Abstract
Deregulation of E2F transcriptional control has been implicated in oncogenic transformation. Consistent with this idea, we recently demonstrated that during hepatocarcinogenesis in c-myc/TGFalpha double transgenic mice, there is increased expression of E2F-1 and E2F-2, as well as induction of putative E2F target genes. Therefore, we generated transgenic mice expressing E2F-1 under the control of the albumin enhancer/promoter to test the hypothesis that E2F family members may contribute to liver tumor development. Overexpression of E2F-1 resulted in mild but persistent increases in cell proliferation and death during postnatal liver growth, and no increases in hepatic regenerative growth in response to partial hepatectomy. Nevertheless, from 2 months postnatally E2F-1 transgenic mice exhibited prominent hepatic histological abnormalities including preneoplastic foci adjacent to portal tracts and pericentral large cell dysplasia. From 6 to 8 months onward, there was an abrupt increase in the number of neoplastic nodules ('adenomas') with 100% incidence by 10 months. Some adenomas showed evidence of malignant transformation, and two of six mice killed at 12 months showed trabecular hepatocellular carcinoma. Endogenous c-myc was up-regulated in the early stages of E2F-1 hepatocarcinogenesis, whereas p53 was overexpressed in the tumors, suggesting that both E2F-1-mediated proliferation and apoptosis are operative but at different stages of hepatocarcinogenesis. In conclusion, E2F-1 overexpression in the liver causes dysplasia and tumors and suggests a cooperation between E2F-1 and c-myc oncogenes during liver oncogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Albumins / genetics
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Animals
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Apoptosis / physiology
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Carrier Proteins*
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Cell Cycle Proteins*
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Cell Division / physiology
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Crosses, Genetic
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DNA-Binding Proteins*
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F2 Transcription Factor
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Enhancer Elements, Genetic / genetics
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Female
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Gene Expression Regulation, Neoplastic
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Genes, myc / genetics
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Hepatocytes / cytology
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Hepatocytes / metabolism
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Hepatocytes / physiology
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Humans
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Liver / metabolism
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Liver / pathology
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Liver / physiology
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Liver Neoplasms, Experimental / genetics*
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Liver Neoplasms, Experimental / metabolism
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Liver Neoplasms, Experimental / pathology
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Liver Regeneration / physiology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred CBA
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Mice, Transgenic
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Precancerous Conditions / genetics
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Precancerous Conditions / metabolism
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-myc / biosynthesis
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Proto-Oncogene Proteins c-myc / genetics
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Tumor Suppressor Protein p53 / biosynthesis
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / physiology
Substances
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Albumins
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Arid4a protein, mouse
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F1 protein, human
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E2F2 Transcription Factor
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E2F2 protein, human
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E2f1 protein, mouse
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Proto-Oncogene Proteins c-myc
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors
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Tumor Suppressor Protein p53