Hepatitis B virus X protein differentially affects the ubiquitin-mediated proteasomal degradation of β-catenin depending on the status of cellular p53

Abstract

Abnormal accumulation of beta-catenin is considered to be a strong driving force in hepatocellular carcinogenesis; however, the mechanism of beta-catenin accumulation in tumours is unclear. Here, it was demonstrated that hepatitis B virus X protein (HBx) differentially regulates the level of beta-catenin through two ubiquitin-dependent proteasome pathways depending on p53 status. In the presence of p53, HBx downregulated beta-catenin through the activation of a p53-Siah-1 proteasome pathway. For this purpose, HBx upregulated Siah-1 expression at the transcriptional level via activation of p53. In the absence of p53, however, HBx stabilized beta-catenin through the inhibition of a glycogen synthase kinase-3beta-dependent pathway. Interestingly, HBx variants with a Pro-101 to Ser substitution were unable to activate p53 and thus could stabilize beta-catenin irrespective of p53 status. Based on these findings, a model of beta-catenin regulation by HBx is proposed whereby the balance between the two opposite activities of HBx determines the overall expression level of beta-catenin. Differential regulation of beta-catenin by HBx depending on host (p53 status) and viral factors (HBx sequence variation) helps not only to explain the observation that cancers accumulating beta-catenin also exhibit a high frequency of p53 mutations but also to understand the contradictory reports on the roles of HBx during hepatocellular carcinogenesis.