
10.1177/1947601910370700
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发表时间：
2010-04-01
期刊：
影响因子：
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通讯作者：
Ronai ZA
中科院分区：
文献类型：
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作者：
Li S;Ezhevsky S;Dewing A;Cato MH;Scortegagna M;Bhoumik A;Breitwieser W;Braddock D;Eroshkin A;Qi J;Chen M;Kim JY;Jones S;Jones N;Rickert R;Ronai ZA
转录因子 ATF2 先前被证明是 ATM 底物。被 ATM 磷酸化后，ATF2 通过定位到 DNA 修复灶并控制细胞周期停滞，在 DNA 损伤反应中表现出转录独立的功能。为了评估这种磷酸化的生理意义，我们培育了 ATF2 突变小鼠，其中 ATM 磷酸受体位点 (S472/S480) 发生突变 (ATF2KI)。 ATF2KI 小鼠比野生型 (ATF2 WT) 小鼠对电离辐射 (IR) 更敏感：IR 后，ATF2KI 小鼠肠隐窝细胞中表现出更高水平的细胞凋亡，并且肝脂肪变性受损。分子分析发现，IR 处理的 ATF2KI 小鼠的细胞和组织中细胞周期调节蛋白 p21Cip/Waf1 的激活受损，且与 p53 无关。对 p53KO 与 ATF2KI 小鼠杂交的肿瘤发育分析表明，肿瘤发育所需的时间显着减少。此外，当经历两阶段皮肤癌变过程时，与对照小鼠相比，ATF2KI小鼠出现皮肤肿瘤的速度更快、发生率更高，并且还进展为更恶性的癌症。使用 3 个小鼠模型，我们确定了 ATM 磷酸化 ATF2 在细胞对 DNA 损伤的急性反应和维持基因组稳定性中的重要性。
The transcription factor ATF2 was previously shown to be an ATM substrate. Upon phosphorylation by ATM, ATF2 exhibits a transcription-independent function in the DNA damage response through localization to DNA repair foci and control of cell cycle arrest. To assess the physiological significance of this phosphorylation, we generated ATF2 mutant mice in which the ATM phosphoacceptor sites (S472/S480) were mutated (ATF2KI). ATF2KI mice are more sensitive to ionizing radiation (IR) than wild-type (ATF2 WT) mice: following IR, ATF2KI mice exhibited higher levels of apoptosis in the intestinal crypt cells and impaired hepatic steatosis. Molecular analysis identified impaired activation of the cell cycle regulatory protein p21Cip/Waf1 in cells and tissues of IR-treated ATF2KI mice, which was p53 independent. Analysis of tumor development in p53KO crossed with ATF2KI mice indicated a marked decrease in amount of time required for tumor development. Further, when subjected to two-stage skin carcinogenesis process, ATF2KI mice developed skin tumors faster and with higher incidence, which also progressed to the more malignant carcinomas, compared with the control mice. Using 3 mouse models, we establish the importance of ATF2 phosphorylation by ATM in the acute cellular response to DNA damage and maintenance of genomic stability.