RRC ID 18966
Author Dhawan P, Christakos S.
Title Novel regulation of 25-hydroxyvitamin D3 24-hydroxylase (24(OH)ase) transcription by glucocorticoids: cooperative effects of the glucocorticoid receptor, C/EBP beta, and the Vitamin D receptor in 24(OH)ase transcription.
Journal J Cell Biochem
Abstract Glucocorticoid-induced bone loss has been proposed to involve direct effects on bone cells as well as alterations in calcium absorption and excretion. Since vitamin D is important for the maintenance of calcium homeostasis, in the present study the effects of glucocorticoids on vitamin D metabolism through the expression of 24(OH)ase, an enzyme involved in the catabolism of 1,25(OH)(2)D(3), were examined. Injection of vitamin D replete mice with dexamethasone (dex) resulted in a significant induction in 24(OH)ase mRNA in kidney, indicating a regulatory effect of glucocorticoids on vitamin D metabolism. Whether glucocorticoids can affect 24(OH)ase transcription is not known. Here we demonstrate for the first time a glucocorticoid receptor (GR) dependent enhancement of 1,25(OH)(2)D(3)-induced 24(OH)ase transcription. Dex treatment of GR and vitamin D receptor (VDR) transfected COS-7 cells and dex treatment of osteoblastic cells (in which VDR and GR are present endogenously) potentiated 1,25(OH)(2)D(3)-induced 24(OH)ase transcription. In addition, GR was found to cooperate with C/EBP beta to enhance VDR-mediated 24(OH)ase transcription. Using the rat 24(OH)ase promoter with the C/EBP site mutated, GR-mediated potentiation of 1,25(OH)(2)D(3)-induced 24(OH)ase transcription was inhibited. Immunoprecipitation indicated that that GR can interact with C/EBP beta and ChIP/re-ChIP analysis showed that C/EBP beta and GR bind simultaneously to the 24(OH)ase promoter. These findings indicate a novel mechanism whereby glucocorticoids can alter VDR-mediated 24(OH)ase transcription through functional cooperation between C/EBP beta and GR that results in an enhanced ability of C/EBP beta to cooperate with VDR in the regulation of 24(OH)ase.
Volume 110(6)
Pages 1314-23
Published 2010-8-15
DOI 10.1002/jcb.22645
PMID 20564225
MeSH 3T3 Cells Animals Binding Sites / genetics Blotting, Northern Blotting, Western CCAAT-Enhancer-Binding Protein-beta / genetics CCAAT-Enhancer-Binding Protein-beta / metabolism COS Cells Cell Line, Tumor Chlorocebus aethiops Dexamethasone / pharmacology Gene Expression Regulation / drug effects* Glucocorticoids / pharmacology* Kidney / drug effects Kidney / metabolism Mice Mutation Promoter Regions, Genetic / drug effects Protein Binding / drug effects Receptors, Calcitriol / genetics Receptors, Calcitriol / metabolism Receptors, Glucocorticoid / genetics Receptors, Glucocorticoid / metabolism Reverse Transcriptase Polymerase Chain Reaction Steroid Hydroxylases / genetics* Steroid Hydroxylases / metabolism Transcription, Genetic / drug effects* Transfection Vitamin D3 24-Hydroxylase
IF 4.237
Times Cited 33
Human and Animal Cells MC3T3-E1(RCB1126)