Role of NF-kappa B and Myc proteins in apoptosis induced by hepatitis B virus HBx protein

Chronic infection with hepatitis B virus (HBV) promotes a high level of liv er disease and cancer in humans. The HBV HBx gene encodes a small regulator y protein that is essential for viral replication and is suspected to play a role in viral pathogenesis. HBx stimulates cytoplasmic signal transductio n pathways, moderately stimulates a number of transcription factors, includ ing several nuclear factors, and in certain settings sensitizes cells to ap optosis 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-kappaB, c-Myc, and TNF-alpha in apoptotic killing of cells by HBx. RelA/NF-kappaB is shown to be induced by HBx and to suppress HBx-me diated apoptosis. HBx also induces c-Rel/NF-kappaB, which can promote apopt otic 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 killi ng of cells. Thus, HBx induction of NF-kappaB family members masks its abil ity to directly mediate apoptosis, whereas ablation of NF-kappaB 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 plu s TNF-alpha. This study therefore defines a specific set of parameters whic h must be met for HBx to possibly contribute to HBV pathogenesis.