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Abrogation of p53-induced Apoptosis by the Hepatitis B Virus X Gene¹

Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255 [X. W. W., M. K. G., H. Y., K. F., C. C. H.]; Department of Cell Biology and Genetics, Medical Genetics Center, Erasmus University Rotterdam, 3000 DR Rotterdam, the Netherlands [W. V., J. H. J. H.]; and Fur Experimentelle Virologie and Immunologie, Heinrich-Pette-Institut, An Der Universitat Hamburg, D-20251 Hamburg, Germany [H-W. S.]

The p53 tumor suppressor gene product is a transcriptional transactivator and a potent apoptotic inducer. The fact that many of the DNA tumor virus oncoproteins bind to p53 and affect these p53 functions indicates that this interaction is an important step in oncogenic transformation. We and others have recently demonstrated that the hepatitis B virus 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 efficiently blocks p53-mediated apoptosis and describe the results of studies exploring two possible mechanisms of HBx action. First, inhibition of apoptosis may 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 involved in the apoptotic pathway. Data consistent with this hypothesis include HBx reduction of p53-mediated p21^WAF1 expression. Alternatively, HBx could affect p53 binding to the TFIIH transcription-nucleotide 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 constituents of the core TFIIH is a process that may be involved in apoptosis. Because the HBx gene is frequently integrated into the genome of hepatocellular carcinoma cells, inhibition of p53-mediated apoptosis by HBx may provide a clonal selective advantage for hepatocytes expressing this integrated viral gene during the early stages of human liver carcinogenesis.

¹ W. V. and J. H. J. H. gratefully acknowledge financial support from the Dutch Cancer Society (project EUR 94–763) and the Medica Sciences section of the Dutch Scientific Organization (project 501-93 and 151). M. G. and H. Y. were Howard Hughes Medical Institute-NIH Research Scholars.

² To whom requests for reprints should be addressed, at Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Building 37, Room 2C01, 37 Convent Drive, MSC 4255, Bethesda, MD 20892-4255.

Received 10/ 5/95. Accepted 11/ 1/95.

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