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FEBS Lett. 2009 Jun 18;583(12):2126-30. doi: 10.1016/j.febslet.2009.05.031. Epub 2009 May 23.

Early growth response 1 loops the CYP2B6 promoter for synergistic activation by the distal and proximal nuclear receptors CAR and HNF4alpha.

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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.


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.

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