The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation
The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation
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DOI：
10.4161/cc.4.10.2107
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发表时间：
2005-10-01
期刊：
影响因子：
4.3
通讯作者：
Fujita, J
中科院分区：
文献类型：
--
作者：
Higashitsuji, H;Liu, Y;Fujita, J
泛素依赖性蛋白水解介导多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7锚蛋白重复序列蛋白，最初被鉴定为一种在肝细胞癌中普遍过表达的癌蛋白，并且作为一种与26S蛋白酶体的19S调节复合体相关的蛋白独立存在。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，我们已经证明gankyrin在暴露于dna损伤剂的细胞中具有抗凋亡活性。Gankyrin与p53的主要E3泛素连接酶MDM2结合，增加p53的泛素化和降解。Gankyrin增加CDK4和MDM2的活性，促进多泛素化蛋白靶向26S蛋白酶体。此外，抑制gankyrin可诱导癌细胞凋亡。因此，甘肽是一种有潜力的抗癌药物。
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.