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Journal of Virology, January 2001, p. 215-225, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.215-225.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Role of NF-kappa B and Myc Proteins in Apoptosis Induced by Hepatitis B Virus HBx Protein

Fei Su,dagger Christian N. Theodosis, and Robert J. Schneider*

Department of Microbiology, New York University School of Medicine, New York, New York 10016

Received 31 May 2000/Accepted 29 September 2000

Chronic infection with hepatitis B virus (HBV) promotes a high level of liver disease and cancer in humans. The HBV HBx gene encodes a small regulatory protein that is essential for viral replication and is suspected to play a role in viral pathogenesis. HBx stimulates cytoplasmic signal transduction pathways, moderately stimulates a number of transcription factors, including several nuclear factors, and in certain settings sensitizes cells to apoptosis by proapoptotic stimuli, including tumor necrosis factor alpha (TNF-alpha ) and etopocide. Paradoxically, HBx activates members of the NF-kappa B transcription factor family, some of which are antiapoptotic in function. HBx induces expression of Myc protein family members in certain settings, and Myc can sensitize cells to killing by TNF-alpha . We therefore examined the roles of NF-kappa B, c-Myc, and TNF-alpha in apoptotic killing of cells by HBx. RelA/NF-kappa B is shown to be induced by HBx and to suppress HBx-mediated apoptosis. HBx also induces c-Rel/NF-kappa B, which can promote apoptotic cell death in some contexts or block it in others. Induction of c-Rel by HBx was found to inhibit its ability to directly mediate apoptotic killing of cells. Thus, HBx induction of NF-kappa B family members masks its ability to directly mediate apoptosis, whereas ablation of NF-kappa B reveals it. Investigation of the role of Myc protein demonstrates that overexpression of Myc is essential for acute sensitization of cells to killing by HBx plus TNF-alpha . This study therefore defines a specific set of parameters which must be met for HBx to possibly contribute to HBV pathogenesis.

* Corresponding author. Mailing address: Department of Microbiology, NYU School of Medicine, 550 First Ave., New York, NY 10016. Phone: (212) 263-6006. Fax: (212) 263-8276. E-mail: schner01{at}popmail.med.nyu.edu.

dagger Present address: Rockefeller University, New York, NY 10012.

Journal of Virology, January 2001, p. 215-225, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.215-225.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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