Hepatitis B virus X protein differentially affects the ubiquitin-mediated proteasomal degradation of beta-catenin depending on the status of cellular p53.
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.
Jung
Jin Kyu
JK
Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
Kwun
Hyun Jin
HJ
Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
Lee
Jung-Ok
JO
Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
Arora
Payal
P
Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
Jang
Kyung Lib
KL
Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
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
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