Analysis of hepatocarcinogenesis via the complex between the E3 ubiquitin ligase MDM2 and gankyrin

肝细胞癌是亚洲和非洲最常见的癌症之一，在亚洲和非洲，肝炎病毒感染和对特定致癌物的暴露是普遍存在的，Gankyrin在大多数肝细胞癌中过表达。Gankyrin与S6蛋白酶体ATPase相互作用，加速肿瘤抑制因子pRb的降解。Gankyrin是一种抗细胞凋亡的癌蛋白，可促进另一种肿瘤抑制因子P53的降解。Gankyrin与MDM2结合，MDM2是P53的E3泛素连接酶，并增强泛素化活性。因此，Gankyrin是一种辅助因子，可以增加MDM2在P53上的活性，并可能将多泛素化的P53靶向26S蛋白酶体。甘草蛋白与多种蛋白质相互作用，形成高分子量的复合体。在另一个复合体中，gankyrin与NF-kB结合，通过SIRT1(一种III型组蛋白去乙酰化酶)调节乙酰化，在转录水平上抑制其活性。Gankyrin主要在人肝癌发生的早期阶段发挥致癌作用，Gankyrin过表达诱导的IGFBP-5可能参与了Gankyrin过表达促进肿瘤生长、细胞运动、体外侵袭和体内肿瘤形成。Gankyrin过度表达与人食管鳞癌的预后不良有关。

Hepatocellular carcinoma is one of the most common cancers in Asia and Africa, where hepatitis virus infection and exposure to specific liver carcinogens are prevalent Gankyrin is overexpressed in most hepatocellular carcinomas. Gankyrin interacts with the S6 proteasomal ATPase and accelerates the degradation of the tumor suppressor pRb. Gankyrin is an anti-apoptofic oncoprotein and increases the degradation of another tumor suppressor p53. Gankyrin binds to Mdm2, an E3 ubiquitin ligase for p53, and potentiates the ubiquitylating activity. Thus, gankyrin is a cofactor that increases the activities of Mdm2 on p53 and probably targets polyubiquitylated p53 into the 26S proteasome. Gankyrin interacts with multiple proteins and forms the high-molecular-weight complex. In another complex, gankyrin binds to NF-kB and suppresses its activity at the transcriptional level by modulating acetylation via SIRT1, a class III histone deacetylase. Gankyrin plays an oncogenic role mainly at the early stages of human hepatocarcinogenesis, and IGFBP-5 inducible by gankyrin overexpression may be involved in it Gankyrin overexpression increases tumor growth, cell motility, invasiveness in vitro and tumor formation in vivo. Gankyrin overexpression is associated with poor prognosis in human esophageal squamous cell carcinoma.