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Regulation of rat cytochrome P450C24 (CYP24) gene expression: evidence for functional cooperation of Ras-Activated Ets transcription factors with the vitamin D receptor in 1,25-dihydroxyvitamin D3-mediated induction

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dc.contributor.authorDwivedi, P.
dc.contributor.authorOmdahl, J.
dc.contributor.authorKola, I.
dc.contributor.authorHume, D.
dc.contributor.authorMay, B.
dc.date.issued2000
dc.description.abstractTranscription of the rat CYP24 gene is induced by 1, 25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) through two vitamin D response elements (VDREs). A functional Ras-dependent Ets-binding site (EBS) was located downstream from the proximal VDRE and was critical to 1,25(OH)(2)D(3)-mediated induction. Cotransfection of Ets-1 and Ets-2 stimulated induction, which was lost when the EBS was mutated. Multiple nuclear-protein complexes from COS-1 cells bound to the EBS in which three complexes were immunologically related to Ets-1. Transcriptional synergy was observed between the proximal VDRE and adjacent EBS as was the attendant formation of a ternary complex between vitamin D receptor- retinoid X receptor (VDR. RXR) and Ets-1. In the absence of 1,25-(OH)(2)D(3) or in the presence of an inactive proximal VDRE, the EBS failed to respond to exogenous Ets-1. However, Ets-1 increased basal expression when cotransfected with a mutant VDR. The inductive action of 1, 25-(OH)(2)D(3) was substantially increased by Ras, which was ablated by mutagenesis of the EBS or by expression of a mutated Ets-1 protein (T38A). EBS contribution to hormone induction was prevented by manumycin A, an inhibitor of Ras farnesylation. A fundamental role was established for transcriptional cooperation between Ras-activated Ets proteins and the VDR.RXR complex in mediating 1, 25-(OH)(2)D(3) action on the CYP24 promoter.
dc.description.statementofresponsibilityPrem P. Dwivedi, John L. Omdahl, Ismail Kola, David A. Hume and Brian K. May
dc.identifier.citationJournal of Biological Chemistry, 2000; 275(1):47-55
dc.identifier.doi10.1074/jbc.275.1.47
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.urihttp://hdl.handle.net/2440/27989
dc.language.isoen
dc.publisherAmer Soc Biochemistry Molecular Biology Inc
dc.rights© 2000 by The American Society for Biochemistry and Molecular Biology, Inc
dc.source.urihttps://doi.org/10.1074/jbc.275.1.47
dc.subjectAnimals
dc.subjectRats
dc.subjectCalcitriol
dc.subjectCytochrome P-450 Enzyme System
dc.subjectSteroid Hydroxylases
dc.subjectras Proteins
dc.subjectProto-Oncogene Proteins c-raf
dc.subjectProto-Oncogene Proteins
dc.subjectNuclear Proteins
dc.subjectReceptors, Retinoic Acid
dc.subjectRetinoid X Receptors
dc.subjectReceptors, Calcitriol
dc.subjectTranscription Factors
dc.subjectTranscription Factor AP-1
dc.subjectGene Expression Regulation, Enzymologic
dc.subjectBinding Sites
dc.subjectResponse Elements
dc.subjectProtein Binding
dc.subjectDimerization
dc.subjectProto-Oncogene Proteins c-ets
dc.subjectProto-Oncogene Protein c-ets-1
dc.subjectPromoter Regions, Genetic
dc.subjectTranscriptional Activation
dc.subjectVitamin D3 24-Hydroxylase
dc.titleRegulation of rat cytochrome P450C24 (CYP24) gene expression: evidence for functional cooperation of Ras-Activated Ets transcription factors with the vitamin D receptor in 1,25-dihydroxyvitamin D3-mediated induction
dc.typeJournal article
pubs.publication-statusPublished

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