Department of Medical Genetics, Peking University Health Science Center, 38 Xueyuan Road, 100191, Beijing, China.
Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
Oncogene. 2019 Apr;38(14):2501-2515. doi: 10.1038/s41388-018-0605-5. Epub 2018 Dec 7.
MDM2 (Murine double minute 2) acts as a key repressor for p53-mediated tumor-suppressor functions, which includes cellular senescence. We found that MDM2 can promote cellular senescence by modulating WRN stability. Werner syndrome (WS), caused by mutations of the WRN gene, is an autosomal recessive disease, which is characterized by premature aging. Loss of WRN function induces cellular senescence in human cancer cells. Here, we found that MDM2 acts as an E3 ligase for WRN protein. MDM2 interacts with WRN both in vivo and in vitro. MDM2 induces ubiquitination of WRN and dramatically downregulates the levels of WRN protein in human cells. During DNA damage response, WRN is translocated to the nucleoplasm to facilitate its DNA repair functions; however, it is degraded by the MDM2-mediated ubiquitination pathway. Moreover, the senescent phenotype induced by DNA damage reagents, such as Etoposide, is at least in part mediated by MDM2-dependent WRN degradation as it can be significantly attenuated by ectopic expression of WRN. These results show that MDM2 is critically involved in regulating WRN function via ubiquitin-dependent degradation and reveal an unexpected role of MDM2 in promoting cellular senescence through a p53-independent manner.
MDM2（鼠双微体 2）作为 p53 介导的肿瘤抑制功能的关键抑制剂，包括细胞衰老。我们发现 MDM2 可以通过调节 WRN 的稳定性来促进细胞衰老。WRN 基因的突变导致 Werner 综合征（WS），这是一种常染色体隐性遗传病，其特征是早衰。WRN 功能的丧失会诱导人类癌细胞发生细胞衰老。在这里，我们发现 MDM2 作为 WRN 蛋白的 E3 连接酶。MDM2 在体内和体外都与 WRN 相互作用。MDM2 诱导 WRN 的泛素化，并显著下调人细胞中 WRN 蛋白的水平。在 DNA 损伤反应过程中，WRN 易位到核质中，以促进其 DNA 修复功能；然而，它被 MDM2 介导的泛素化途径降解。此外，WRN 依赖性降解介导了由 DNA 损伤试剂（如依托泊苷）诱导的衰老表型，因为其可以通过 WRN 的异位表达显著减弱。这些结果表明，MDM2 通过泛素依赖性降解来调节 WRN 功能，并揭示了 MDM2 通过 p53 非依赖性方式促进细胞衰老的意外作用。
