Hyperthermia activates a subset of ataxia-telangiectasia mutated effectors independent of DNA strand breaks and heat shock protein 70 status
Hyperthermia activates a subset of ataxia-telangiectasia mutated effectors independent of DNA strand breaks and heat shock protein 70 status
复制标题
DOI：
10.1158/0008-5472.can-06-4328
复制
发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Pandita, Tej K.
中科院分区：
文献类型：
--
作者：
Hunt, Clayton R.;Pandita, Raj K.;Pandita, Tej K.
所有细胞都具有复杂耦合的传感和信号传导机制，这些机制在暴露于遗传毒性剂（如电离辐射（IR））后调节细胞结果。在IR诱导的信号传导途径中，特定的蛋白事件，如共济失调-毛细血管扩张突变蛋白（ATM）激活和组蛋白h2 AX磷酸化（γ-h2 AX），在机制上得到了很好的表征。如何改变这些机制，特别是通过临床相关药物，尚不清楚。在这里，我们表明，高温，一种有效的放射增敏剂，可以诱导与IR信号在细胞中的几个步骤。热疗诱导γ-H2 AX灶的形成类似于响应于IR暴露而形成的灶，并且热诱导的γ-H2 AX灶的形成依赖于ATM但不依赖于热休克蛋白70表达。热疗还增强ATM激酶活性和增加细胞ATM自磷酸化。高血压诱导的ATM磷酸化的增加是独立的Mre 11功能。与IR类似，高温也诱导MDO灶形成;然而，它没有诱导与照射相关的所有特征信号，因为在加热的细胞中没有观察到53 BP 1和SMC 1灶的形成，但在照射的细胞中发生。此外，在III暴露的细胞中观察到染色体DNA链断裂的诱导，但在加热的细胞中未观察到。这些结果表明，高温激活的信号通路与IR诱导的DNA损伤激活的信号通路重叠。此外，ATM或IR诱导的信号传导途径的其他组分通过热的预先活化可能干扰染色体DNA双链断裂修复所需的正常IR诱导的信号传导，从而导致细胞辐射敏感性增加。
All cells have intricately coupled sensing and signaling mechanisms that regulate the cellular outcome following exposure to genotoxic agents such as ionizing radiation (IR). In the IR-induced signaling pathway, specific protein events, such as ataxia-telangiectasia mutated protein (ATM) activation and histone h2AX phosphorylation (gamma-h2AX), are mechanistically well characterized. How these mechanisms can be altered, especially by clinically relevant agents, is not clear. Here we show that hyperthermia, an effective radiosensitizer, can induce several steps associated with IR signaling in cells. Hyperthermia induces gamma-H2AX foci formation similar to foci formed in response to IR exposure, and heat-induced, gamma-H2AX foci formation is dependent on ATM but independent of heat shock protein 70 expression. Hyperthermia also enhanced ATM kinase activity and increased cellular ATM autophosphorylation. The hyperthermia-induced increase in ATM phosphorylation was independent of Mre11 function. Similar to IR, hyperthermia also induced MDO foci formation; however, it did not induce all of the characteristic signals associated with irradiation because formation of 53BP1 and SMC1 foci was not observed in heated cells but occurred in irradiated cells. Additionally, induction of chromosomal DNA strand breaks was observed in III-exposed but not in heated cells. These results indicate that hyperthermia activates signaling pathways that overlap with those activated by IR-induced DNA damage. Moreover, prior activation of ATM or other components of the IR-induced signaling pathway by heat may interfere with the normal IR-induced signaling required for chromosomal DNA double-strand break repair, thus resulting in increased cellular radiosensitivity.