FAS-DEPENDENT APOPTOSIS IS IMPAIRED BY SV40 T-ANTIGEN IN TRANSGENIC LIVER

A transgenic mouse model for hepatocarcinoma has been previously produ ced by targeting SV40 T-antigen expression to the liver. To evaluate t he perturbation of cell death occurring during hepatocarcinogenesis, w e examined the Fas-induced apoptosis on hepatocytes expressing T-antig en. Whereas anti-Fas antibody induced apoptosis in primary cultured no rmal hepatocytes, they imparted a weak cytotoxicity on primary culture d hepatocytes expressing T-antigen. This resistance of hepatic Fas-med iated apoptosis appears to result in an enhancement of a protective me chanism involving the protein kinase C signaling pathway rather than i n a down-regulation of Fas-antigen expression. We further demonstrated that anti-Fas antibody does not have as efficient a lethal effect in T-antigen transgenic mice as in wild-type mice, The livers of transgen ic mice injected with anti-Fas mAbs showed large intact regions with a few scattered apoptotic bodies: these regions strictly corresponded w ith carcinoma nodules, expressing high level of T-antigen. Our results describe a novel function for SV40 T-antigen which could contribute t o viral pathogenesis by protecting infected cells against the host apo ptotic defense mechanism.