The oncoprotein p28^GANK establishes a positive feedback loop in p-catenin signaling

p28^GANK （also known as PSMD10 or gankyrin） is a novel oncoprotein that is highly expressed in hepatocellular carcinoma （HCC）. Through its interaction with various proteins, p28^GANK mediates the degradation of the tumor sup- pressor proteins Rb and p53. Although p53 was reported to downregulate β-catenin, whether p28^GANK is involved in the regulation of β-catenin remains uncertain. Here we report that both growth factors and Ras upregulate p28^GANK expression through the activation of the phosphoinositide 3-kinase-AKT pathway. Upregulation of p28^GANK expression subsequently enhanced the transcription activity of β-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28^GANK-mediated activation of β-catenin. p28^GANK overexpression also reduced E-cadherin protein levels, leading to increased release of free β-catenin into the cytoplasm from the cadherin-bound pool. Interestingly, exogenous expression of p28tANK resulted in elevated expression of the endogenous protein. We also observed that both β-catenin and c-Myc were transcriptional activators of p28^GANK, and a correlation between p28^GANK overexpression and c-Myc, cyclin DI and β-catenin activation in primary human HCC. Together, these results suggest that p28^GANK expression is regulated by a positive feedback loop involving β-catenin, which may play a critical role in tumorigenesis and the progression of HCC.