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

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2515-2530
Number of pages16
JournalOncogene
Volume22
Issue number16
DOIs
StatePublished - Apr 24 2003

Fingerprint

Viral Tumor Antigens
Hepatocytes
Apoptosis
Hepatocellular Carcinoma
Liver
Carbohydrates
Carbohydrate-Restricted Diet
Diet
Polyomavirus Transforming Antigens
Phosphoenolpyruvate
Hepatomegaly
Growth
Caspases
Oncogenes
Cell Cycle
Phosphorylation

Keywords

  • Akt
  • Apoptosis
  • Caspase
  • Fas
  • Hepatocytes
  • T-Antigen

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Induction of hepatocyte proliferation and death by modulation of T-antigen expression. / Comerford, Sarah A; Clouthier, David E.; Hinnant, Elizabeth A.; Hammer, Robert E.

In: Oncogene, Vol. 22, No. 16, 24.04.2003, p. 2515-2530.

Research output: Contribution to journalArticle

Comerford, Sarah A ; Clouthier, David E. ; Hinnant, Elizabeth A. ; Hammer, Robert E. / Induction of hepatocyte proliferation and death by modulation of T-antigen expression. In: Oncogene. 2003 ; Vol. 22, No. 16. pp. 2515-2530.
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