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
Date
2000
Authors
Dwivedi, P.
Omdahl, J.
Kola, I.
Hume, D.
May, B.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Biological Chemistry, 2000; 275(1):47-55
Statement of Responsibility
Prem P. Dwivedi, John L. Omdahl, Ismail Kola, David A. Hume and Brian K. May
Conference Name
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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2000 by The American Society for Biochemistry and Molecular Biology, Inc