title: Hepatitis B virus X protein differentially affects the ubiquitin-mediated proteasomal degradation of beta-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.
authors.affiliation: Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
authors.forename: Jin Kyu
authors.initials: JK
authors.lastname: Jung
authors.affiliation: Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kwun
authors.affiliation: Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
authors.forename: Jung-Ok
authors.initials: JO
authors.lastname: Lee
authors.affiliation: Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
authors.forename: Payal
authors.initials: P
authors.lastname: Arora
authors.affiliation: Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
authors.forename: Kyung Lib
authors.initials: KL
authors.lastname: Jang
mesh_terms: D019943:Amino Acid Substitution; D006528:Carcinoma, Hepatocellular / Q000209:etiology; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D014644:Genetic Variation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006509:Hepatitis B / Q000150:complications; D006515:Hepatitis B virus / Q000737:chemistry* / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025801:Ubiquitin / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
chemical_list: D009687:Nuclear Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin; C057628:hepatitis B virus X protein; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex