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Published on: September 12, 2019
Hepatic expression of SV40 small-T antigen blocks the in vivo CD95-mediated apoptosis
R Gillet1, C Cavard, G Grimber
1INSERM U380, Institut Cochin de Génétique Moléculaire, 22 rue Méchain, Paris, 75014, France.
Abstract:
We have previously demonstrated that CD95-mediated apoptosis of hepatocytes is blocked in a murine model of hepatocarcinogenesis due to the expression of SV40 early sequences encoding the large-T and small-t antigens. In this study, we set out to pinpoint the sequences involved in this apoptosis-resistant phenotype, and tested several mutants of the SV40 early region for their ability to confer protection against CD95-induced apoptosis in transgenic mice. We show that resistance to apoptosis is independent of the transforming character of the mutants and demonstrate that the expression of the small-t antigen alone in transgenic mice is sufficient to confer this resistance. Our data also reveal an increased level of activated Akt kinase in these transgenic mice, and this could account for this hitherto unknown function of the SV40 small-t antigen.
Insights
Simian virus 40 (SV40) small-t antigen confers resistance to hepatocyte apoptosis by activating Akt kinase. This finding reveals a novel role for SV40 small-t antigen in preventing programmed cell death.
Area of Science:
- Hepatology
- Virology
- Molecular Biology
Background:
- Hepatocyte apoptosis is crucial in liver homeostasis and disease.
- Hepatocellular apoptosis is blocked during hepatocarcinogenesis by Simian virus 40 (SV40) early region expression.
- SV40 large-T and small-t antigens are implicated in blocking CD95-mediated apoptosis.
Purpose of the Study:
- To identify specific Simian virus 40 (SV40) sequences responsible for conferring resistance to CD95-induced apoptosis.
- To investigate the role of SV40 small-t antigen in apoptosis resistance.
- To explore the molecular mechanisms underlying SV40-mediated apoptosis resistance.
Main Methods:
- Transgenic mouse models expressing Simian virus 40 (SV40) early region mutants.
- Assessment of resistance to CD95-induced apoptosis in hepatocytes.
- Analysis of activated Akt kinase levels.
Main Results:
- Apoptosis resistance was conferred by Simian virus 40 (SV40) small-t antigen alone.
- The transforming ability of SV40 mutants did not correlate with apoptosis resistance.
- Transgenic mice expressing SV40 small-t antigen showed increased activated Akt kinase levels.
Conclusions:
- Simian virus 40 (SV40) small-t antigen is sufficient to confer resistance to CD95-induced hepatocyte apoptosis.
- SV40 small-t antigen's role in apoptosis resistance is independent of its transforming activity.
- Increased Akt kinase activation by SV40 small-t antigen may explain this novel anti-apoptotic function.
