1887

Abstract

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

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2007-08-01
2024-03-28
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