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https://hdl.handle.net/2440/27989
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Type: | Journal article |
Title: | 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 |
Author: | Dwivedi, P. Omdahl, J. Kola, I. Hume, D. May, B. |
Citation: | Journal of Biological Chemistry, 2000; 275(1):47-55 |
Publisher: | Amer Soc Biochemistry Molecular Biology Inc |
Issue Date: | 2000 |
ISSN: | 0021-9258 1083-351X |
Statement of Responsibility: | Prem P. Dwivedi, John L. Omdahl, Ismail Kola, David A. Hume and Brian K. May |
Abstract: | Transcription 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. |
Keywords: | Animals Rats Calcitriol Cytochrome P-450 Enzyme System Steroid Hydroxylases ras Proteins Proto-Oncogene Proteins c-raf Proto-Oncogene Proteins Nuclear Proteins Receptors, Retinoic Acid Retinoid X Receptors Receptors, Calcitriol Transcription Factors Transcription Factor AP-1 Gene Expression Regulation, Enzymologic Binding Sites Response Elements Protein Binding Dimerization Proto-Oncogene Proteins c-ets Proto-Oncogene Protein c-ets-1 Promoter Regions, Genetic Transcriptional Activation Vitamin D3 24-Hydroxylase |
Rights: | © 2000 by The American Society for Biochemistry and Molecular Biology, Inc |
DOI: | 10.1074/jbc.275.1.47 |
Published version: | http://dx.doi.org/10.1074/jbc.275.1.47 |
Appears in Collections: | Aurora harvest 2 Molecular and Biomedical Science publications |
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