P53-INDEPENDENT APOPTOTIC EFFECTS OF THE HEPATITIS-B VIRUS HBX PROTEIN IN-VIVO AND IN-VITRO

The hepatitis B virus protein HBx is a promiscuous transactivator impl icated in both cell growth and death and in the development of hepatoc ellular carcinoma. We recently reported that HBx can potentiate c-myc- induced liver oncogenesis in a transgenic model where low level expres sion of HBx induces no pathology, To assess if HBx could affect the he patocyte turnover, we investigated the HBx-elicited apoptotic response s in transgenic livers and in primary hepatocyte cultures. Here we sho w that transgenic expression of HBx is associated with a twofold incre ase of spontaneous cell death in the mouse liver, The finding that apo ptosis was enhanced to similar extents in HBx mice carrying homozygous p53 null mutations implied that functionally intact p53 was not requi red to transduce the death signal, A direct, dose-dependent apoptotic function of HBx was demonstrated in transient transfections of liver-d erived cell lines. We further show that stable expression of HBx at lo w, presumably physiological levels in primary hepatocytes, induced cel lular susceptibility to diverse apoptotic insults, including growth fa ctor deprivation, treatment with anti-Fas antibodies or doxorubicine a nd oxidative stress, HBx expression, but not p53 status profoundly aff ected the commitment of cells to die upon apoptotic stimuli, These dat a strengthen the notion that HEX may contribute to HBV pathogenesis by enhancing apoptotic death in the chronically infected liver.