Early growth response 1 loops the CYP2B6 promoter for synergistic activation by the distal and proximal nuclear receptors CAR and HNF4alpha.
Nuclear xenobiotic receptor CAR activates transcription of the CYP2B6 gene by directly binding to the distal enhancer PB responsive enhancer module (PBREM). This CAR-mediated activation is synergized by transcription factors early growth response 1 (EGR1) and hepatocyte-enriched nuclear factor 4alpha (HNF4alpha) that bind to the proximal element OA response element KI (OARE(KI)) [Inoue, K., & Negishi, M. (2008). Nuclear receptor CAR requires early growth response 1 to activate the human cytochrome P450 2B6 gene. J. Biol. Chem. 283, 10425-10432]. Two additional EGR1 binding sites have now been found just downstream from PBREM. Internal deletion of EGR1 sites within the context of the -1.8 kb CYP2B6 promoter, which contains both PBREM and OARE(KI), revealed that the distal and proximal EGR1 sites are essential for EGR1 to synergize CAR-mediated transcription. Chromatin conformation capture 3C assays demonstrated that ERG1 may loop the distal PBREM towards the proximal OARE(KI) so that together, CAR and HNF4alpha synergistically activate the CYP2B6 promoter.
Inoue
Kaoru
K
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Negishi
Masahiko
M
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D065702:Cytochrome P-450 CYP2B6; D017931:DNA Primers / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016297:Mutagenesis, Site-Directed; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020239:Receptor Cross-Talk; D011991:Receptors, Virus / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D017931:DNA Primers; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D011991:Receptors, Virus; D011994:Recombinant Proteins; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating