Direct activation of ATM by resveratrol under oxidizing conditions.
Direct activation of ATM by resveratrol under oxidizing conditions.
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DOI：
10.1371/journal.pone.0097969
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Paull TT
中科院分区：
文献类型：
--
作者：
Lee JH;Guo Z;Myler LR;Zheng S;Paull TT
白藜芦醇已被广泛报道，以减少模型系统中的癌症进展，并选择性地诱导转化细胞系中的细胞死亡。据报道，哺乳动物细胞中的许多酶对白藜芦醇有反应，包括在DNA损伤识别、信号传导和修复中起作用的共济失调-毛细血管扩张突变（ATM）蛋白激酶。在这里，我们调查的ATM白藜芦醇暴露在正常和转化的人类细胞系的反应，发现ATM自磷酸化和底物磷酸化的刺激白藜芦醇的方式，促进活性氧（ROS）。我们观察了白藜芦醇在体外对纯化的ATM的直接刺激作用，发现白藜芦醇增加了该激酶对模型底物的催化效率。在纯化的系统中，我们还观察到氧化的需要，因为白藜芦醇对ATM信号传导的影响被阻止ATM中二硫键形成的试剂大大降低。这些结果表明，白藜芦醇对ATM的影响是直接的，并提出了转化细胞的氧化环境促进ATM活性和阻断细胞增殖的机制。
Resveratrol has been widely reported to reduce cancer progression in model systems and to selectively induce cell death in transformed cell lines. Many enzymes have been reported to respond to resveratrol in mammalian cells, including the Ataxia-Telangiectasia Mutated (ATM) protein kinase that acts in DNA damage recognition, signaling, and repair. Here we investigate the responses of ATM to resveratrol exposure in normal and transformed human cell lines and find that ATM autophosphorylation and substrate phosphorylation is stimulated by resveratrol in a manner that is promoted by reactive oxygen species (ROS). We observe direct stimulatory effects of resveratrol on purified ATM in vitro and find that the catalytic efficiency of the kinase on a model substrate is increased by resveratrol. In the purified system we also observe a requirement for oxidation, as the effect of resveratrol on ATM signaling is substantially reduced by agents that prevent disulfide bond formation in ATM. These results demonstrate that resveratrol effects on ATM are direct, and suggest a mechanism by which the oxidizing environment of transformed cells promotes ATM activity and blocks cell proliferation.
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DOI：
10.1038/nrd3738
发表时间：
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期刊：
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