Chromium (VI) activates ataxia telangiectasia mutated (ATM) protein - Requirement of ATM for both apoptosis and recovery from terminal growth arrest
Chromium (VI) activates ataxia telangiectasia mutated (ATM) protein - Requirement of ATM for both apoptosis and recovery from terminal growth arrest
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DOI：
10.1074/jbc.m210560200
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发表时间：
2003-05-16
影响因子：
4.8
通讯作者：
Patierno, SR
中科院分区：
文献类型：
--
作者：
Ha, N;Ceryak, S;Patierno, SR
共济失调毛细血管扩张突变（ATM）蛋白在DNA双链断裂（DSB）检测的早期阶段起着核心作用，并控制细胞对这种损伤的反应。尽管共济失调毛细血管扩张症细胞对电离辐射诱导的克隆性致死性高度敏感，但其进行电离辐射诱导的细胞凋亡的能力却自相矛盾地缺乏。这种矛盾说明了ATM在DNA损伤反应中的核心作用的复杂性，以及进一步理解的必要性。某些六价铬（Cr（VI））化合物被认为是职业性呼吸道致癌物，其剂量具有遗传毒性和细胞毒性。Cr（VI）可引起广泛的DNA损伤，但Cr（VI）诱导的DSB未见报道。在这里，我们研究了ATM在细胞对Cr（VI）的反应中的作用，发现Cr（VI）激活ATM。我们还表明，ATM，p53 Ser-15和Chk 2 Thr-68的生理目标，被磷酸化铬（VI）暴露在ATM依赖的方式。我们发现，ATM-/-细胞显着耐铬（VI）诱导的细胞凋亡，但相当多的铬（VI）诱导的克隆致死性比野生型细胞更敏感，表明耐铬（VI）诱导的细胞凋亡并没有赋予选择性生存优势。然而，长期生长停滞的分析揭示了一个显着的差异：ATM-/-细胞明显不能从Cr（VI）诱导的生长停滞中恢复。这表明，终末生长停滞是这些抗凋亡细胞的命运。总之，ATM参与细胞对复杂遗传毒素的反应，可能不会直接诱导DSB。我们的数据表明，ATM是一个主要的信号启动基因毒素诱导的细胞凋亡，但矛盾的是，也有助于维持细胞的生存，促进恢复/逃离终端生长停滞。这些结果还强烈表明，终末生长停滞不仅仅是一种延长的甚至不可逆的检查点停滞形式，而是一种独立和独特的细胞命运途径。
The ataxia telangiectasia mutated (ATM) protein plays a central role in early stages of DNA double strand break (DSB) detection and controls cellular responses to this damage. Although hypersensitive to ionizing radiation-induced clonogenic lethality, ataxia telangiectasia cells are paradoxically deficient in their ability to undergo ionizing radiation-induced apoptosis. This contradiction illustrates the complexity of the central role of ATM in DNA damage response and the need for further understanding. Certain hexavalent chromium (Cr(VI)) compounds are implicated as occupational respiratory carcinogens at doses that are both genotoxic and cytotoxic. Cr(VI) induces a broad spectrum of DNA damage, but Cr(VI)-induced DSBs have not been reported. Here, we examined the role of ATM in the cellular response to Cr(VI) and found that Cr(VI) activates ATM. We also show that physiological targets of ATM, p53 Ser-15 and Chk2 Thr-68, were phosphorylated by Cr(VI) exposure in an ATM-dependent fashion. We found that ATM-/- cells were markedly resistant to Cr(VI)induced apoptosis but considerably more sensitive to Cr(VI)-induced clonogenic lethality than wild type cells, indicating that resistance to Cr(VI)-induced apoptosis did not confer a selective survival advantage. However, analysis of long term growth arrest revealed a striking difference: ATM-/- cells were markedly less able to recover from Cr(VI)-induced growth arrest. This indicates that terminal growth arrest is the fate of these apoptosis-resistant cells. In summary, ATM is involved in cellular response to a complex genotoxin that may not directly induce DSBs. Our data suggest that ATM is a major signal initiator for genotoxin-induced apoptosis but, paradoxically, also contributes to maintenance of cell survival by facilitating recovery/escape from terminal growth arrest. The results also strongly suggest that terminal growth arrest is not merely an extended or even irreversible form of checkpoint arrest, but instead an independent and unique cell fate pathway.