Zhang Y, Xiong Y, Yarbrough W G
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, 27599-3280, USA.
Cell. 1998 Mar 20;92(6):725-34. doi: 10.1016/s0092-8674(00)81401-4.
The INK4a-ARF locus encodes two unrelated proteins that both function in tumor suppression. p16INK4 binds to and inhibits the activity of CDK4 and CDK6, and ARF arrests the cell cycle in a p53-dependent manner. We show here that ARF binds to MDM2 and promotes the rapid degradation of MDM2. This interaction is mediated by the exon 1beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53 stabilization and accumulation. The functional consequence of ARF-regulated p53 levels via MDM2 proteolysis is evidenced by the ability of ectopically expressed ARF to restore a p53-imposed G1 cell cycle arrest that is otherwise abrogated by MDM2. Thus, deletion of the ARF-INK4a locus simultaneously impairs both the INK4a-cyclin D/CDK4-RB and the ARF-MDM2-p53 pathways.
INK4a-ARF基因座编码两种不相关的蛋白质，它们都在肿瘤抑制中发挥作用。p16INK4与CDK4和CDK6结合并抑制其活性，而ARF以p53依赖的方式使细胞周期停滞。我们在此表明，ARF与MDM2结合并促进MDM2的快速降解。这种相互作用由ARF的外显子1β编码的N端结构域和MDM2的C端区域介导。ARF促进的MDM2降解与MDM2修饰以及同时发生的p53稳定和积累有关。通过MDM2蛋白水解，ARF调节p53水平的功能后果可通过异位表达的ARF恢复p53施加的G1细胞周期停滞的能力得到证明，否则该停滞会被MDM2消除。因此，ARF-INK4a基因座的缺失同时损害了INK4a-细胞周期蛋白D/CDK4-RB和ARF-MDM2-p53两条途径。
