Gankyrin Is Required For Ras-driven Tumorigenesis Through Regulation Of PI3K Signaling

Gankyrin is a new oncoprotein with potent cell cycle and apoptotic properties that is overexpressed early in hepatocarcinogenesis and in hepatocellular carcinomas. Gankyrin is a small protein(25kDa with 226 amino acids)that contains seven ankyrin repeats and is highly conserved.Gankyrin is a subunit of the 26S proteasome that specifically interacts with the S6b ATPase of the 19S regulator.Gankyrin was initially characterized as the p28 component of the 26S proteasome,and was recently identified as an oncoprotein.Our previous study showed an increased Gankyrin expression in Ras transformed NIH3T3 cells(Jin et al,2006).These provide an important insight into the function of Gankyrin in Ras mediated transformation and tumorigenesis.In this study,we performed RNA interference to evaluate Gankyrin effect on tumorigenesis and preliminary analysis on its biological function in Ras signaling,to help us understand its mechanisms.Here,we show a novel and indispensable role of Gankyrin in Ras-driven tumor formation.H-Ras G12V transformed NIH3T3 cells have increased Gankyrin expression,which appears to be functionally relevant since Gankyrin silencing blocks Ras transformation and tumorigenesis.We further found that the blockade is achieved through inhibiting the phosphinositide 3-kinases(PI3K)pathway,a critical mediator of Ras-driven tumorigenesis,but not the MAPK pathway.Gankyrin knockdown abolished Ras-induced Akt activation.And introduction of a constitutive PI3K activator p110CAAX into the cells with Gankyrin knockdown rescued Ras-driven tumorigenesis.Importantly,Gankyfin depletion also abolishes tumorigenesis in human cancer cells with mutated K-Ras.Thus,Gankyrin acts as a major regulator in Ras-mediated tumorigenesis and a potential target for the cancer treatment.Targeting this aspect of Gankyrin function may hold promise as an approach to the management of actual Ras-driven cancers.