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Fas-dependent apoptosis is impaired by SV40 T-antigen in transgenic liver
N Rouquet1, I Allemand, T Molina
1INSERM U-380, ICGM, Paris, France.
Abstract:
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.
Insights
SV40 T-antigen protects liver cells from Fas-induced apoptosis, a key cell death pathway. This resistance enhances protective mechanisms, contributing to viral pathogenesis and hepatocarcinoma development.
Area of Science:
- Hepatology
- Molecular Biology
- Immunology
Background:
- Hepatocellular carcinoma (HCC) is a major global health concern.
- Understanding cell death regulation is crucial for cancer research.
- SV40 T-antigen is implicated in viral pathogenesis and tumorigenesis.
Purpose of the Study:
- To investigate the role of Fas-mediated apoptosis in hepatocarcinogenesis.
- To determine how SV40 T-antigen affects hepatocyte apoptosis.
- To elucidate the mechanisms underlying resistance to apoptosis in T-antigen expressing cells.
Main Methods:
- Primary hepatocyte culture from T-antigen transgenic mice and wild-type controls.
- Assessment of Fas-induced apoptosis using anti-Fas antibodies.
- Analysis of protein kinase C signaling pathway activation.
- In vivo studies using anti-Fas monoclonal antibodies (mAbs) in transgenic and wild-type mice.
Main Results:
- Hepatocytes expressing SV40 T-antigen exhibited resistance to Fas-induced apoptosis compared to normal hepatocytes.
- This resistance was associated with enhanced protein kinase C signaling, not reduced Fas expression.
- In vivo administration of anti-Fas mAbs showed reduced efficacy in T-antigen transgenic mice.
- Carcinoma nodules in transgenic mice displayed intact regions resistant to apoptosis.
Conclusions:
- SV40 T-antigen confers resistance to Fas-mediated apoptosis in hepatocytes.
- This resistance is mediated by enhanced protective signaling pathways.
- SV40 T-antigen may promote viral pathogenesis by evading host apoptotic defenses, contributing to hepatocarcinoma.