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Induction of hepatocyte proliferation and death by modulation of T-Antigen expression

Oncogene volume 22, pages 2515–2530 (2003)Cite this article

Abstract

Mice expressing SV40 T-Antigen in liver under control of the phosphoenolpyruvate carboxykinase promoter were generated. By altering the carbohydrate content of the diet, TAg expression, the rate of hepatocyte proliferation and apoptosis, and hence hepatocarcinogenesis, could be regulated. Carbohydrate-mediated suppression of TAg resulted in slow hepatic growth that progressed to focal hepatocellular carcinoma (HCC) after a long latency period. In contrast, induction of TAg by feeding mice a low carbohydrate diet resulted in massive hepatomegaly that progressed rapidly to diffuse multifocal HCC. Hepatic TAg expression could be efficiently repressed by switching mice from the low to the high-carbohydrate diet, which if instigated prior to the development of HCC, resulted in rapid regression through a p53-independent reduction in hepatocyte proliferation and an increase in hepatocyte apoptosis. Although liver growth was accompanied by compensatory hepatocyte apoptosis, an apoptotic deficit developed following chronic exposure to high levels of TAg. This was associated with Akt phosphorylation and increased expression of the antiapoptotic molecules bfl-1/A1, TIAP, and A20. Mice were resistant to Fas-induced hepatocellular apoptosis due to severely impaired caspase activation and failed activation of the mitochondrial amplification loop. This model will be useful to investigate oncogene-mediated disruption of the cell cycle and apoptosis, and to determine which processes constitute fixed, or reversible aspects of the tumorigenic process.

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Acknowledgements

SAC and DEC contributed equally to the work. We thank Mike McNally and Matt Hammer for excellent technical assistance; Mario Villarreal for animal care and Royce Potter for help in preparing the manuscript. We acknowledge Mark Magnuson for constructing the transgene and Mary Short for assistance in the early phase of the project. The work was supported by the National Institutes of Health (DK 53789), The Cecil and Ida Green Center for Reproductive Biology Sciences and the Perot Family Foundation.

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Author notes

  1. David E Clouthier

    Present address: Department of Molecular, Cellular and Craniofacial Biology, Birth Defects Center, University of Louisville School of Dentistry, 501 S. Preston St., Louisville, KY, 40292, USA

Authors and Affiliations

  1. Department of Biochemistry,

    Sarah A Comerford, David E Clouthier, Elizabeth A Hinnant & Robert E Hammer

  2. Cecil and Ida Green Center for Reproductive Biology Sciences,

    Sarah A Comerford, Elizabeth A Hinnant & Robert E Hammer

  3. Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center at Dallas, Dallas, 75390-9050, TX, USA

    Elizabeth A Hinnant & Robert E Hammer

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  1. Sarah A Comerford
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Correspondence to Robert E Hammer.

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Comerford, S., Clouthier, D., Hinnant, E. et al. Induction of hepatocyte proliferation and death by modulation of T-Antigen expression. Oncogene 22, 2515–2530 (2003). https://doi.org/10.1038/sj.onc.1206259

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