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New insights into the regulation of CYP2C9 gene expression: The role of the transcription factor GATA-4

2010-03Journal article Open access
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dc.contributor.authorMwinyi, Jessica
dc.contributor.authorNekvindova, Jana
dc.contributor.authorCavaco, Isa
dc.contributor.authorHofmann, Yvonne
dc.contributor.authorPedersen, Rasmus Steen
dc.contributor.authorLandman, Ellie
dc.contributor.authorMkrtchian, Souren
dc.contributor.authorIngelman-Sundberg, Magnus
dc.date.accessioned2018-12-07T14:53:44Z
dc.date.available2018-12-07T14:53:44Z
dc.date.issued2010-03
dc.description.abstractCYP2C9 is an important drug-metabolizing enzyme that metabolizes, e. g., warfarin, antidiabetics, and antiphlogistics. However, the endogenous regulation of this enzyme is largely unknown. In this study, we examined the role of GATA transcription factors in the gene expression of CYP2C9. We investigated four putative GATA binding sites within the first 200 base pairs of CYP2C9 promoter at the positions I: -173/-170, II: -167/-164, III: -118/ -115, and IV: -106/-103. Luciferase activity driven by a wildtype CYP2C9 promoter construct was strongly up-regulated in Huh-7 cells upon cotransfection with expression plasmids for GATA-2 and GATA-4, whereas mutations introduced into GATA binding site III or I and II reduced this induction to a significant extent. Electrophoretic mobility shift assays revealed specific binding of GATA-4 and GATA-6 to the oligonucleotides containing GATA binding sites I and II. Furthermore, the association of GATA-4 with CYP2C9 promoter was confirmed by chromatin immunoprecipitation assays in HepG2 cells. Taken together, these data strongly suggest an involvement of liver-specific transcription factor GATA-4 in the transcriptional regulation of CYP2C9.
dc.description.sponsorshipSwedish Research Council; Stockholm County Council; Danish Agency of Science, Technology and Innovation; Lundbeck Foundation; Portuguese Foundation for Science and Technology [SFRH/BPD/34152/2006 IBB/CBME]
dc.identifier.doi10.1124/dmd.109.029405
dc.identifier.issn0090-9556
dc.identifier.issn1521-009X
dc.identifier.urihttp://hdl.handle.net/10400.1/11665
dc.language.isoeng
dc.peerreviewedyes
dc.publisherAmer Soc Pharmacology Experimental Therapeutics
dc.relationMOLECULAR GENETIC AND ENZYMATIC BASIS OF INTERINDIVIDUAL AND INTERETHNIC DIFFERENCES IN DRUG METABOLISM
dc.subjectRat Granulosa-Cells
dc.subjectCytochrome P4502C9
dc.subjectNuclear Factor-4-Alpha
dc.subjectCyp19 Expression
dc.subjectHeart
dc.subjectHepatocyte-Nuclear-Factor-4-Alpha
dc.subjectPolymorphisms
dc.subjectTransporters
dc.subjectMetabolism
dc.subjectActivation
dc.titleNew insights into the regulation of CYP2C9 gene expression: The role of the transcription factor GATA-4
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleMOLECULAR GENETIC AND ENZYMATIC BASIS OF INTERINDIVIDUAL AND INTERETHNIC DIFFERENCES IN DRUG METABOLISM
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F34152%2F2006/PT
oaire.citation.endPage421
oaire.citation.issue3
oaire.citation.startPage415
oaire.citation.titleDrug Metabolism and Disposition
oaire.citation.volume38
person.familyNameLopes Neve Cavaco
person.givenNameIsa da Conceição
person.identifier.orcid0000-0002-8629-7129
person.identifier.scopus-author-id6602806914
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublication621412af-f03a-4940-bd7e-2bada5f7cfc8
relation.isAuthorOfPublication.latestForDiscovery621412af-f03a-4940-bd7e-2bada5f7cfc8
relation.isProjectOfPublicationb82a552a-eeb8-4416-a2b1-05d8977f878a
relation.isProjectOfPublication.latestForDiscoveryb82a552a-eeb8-4416-a2b1-05d8977f878a

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