Inoue Kaoru, Negishi Masahiko
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.
FEBS Lett. 2009 Jun 18;583(12):2126-30. doi: 10.1016/j.febslet.2009.05.031. Epub 2009 May 23.
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.
核异生素受体CAR通过直接结合远端增强子PB反应性增强子模块（PBREM）来激活CYP2B6基因的转录。这种由CAR介导的激活作用会与转录因子早期生长反应1（EGR1）和肝富集核因子4α（HNF4α）协同作用，它们会结合到近端元件OA反应元件KI（OARE(KI)）上[井上，K.，& 根岸，M.（2008年）。核受体CAR需要早期生长反应1来激活人类细胞色素P450 2B6基因。《生物化学杂志》283，10425 - 10432]。现在在PBREM下游又发现了另外两个EGR1结合位点。在包含PBREM和OARE(KI)的 - 1.8 kb CYP2B6启动子范围内对EGR1位点进行内部缺失，结果表明远端和近端EGR1位点对于EGR1协同CAR介导的转录至关重要。染色质构象捕获3C分析表明，ERG1可能会使远端的PBREM向近端的OARE(KI)环化，从而使CAR和HNF4α一起协同激活CYP2B6启动子。
