한빛사 논문
Abstract
Kyun-Hwan Kim and Baik L. Seong
Department of Biotechnology, College of Engineering and Bioproducts Research Center, Yonsei University, Seoul 120-749, Korea
To whom correspondence should be addressed
Baik L. Seong
Received 16 August 2002; Revised 14 January 2003; Accepted 11 March 2003.
Abstract
Despite its implication in the progression of hepatitis B virus (HBV)-associated liver disease, the pro-apoptotic function of HBx protein remains poorly understood. We show that the expression of HBx leads to hyperactivation of caspase-8 and caspase-3 upon treatment with tumor necrosis factor- (TNF-) or anti-Fas antibody, and this activation is correlated with the sensitivity to apoptosis. We demonstrate cytoplasmic co-localization and direct interaction between HBx and the cellular FLICE inhibitory protein (c-FLIP), a key regulator of the death-inducing signaling complex (DISC). Deletion analysis shows that the death effector domain 1 (DED1) of c-FLIP is important for the observed interaction. Overexpression of c-FLIP rescued the cells from HBx-mediated apoptosis, with both the full-length HBV genome and HBx expression vectors. Moreover, c-FLIP and caspase-8 inhibitor considerably protected cells from HBx-mediated apoptosis. These data suggest that HBx abrogates the apoptosis-inhibitory function of c-FLIP and renders the cell hypersensitive towards the TNF- apoptotic signal even below threshold concentration. This provides a novel mechanism for deregulation of hepatic cell growth in HBV patients and a new target for intervention in HBV-associated liver cancer and disease.
Keywords: apoptosis, FLIP, hepatitis B virus, HBx protein, TNF-
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