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首页> 外文期刊>Cell cycle >Phosphorylation of von Hippel-Lindau protein by checkpoint kinase 2 regulates p53 transactivation.
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Phosphorylation of von Hippel-Lindau protein by checkpoint kinase 2 regulates p53 transactivation.

机译：von Hippel-Lindau蛋白通过检查点激酶2的磷酸化调节p53反式激活。

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摘要

von-Hippel Lindau protein (pVHL) suppresses tumorigenesis in the kidney, in part through regulation of hypoxia-inducible factor alpha (HIF alpha). However, HIF has been proposed to be necessary but insufficient for renal tumorigenesis. p53 was implicated as a transcription factor that is regulated by pVHL, but the molecular mechanism by which pVHL regulates p53 on DNA damage is unknown. We demonstrated that checkpoint kinase-2 (Chk2) binds to the beta-domain of pVHL and phosphorylates Ser 111 on DNA damage. Notably, this modification enhances pVHL-mediated transactivation of p53 by recruiting p300 and Tip60 to the chromatin of p53 target gene. Further, the naturally occurring pVHL mutants pVHL-S111R and pVHL-S111C showed diminished binding to coactivators, ultimately retarding p53-mediated growth arrest and apoptosis. In this study, we determined the molecular mechanism by which pVHL transactivates p53 on DNA damage and demonstrated that p53-related pVHL subtype mutants regulate tumorigenecity in VHL diseases.
机译：von-Hippel Lindau蛋白（pVHL）部分通过调节缺氧诱导因子α（HIF alpha）抑制肾脏的肿瘤发生。然而，已经提出HIF对于肾脏肿瘤发生是必要的但不足。 p53被认为是受pVHL调节的转录因子，但是pVHL调节p53对DNA损伤的分子机制尚不清楚。我们证明了检查点激酶2（Chk2）结合到pVHL的β域，并磷酸化Ser 111的DNA损伤。值得注意的是，这种修饰通过将p300和Tip60募集到p53靶基因的染色质上来增强pVHL介导的p53的反式激活。此外，天然存在的pVHL突变体pVHL-S111R和pVHL-S111C与共激活因子的结合减弱，最终阻碍了p53介导的生长停滞和凋亡。在这项研究中，我们确定了pVHL激活p53对DNA损伤的分子机制，并证明了p53相关的pVHL亚型突变体可调节VHL疾病的致癌性。

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