Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation
Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation
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DOI：
10.1038/sj.emboj.7600486
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发表时间：
2005-01-12
期刊：
影响因子：
11.4
通讯作者：
Sugimura, H
中科院分区：
文献类型：
--
作者：
Uchida, CH;Miwa, SC;Sugimura, H
视网膜母细胞瘤基因产物（Retinoblastoma gene product，pRB）在细胞周期调控和肿瘤抑制中起重要作用。已知pRB的下调可通过废除pRB途径刺激致癌作用，但其机制尚未阐明。在这项研究中，我们发现Mdm 2，一种p53的泛素连接酶，促进pRB的泛素依赖性降解。pRB在体内和体外都能被野生型Mdm 2有效地泛素化，但其他RB家族蛋白却不能。在RING指结构域中具有取代的突变体Mdm 2显示出pRB的显性负稳定。Mdm 2的敲除和敲低均引起pRB的积累。此外，Mdm 2抑制pRB介导的Saos- 2细胞的扁平形成。pRB表达的下调与人肺癌中Mdm 2的高水平表达相关。这些结果表明Mdm 2通过泛素依赖性降解pRB来调节pRB的功能。
Retinoblastoma gene product ( pRB) plays critical roles in regulation of the cell cycle and tumor suppression. It is known that downregulation of pRB can stimulate carcinogenesis via abrogation of the pRB pathway, although the mechanism has not been elucidated. In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin- dependent degradation of pRB. pRB was efficiently ubiquitinated by wild- type Mdm2 in vivo as well as in vitro, but other RB family proteins were not. Mutant Mdm2 with a substitution in the RING finger domain showed dominant- negative stabilization of pRB. Both knockout and knockdown of Mdm2 caused accumulation of pRB. Moreover, Mdm2 inhibited pRB- mediated flat formation of Saos- 2 cells. Downregulation of pRB expression was correlated with a high level of expression of Mdm2 in human lung cancers. These results suggest that Mdm2 regulates function of pRB via ubiquitin- dependent degradation of pRB.