ABROGATION OF P53-INDUCED APOPTOSIS BY THE HEPATITIS-B VIRUS-X GENE

The p53 tumor suppressor gene product is a transcriptional transactiva tor and a potent apoptotic inducer. The fact that many of the DNA tumo r virus oncoproteins bind to p53 and affect these p53 functions indica tes that this interaction is an important step in oncogenic transforma tion, We and others have recently demonstrated that the hepatitis B vi rus oncoprotein, HBx, can form a complex with p53 and inhibit its DNA consensus sequence binding and transcriptional transactivator activity , Using a microinjection technique, we report here that HBx efficientl y blocks p53-mediated apoptosis and describe the results of studies ex ploring two possible mechanisms of HBx action. First, inhibition of ap optosis mag be a consequence of the failure of p53, in the presence of HBx, to upregulate genes, such as p21(WAF1), Bax, or Fas, that are in volved in the apoptotic pathway, Data consistent with this hypothesis include HBx reduction of p53-mediated p21(WAF1) expression, Alternativ ely, HBx could affect p53 binding to the TFIIH transcription-nucleotid e excision repair complex as HBx binds to the COOH terminus of p53 and inhibits its binding to XPB or XPD. Binding of p53 to these constitue nts of the core TFIIH is a process that may be involved in apoptosis, Because the HBx gene is frequently integrated into the genome of hepat ocellular carcinoma cells, inhibition of p53-mediated apoptosis by HBx may provide a clonal selective advantage for hepatocytes expressing t his integrated viral gene during the early stages of human liver carci nogenesis.