Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas

Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia an d Africa, where hepatitis virus infection and exposure to specific liver ca rcinogens are prevalent(1,2). Although inactivation of some tumor suppresso r genes such as p53 and p16(INK4A) has been identified(3), no known oncogen e is commonly activated in hepatocellular carcinomas. Here we have isolated genes overexpressed in hepatocellular carcinomas by cDNA subtractive hybri dization(4), and identified an oncoprotein consisting of six ankyrin repeat s (gankyrin). The expression of gankyrin was increased in all 34 hepatocell ular carcinomas studied. Gankyrin induced anchorage-independent growth and tumorigenicity in NIH/3T3 cells. Gankyrin bound to the product of the retin oblastoma gene (RB1), increasing its phosphorylation and releasing the acti vity of the transcription factor E2F-1. Gankyrin accelerated the degradatio n of RB1 in vitro and in vivo, and was identical to or interacted with a su bunit of the 265 proteasome(5,6). These results demonstrate the importance of ubiquitin-proteasome pathway in the regulation of cell growth and oncoge nic transformation, and indicate that gankyrin overexpression contributes t o hepatocarcinogenesis by destabilizing RB1.