title: Activation of the insulin-like growth factor II transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma.
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.
authors.affiliation: Bioscience Research Division, Korea Research Institute of Bioscience and Biotechnology, Yusong, Taejon.
authors.forename: Y I
authors.initials: YI
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: G C
authors.initials: GC
authors.lastname: Das
authors.forename: U S
authors.initials: US
authors.lastname: Park
authors.forename: S M
authors.initials: SM
authors.lastname: Park
authors.forename: Y I
authors.initials: YI
authors.lastname: Lee
mesh_terms: D016604:Aflatoxin B1 / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000503:physiopathology; D002460:Cell Line; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila / Q000166:cytology; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D015870:Gene Expression; D006511:Hepatitis B Antigens / Q000378:metabolism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D016296:Mutagenesis / Q000187:drug effects; D009153:Mutagens / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism; D035181:TATA-Box Binding Protein; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D004268:DNA-Binding Proteins; D006511:Hepatitis B Antigens; D009153:Mutagens; D016329:Sp1 Transcription Factor; D035181:TATA-Box Binding Protein; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D007335:Insulin-Like Growth Factor II; D016604:Aflatoxin B1