Abstract
Aflatoxin B1 (AFB1) induced mutation of the p53 gene at codon 249 (p53mt249) is critical during the formation of hepatocellular carcinoma (HCC) following hepatitis B virus (HBV) infection. p53mt249 markedly increases insulin-like growth factor II (IGF-II) transcription largely from promoter 4, accumulating the fetal form of IGF-II. Modulation of the transcription factor binding to IGF-II P4 by wild-type p53 and p53mt249 was identified. Wild-type p53 inhibited binding of transcription factors Sp1 and TBP on the P4 promoter, while p53mt249 enhanced the formation of transcriptional complexes through enhanced DNA-protein (Sp1 or TBP) and protein-protein (Sp1 and TBP) interactions. p53mt249 stimulates transcription factor Sp1 phosphorylation which might be a cause of increased transcription factor binding on the P4 promoter while wild-type p53 does not. Transfection of hepatocytes with p53mt249 impaired induction of apoptosis by the HBV-X protein and TNF-alpha. Therefore, the blocking of apoptosis through enhanced production of IGF-II should provide a favorable opportunity for the selection of transformed hepatocytes. These results explain the molecular basis for the genesis of HCC by p53mt249 which was found to be induced by a potent mutagen, AFB1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aflatoxin B1 / pharmacology*
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Animals
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Apoptosis
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / physiopathology
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Cell Line
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Cell Line, Transformed
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DNA-Binding Proteins / metabolism
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Drosophila / cytology
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Electrophoresis, Polyacrylamide Gel / methods
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Gene Expression
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Hepatitis B Antigens / metabolism
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Humans
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Insulin-Like Growth Factor II / genetics*
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Liver Neoplasms / metabolism*
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Liver Neoplasms / physiopathology
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Mutagenesis / drug effects
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Mutagens / pharmacology*
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Promoter Regions, Genetic
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Sp1 Transcription Factor / metabolism
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TATA-Box Binding Protein
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Trans-Activators / metabolism
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Transcription Factors / metabolism
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Transcriptional Activation*
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Suppressor Protein p53 / drug effects
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Viral Regulatory and Accessory Proteins
Substances
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DNA-Binding Proteins
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Hepatitis B Antigens
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Mutagens
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Sp1 Transcription Factor
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TATA-Box Binding Protein
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Trans-Activators
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Protein p53
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Viral Regulatory and Accessory Proteins
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hepatitis B virus X protein
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Insulin-Like Growth Factor II
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Aflatoxin B1