Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response element-directed transactivation.
Hepatitis B virus is a major risk factor in human hepatocellular carcinomas. We have used protein affinity chromatography to show that the 17-kDa hepatitis B virus gene product, HBx, binds directly to the human tumor suppressor gene product, p53. Interaction of HBx with p53 did not prevent p53 from specifically binding DNA. Instead, HBx enhanced p53's oligomerization state on a DNA oligonucleotide containing a p53 response element. Optimal binding of HBx to p53 required intact p53, but weaker binding to both the N-terminal activation domain of p53 and a protein fragment containing the C-terminal DNA-binding and oligomerization domains of p53 was observed. In transient transfection experiments with human Calu-6 cells, HBx inhibited transactivation by p53 of a reporter gene containing a p53 response element. Also, HBx inhibited p53-stimulated transcription in vitro even when added to the reaction mixture after the formation of the preinitiation complex. Interaction of HBx with p53 did not prevent the activation domain of p53 from binding two general initiation factors, the TATA-box binding protein subunit of TFIID and the p62 subunit of TFIIH. To explain these results, we propose that localization of HBx to a promoter by interaction with DNA-bound p53 enables a repression domain in HBx to directly contact the basal transcription machinery and thereby repress transcription.
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
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Truant
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Antunovic
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Greenblatt
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Prives
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Cromlish
D001483:Base Sequence; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000235:genetics*; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D054334:Viral Regulatory and Accessory Proteins
D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein