Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Oncogene. 2010 Jan 14;29(2):297-304. doi: 10.1038/onc.2009.314. Epub 2009 Sep 28.
MDM2 is an E3 ligase that promotes ubiquitin-mediated destruction of p53. Cellular stresses such as DNA damage can lead to p53 activation due in part to MDM2 destabilization. Here, we show that the stability of MDM2 is regulated by an ubiquitin-like NEDD8 pathway and identify NEDP1 as a chemotherapy-induced isopeptidase that deneddylates MDM2, resulting in MDM2 destabilization concomitant with p53 activation. Concordantly, RNAi-mediated knockdown of endogenous NEDP1 blocked diminution of MDM2 levels and increased chemoresistance of tumor cells. These findings unveil the regulation of MDM2 stability through NEDP1 as a common molecular determinant governing chemotherapy-induced p53-dependent cell death.
MDM2 是一种 E3 连接酶，可促进 p53 的泛素介导的降解。细胞应激，如 DNA 损伤，可导致 p53 激活，部分原因是 MDM2 的不稳定性。在这里，我们表明 MDM2 的稳定性受到类泛素 NEDD8 途径的调节，并鉴定出 NEDP1 作为一种化疗诱导的异构酶，可使 MDM2 去 NEDDylation，导致 MDM2 不稳定，同时激活 p53。相应地，RNAi 介导的内源性 NEDP1 敲低阻断了 MDM2 水平的降低，并增加了肿瘤细胞的化疗耐药性。这些发现揭示了通过 NEDP1 调节 MDM2 稳定性作为一种共同的分子决定因素，调节化疗诱导的 p53 依赖性细胞死亡。
