Retinoblastoma protein modulates gankyrin-MDM2 in regulation of p53 stability and chemosensitivity in cancer cells
Retinoblastoma protein modulates gankyrin-MDM2 in regulation of p53 stability and chemosensitivity in cancer cells
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DOI：
10.1038/onc.2008.43
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发表时间：
2008-07-03
期刊：
影响因子：
8
通讯作者：
Xiao, Z-X J.
中科院分区：
文献类型：
--
作者：
Qiu, W.;Wu, J.;Xiao, Z-X J.
MDM 2是p53的关键泛素E3连接酶，其活性受到一系列调节剂的关键调节，包括ARF，p300，YY 1和最近的gankyrin，一种在人类肝细胞癌中经常过表达的癌蛋白。我们先前已经表明，MDM 2结合并促进视网膜母细胞瘤蛋白（Rb）降解。在这里，我们表明，Rb抑制MDM 2 E3连接酶的活性，导致p53的稳定。此外，我们证明Rb以Gankyrin依赖的方式抑制MDM 2介导的p53泛素化，并且Rb-Gankyrin相互作用对于Rb诱导的p53稳定性至关重要。此外，Rb的急性消融促进了Ganklin介导的p53不稳定，并使癌细胞对化疗诱导的凋亡脱敏。这些结果表明，Rb拮抗gankyrin抑制癌细胞中MDM 2介导的p53泛素化，并表明p53和Rb的状态对癌症化疗的疗效很重要。
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.