Abstract
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-XL 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.
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Acknowledgements
We are grateful to Jean-Claude Martinou for stimulating discussions and critical review of the manuscript, and to Pierre Tiollais for his constant support. We thank Phil J Barr for plasmids pCMV-Bcl-2, pCMV-Bax and pCMV-Bcl-xL, and Catherine Transy for her support and advice in the yeast two-hybrid assays. We also thank Emmanuelle Perret for excellent assistance in confocal microscopy. O Terradillos was supported by fellowships from the Ligue Nationale pour la Recherche contre le Cancer and the Association pour la Recherche sur le Cancer (ARC). This work was supported in part by the ARC grant 9209.
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Terradillos, O., de La Coste, A., Pollicino, T. et al. The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver. Oncogene 21, 377–386 (2002). https://doi.org/10.1038/sj.onc.1205110
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DOI: https://doi.org/10.1038/sj.onc.1205110
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