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首页> 美国卫生研究院文献>Cell Cycle >MEK2 regulates ribonucleotide reductase activity through functional interaction with ribonucleotide reductase small subunit p53R2
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MEK2 regulates ribonucleotide reductase activity through functional interaction with ribonucleotide reductase small subunit p53R2

机译：MEK2通过与核糖核苷酸还原酶小亚基p53R2的功能相互作用来调节核糖核苷酸还原酶活性

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摘要

The p53R2 protein, a newly identified member of the ribonucleotide reductase family that provides nucleotides for DNA damage repair, is directly regulated by p53. We show that p53R2 is also regulated by a MEK2 (ERK kinase 2/MAP kinase kinase 2)-dependent pathway. Increased MEK1/2 phosphorylation by serum stimulation coincided with an increase in the RNR activity in U2OS and H1299 cells. The inhibition of MEK2 activity, either by treatment with a MEK inhibitor or by transfection with MEK2 siRNA, dramatically decreased the serum-stimulated RNR activity. Moreover, p53R2 siRNA, but not R2 siRNA, significantly inhibits serum-stimulated RNR activity, indicating that p53R2 is specifically regulated by a MEK2-dependent pathway. Co-immunoprecipitation analyses revealed that the MEK2 segment comprising amino acids 65–171 is critical for p53R2–MEK2 interaction, and the binding domain of MEK2 is required for MEK2-mediated increased RNR activity. Phosphorylation of MEK1/2 was greatly augmented by ionizing radiation, and RNR activity was concurrently increased. Ionizing radiation-induced RNR activity was markedly attenuated by transfection of MEK2 or p53R2 siRNA, but not R2 siRNA. These data show that MEK2 is an endogenous regulator of p53R2 and suggest that MEK2 may associate with p53R2 and upregulate its activity.
机译：p53R2蛋白是核糖核苷酸还原酶家族的一个新发现成员，可为DNA损伤修复提供核苷酸，它直接受p53调控。我们显示p53R2也受MEK2（ERK激酶2 / MAP激酶激酶2）依赖性途径调控。通过血清刺激增加的MEK1 / 2磷酸化与U2OS和H1299细胞中RNR活性的增加同时发生。通过用MEK抑制剂处理或通过用MEK2 siRNA转染来抑制MEK2活性，显着降低了血清刺激的RNR活性。此外，p53R2 siRNA显着抑制血清刺激的RNR活性，但不抑制R2 siRNA，表明p53R2受MEK2依赖性途径特异性调节。免疫共沉淀分析表明，包含氨基酸65-171的MEK2片段对于p53R2-MEK2相互作用至关重要，而MEK2的结合域是MEK2介导的RNR活性增加所必需的。电离辐射大大增强了MEK1 / 2的磷酸化，同时提高了RNR活性。通过转染MEK2或p53R2 siRNA，而不是R2 siRNA，电离辐射诱导的RNR活性显着减弱。这些数据表明MEK2是p53R2的内源性调节剂，表明MEK2可能与p53R2缔合并上调其活性。

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