Fas-dependent apoptosis is impaired by SV40 T-antigen in transgenic liver.
A transgenic mouse model for hepatocarcinoma has been previously produced by targeting SV40 T-antigen expression to the liver. To evaluate the perturbation of cell death occurring during hepatocarcinogenesis, we examined the Fas-induced apoptosis on hepatocytes expressing T-antigen. Whereas anti-Fas antibody induced apoptosis in primary cultured normal hepatocytes, they imparted a weak cytotoxicity on primary cultured hepatocytes expressing T-antigen. This resistance of hepatic Fas-mediated apoptosis appears to result in an enhancement of a protective mechanism involving the protein kinase C signaling pathway rather than in 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 transgenic mice injected with anti-Fas mAbs showed large intact regions with a few scattered apoptotic bodies: these regions strictly corresponded with carcinoma nodules, expressing high level of T-antigen. Our results describe a novel function for SV40 T-antigen which could contribute to viral pathogenesis by protecting infected cells against the host apoptotic defense mechanism.
Rouquet
N
N
INSERM U-380, ICGM, Paris, France.
Allemand
I
I
Molina
T
T
Bennoun
M
M
Briand
P
P
Joulin
V
V
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D005260:Female; D008099:Liver / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000209:etiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013539:Simian virus 40 / Q000276:immunology*; D019014:fas Receptor / Q000032:analysis / Q000502:physiology*
D000911:Antibodies, Monoclonal; D000952:Antigens, Polyomavirus Transforming; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D011493:Protein Kinase C