The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver

• Published in: Oncogene Vol. 21; no. 3; pp. 377 - 386
• Main Authors: TERRADILLOS, Olivier, DE LA COSTE, Alix, POLLICINO, Teresa, NEUVEUT, Christine, SITTERLIN, Delphine, LECOEUR, Hervé, GOUGEON, Marie-Lise, KAHN, Axel, BUENDIA, Marie-Annick
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 17.01.2002; Nature Publishing Group
• Subjects: Animals; Apoptosis; Biological and medical sciences; Blotting, Western; Caspase 3; Caspases - metabolism; Cell cycle; Cell death; Cell growth; Cytochrome; Cytochrome c Group - metabolism; Cytotoxicity; fas Receptor - immunology; fas Receptor - metabolism; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation; HeLa Cells; Hepatitis B; Hepatocytes - cytology; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Liver - cytology; Liver - metabolism; Liver - pathology; Liver - virology; Liver cancer; Mice; Mice, Transgenic; Mitochondria - enzymology; Mitochondria - metabolism; Molecular and cellular biology; Pathogenesis; Protein Binding; Proteins; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signal transduction; Time Factors; Trans-Activators - genetics; Trans-Activators - metabolism; Transfection; Transgenic animals; Two-Hybrid System Techniques; France; Paris France; Cell proliferation; Antibody; Rodentia; Orthohepadnavirus; Transgenic animal; Gene overexpression; Hepatic disease; Protein; Virus; In vivo; Vertebrata; Mammalia; TP53 Gene; Hepatocyte; Mouse; Hepadnaviridae; Turnover; Digestive diseases; Hepatitis B virus; pK; Protection; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205110

The role of the hepatitis B virus protein HBx in liver cell proliferation and apoptosis remains controversial. Using a transgenic mouse model, we have recently shown that HBx stimulates the apoptotic turnover of hepatocytes, independently of p53. In this paper, we tested whether the proapoptotic function of HBx can interfere with Bcl-2 during hepatic apoptosis in vivo. HBx transgenic mice were crossed with PK-hBcl-2 mice that are protected against Fas killing by constitutive overexpression of Bcl-2 in hepatocytes. In a lethal challenge with Fas antibodies, HBx expressed at low levels restored sensitivity to Fas-mediated apoptosis and fulminant hepatic failure in mice overexpressing Bcl-2. Furthermore, cytochrome c release from mitochondria and caspase 3 activation were restored to normal levels in HBx/Bcl-2 mice during transduction of the Fas signal. Thus, the proapoptotic activity of HBx overcomes or bypasses the inhibitory effect of Bcl-2 against Fas cytotoxicity. This effect was not apparently mediated through downregulation of the PK-hBcl-2 transgene or via delocalization of the Bcl-2 protein, and a direct interaction of HBx with Bcl-2, Bcl-X(L) or Bax could not be evidenced in yeast two-hybrid assays. We further show that apoptosis induced by ectopic expression of HBx is associated with mitochondrial membrane alterations and caspase 3 activation. Our data indicate that the dominant function of HBx upon Bcl-2-regulated control of apoptosis might play an important role in the pathogenesis of chronic hepatitis B.