Qiu W, Wu J, Walsh E M, Zhang Y, Chen C-Y, Fujita J, Xiao Z-X J
Graduate Program in Molecular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Oncogene. 2008 Jul 3;27(29):4034-43. doi: 10.1038/onc.2008.43. Epub 2008 Mar 10.
MDM2 is a key ubiquitin E3 ligase for p53 and its activity is critically regulated by a set of modulators, including ARF, p300, YY1 and recently by gankyrin, an oncoprotein frequently overexpressed in human heptocellular carcinomas. We have previously shown that MDM2 binds to and promotes retinoblastoma protein (Rb) degradation. Here we show that Rb inhibits MDM2 E3 ligase activity resulting in stabilization of p53. In addition, we demonstrated that Rb inhibits MDM2-mediated p53 ubiquitination in a gankyrin-dependent manner and the Rb-gankyrin interaction is critical for Rb-induced p53 stabilization. Furthermore, acute ablation of Rb facilitates gankyrin-mediated p53 destabilization, and desensitizes cancer cells for chemotherapy-induced apoptosis. These results indicate that Rb antagonizes gankyrin to inhibit MDM2-mediate p53 ubiquitination in cancer cells and suggest that the status of both p53 and Rb is important for efficacy of cancer chemotherapy.
MDM2是一种针对p53的关键泛素E3连接酶，其活性受到一组调节剂的严格调控，这些调节剂包括ARF、p300、YY1，最近还发现了一种在人类肝癌中经常过度表达的癌蛋白——甘菊环蛋白（gankyrin）。我们之前已经证明MDM2与视网膜母细胞瘤蛋白（Rb）结合并促进其降解。在此我们表明，Rb抑制MDM2 E3连接酶活性，从而导致p53的稳定。此外，我们还证明Rb以甘菊环蛋白依赖的方式抑制MDM2介导的p53泛素化，并且Rb与甘菊环蛋白的相互作用对于Rb诱导的p53稳定至关重要。此外，Rb的急性缺失促进了甘菊环蛋白介导的p53去稳定化，并使癌细胞对化疗诱导的凋亡不敏感。这些结果表明，Rb拮抗甘菊环蛋白以抑制癌细胞中MDM2介导的p53泛素化，并表明p53和Rb的状态对于癌症化疗的疗效都很重要。
