Higashitsuji Hiroaki, Liu Yu, Mayer R John, Fujita Jun
Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Cell Cycle. 2005 Oct;4(10):1335-7. doi: 10.4161/cc.4.10.2107. Epub 2005 Oct 17.
Ubiquitin-dependent proteolysis mediates selective destruction of various cell cycle regulators, transcription factors and tumor suppressors. Gankyrin, a seven ankyrin-repeat protein, was originally identified as an oncoprotein commonly overexpressed in hepatocellular carcinomas and independently as a protein associated with the 19S regulatory complex of the 26S proteasome. Gankyrin also binds to CDK4 and the tumor suppressor RB, and accelerates phosphorylation and proteasomal degradation of RB. Recently, we have shown that gankyrin has an anti-apoptotic activity in cells exposed to DNA-damaging agents. Gankyrin binds to MDM2, a major E3 ubiquitin ligase for p53, and increases ubiquitylation and degradation of p53. Gankyrin increases activities of CDK4 and MDM2, and facilitates targeting of polyubiquitylated proteins to the 26S proteasome. Furthermore, inhibition of gankyrin induces apoptosis in cancer cells. Therefore, gankyrin is a promising target for potential anticancer therapeutic agents.
泛素依赖性蛋白水解介导各种细胞周期调节因子、转录因子和肿瘤抑制因子的选择性破坏。Gankyrin是一种含有7个锚蛋白重复序列的蛋白质，最初被鉴定为一种在肝细胞癌中普遍过度表达的癌蛋白，并且独立地作为一种与26S蛋白酶体的19S调节复合体相关的蛋白质。Gankyrin还与CDK4和肿瘤抑制因子RB结合，并加速RB的磷酸化和蛋白酶体降解。最近，我们已经表明，Gankyrin在暴露于DNA损伤剂的细胞中具有抗凋亡活性。Gankyrin与MDM2结合，MDM2是p53的主要E3泛素连接酶，并增加p53的泛素化和降解。Gankyrin增加CDK4和MDM2的活性，并促进多聚泛素化蛋白靶向26S蛋白酶体。此外，抑制Gankyrin可诱导癌细胞凋亡。因此，Gankyrin是潜在抗癌治疗药物的一个有前景的靶点。
