Nuclear Receptor CAR Requires Early Growth Response 1 to Activate the Human Cytochrome P450 2B6 Gene.

Nuclear Receptor CAR Requires Early Growth Response 1 to Activate the Human Cytochrome P450 2B6 Gene. Research Abstract Details 

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Nuclear Receptor CAR Requires Early Growth Response 1 to Activate the Human Cytochrome P450 2B6 Gene. Abstract Text:

The nuclear receptor CAR (constitutive active/androstane receptor) is a drug-sensing transcription factor, regulating the hepatic genes that encode various drug-metabolizing enzymes. We have now characterized the novel regulatory mechanism by which the signal molecule EGR1 (early growth response 1) determines CAR-mediated activation of the human CYP2B6 (cytochrome P450 2B6) gene. The CYP2B6 enzyme metabolizes commonly used therapeutics and also activates pro-drugs. The CAR directly binds to the distal enhancer element of the CYP2B6 promoter, which is essential in converging to its drug-sensing function onto promoter activity. However, this binding alone is not sufficient to activate the CYP2B6 promoter; the promoter requires EGR1 to enable CAR to activate the CYP2B6 promoter. Upon stimulation by protein kinase C, EGR1 directly binds to the proximal promoter and coordinates the nearby HNF4alpha (hepatocyte-enriched nuclear factor 4alpha) with CAR at the distal enhancer element to activate the promoter. Thus, synergy of drug activation and the stimulation of cellular signal are necessary for CAR to activate the CYP2B6 gene.

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Nuclear Receptor CAR Requires Early Growth Response 1 to Activate the Human Cytochrome P450 2B6 Gene. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The Journal of biological chemistry

VOLUME: 283

Page Numbers: 10425-32

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 25

MONTH: 02

YEAR: 2008

Nuclear Receptor CAR Requires Early Growth Response 1 to Activate the Human Cytochrome P450 2B6 Gene. Information

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LANGUAGE: eng

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Grant and Affiliation Information for Nuclear Receptor CAR Requires Early Growth Response 1 to Activate the Human Cytochrome P450 2B6 Gene.

AFFILIATION: Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.

Country: United States

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MEDLINETA: J Biol Chem

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