Regulation of tumor suppressor RB pathway via ubiquitin system.

视网膜母细胞瘤基因产物(PRB)在细胞周期调控和肿瘤抑制中发挥重要作用。众所周知，pRb的下调可以通过阻断pRb途径来刺激肿瘤的发生，尽管其机制尚未阐明。在本研究中，我们发现MDM2，一种P53的泛素连接酶，促进了pRb泛素依赖的降解。野生型MDM2在体内和体外均能有效地泛化pRb，而其他Rb家族蛋白则不能。突变的MDM2在环指域发生了显性-负性稳定。MDM2的敲除和敲除都导致了pRb的积累。此外，MDM2还抑制了pRB介导的Saos-2细胞的扁平形成。在人肺癌中，pRb表达下调与MDM2高表达相关。这些结果表明，MDM2通过泛素依赖的PRB降解来调节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.