Document Detail


Analysis of the molecular mechanism for the antagonistic action of a novel 1alpha,25-dihydroxyvitamin D(3) analogue toward vitamin D receptor function.
MedLine Citation:
PMID:  10542279     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have recently reported that 23(S)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647) efficiently blocks the differentiation of HL-60 cells induced by 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) (Miura, D., Manabe, K., Ozono, K., Saito, M., Gao, Q., Norman, A. W., and Ishizuka, S. (1999) J. Biol. Chem. 274, 16392-16399). To clarify the molecular mechanisms of this antagonism, we examined whether TEI-9647 antagonizes the genomic effects of 1alpha,25(OH)(2)D(3). 10(-7) to 10(-9) M TEI-9647 inhibited the transactivation effect of 10(-8) M 1alpha,25(OH)(2)D(3) in a dose-dependent manner, while TEI-9647 alone did not activate the reporter activity driven by SV40 promoter containing two vitamin D response elements in Saos-2 cells. The antagonistic effect of TEI-9647 was also observed using the rat 24-hydroxylase gene promoter, but the effect was weaker in HeLa and COS-7 cells than in Saos-2 cells. TEI-9647 also exhibited antagonism in an assay system where the VDR fused to the GAL4 DNA-binding domain and the reporter plasmid containing the GAL4 binding site were used in Saos-2 cells, but did not in HeLa cells. TEI-9647 reduced the interaction between VDR and RXRalpha according to the results obtained from the mammalian two-hybrid system in Saos-2 cells, but did not in HeLa cells. The two-hybrid system also revealed that the interaction between VDR and SRC-1 was reduced by TEI-9647 in Saos-2 cells. These results demonstrate that the novel 1alpha,25(OH)(2)D(3) analogue, TEI-9647, is the first synthetic ligand for the VDR that efficiently antagonizes the action of 1alpha, 25(OH)(2)D(3), although the extent of its antagonism depends on cell type.
Authors:
K Ozono; M Saito; D Miura; T Michigami; S Nakajima; S Ishizuka
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  274     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1999 Nov 
Date Detail:
Created Date:  1999-12-13     Completed Date:  1999-12-13     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  32376-81     Citation Subset:  IM    
Affiliation:
Department of Environmental Medicine, Osaka Medical Center, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan. j61642@center.osaka-u.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Animals
COS Cells
Calcitriol / analogs & derivatives*,  pharmacology
DNA-Binding Proteins
Fungal Proteins / metabolism
Green Fluorescent Proteins
Ligands
Luminescent Proteins / metabolism
Osteoblasts / metabolism
Promoter Regions, Genetic
Rats
Receptors, Calcitriol / drug effects,  physiology*
Receptors, Retinoic Acid / metabolism
Recombinant Fusion Proteins / metabolism
Retinoid X Receptors
Saccharomyces cerevisiae Proteins*
Transcription Factors / metabolism
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Fungal Proteins; 0/GAL4 protein, S cerevisiae; 0/Ligands; 0/Luminescent Proteins; 0/Receptors, Calcitriol; 0/Receptors, Retinoic Acid; 0/Recombinant Fusion Proteins; 0/Retinoid X Receptors; 0/Saccharomyces cerevisiae Proteins; 0/TEI 9647; 0/Transcription Factors; 147336-22-9/Green Fluorescent Proteins; 32222-06-3/Calcitriol

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