Abstract
Transcriptional activation of myc family proto-oncogenes through the insertion of viral sequences is the predominant mechanism by which woodchuck hepatitis virus (WHV) induces liver tumors in chronically infected animals. The main target is N-myc2, a functional retroposon of the N-myc gene, but c-myc and N-myc are also marginally involved. Here we identify a major, liver-specific regulatory element in the WHV genome (We2) which efficiently activates the N-myc2 promoter in cultured hepatoma cells. In the context of the episomal viral genome, We2 governs the production of pregenomic RNA and thus plays a central role in the control of viral replication. We2 activity is primarily controlled by the liver-enriched HNF1 and HNF4 transcription factors, although NF1 and Oct proteins were also shown to bind in a central region. The expression of HNF1 and HNF4 appears to be maintained in woodchuck tumors. Thus, We2 is a prime candidate for controlling myc gene cis activation during WHV-induced hepatocarcinogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Binding Sites
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DNA, Viral
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DNA-Binding Proteins*
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Hepatitis B Core Antigens / genetics
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Hepatitis B Virus, Woodchuck / genetics*
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Hepatitis B Virus, Woodchuck / physiology
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 1-alpha
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Hepatocyte Nuclear Factor 1-beta
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Hepatocyte Nuclear Factor 4
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Humans
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Liver
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Molecular Sequence Data
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Nuclear Proteins*
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Phosphoproteins / metabolism*
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Promoter Regions, Genetic*
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Proto-Oncogene Proteins c-myc / genetics*
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RNA
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Rabbits
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Regulatory Sequences, Nucleic Acid*
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Retroelements*
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Transcription Factors / metabolism*
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Transcriptional Activation*
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Tumor Cells, Cultured
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Virus Replication
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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DNA, Viral
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DNA-Binding Proteins
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HNF1A protein, human
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HNF1B protein, human
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Hepatitis B Core Antigens
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Hepatocyte Nuclear Factor 1-alpha
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Hepatocyte Nuclear Factor 4
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MLX protein, human
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Nuclear Proteins
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Phosphoproteins
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Proto-Oncogene Proteins c-myc
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Retroelements
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Transcription Factors
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 1-beta
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RNA