Regulation of tumor suppressor RB pathway via ubiquitin system.

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 2，一个泛素连接酶的p53，促进泛素依赖性降解的pRB。pRB是有效的泛素化野生型Mdm 2在体内以及体外，但其他RB家族蛋白没有。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.