Induction of hepatocyte proliferation and death by modulation of T-Antigen expression.
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.
Comerford
Sarah A
SA
Department of Biochemistry and Cecil and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center at Dallas, 75390-9050, USA.
Clouthier
David E
DE
Hinnant
Elizabeth A
EA
Hammer
Robert E
RE
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D006528:Carcinoma, Hepatocellular / Q000209:etiology; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000957:Antigens, Viral, Tumor; D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases