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J Biol Chem, Vol. 274, Issue 45, 32376-32381, November 5, 1999
,25-Dihydroxyvitamin D3 Analogue
toward Vitamin D Receptor Function
,,,, and
From the We have recently reported that
23(S)-25-dehydro-1 Department of Environmental Medicine,
-hydroxyvitamin
D3-26,23-lactone (TEI-9647) efficiently blocks the
differentiation of HL-60 cells induced by 1,25-dihydroxyvitamin
D3 (1,25(OH)2D3) (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
1,25(OH)2D3. 10
7 to
109 M TEI-9647 inhibited the transactivation
effect of 108 M
1,25(OH)2D3 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 RXR 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
1,25(OH)2D3 analogue, TEI-9647, is the first
synthetic ligand for the VDR that efficiently antagonizes the action of 1,25(OH)2D3, although the extent of its
antagonism depends on cell type.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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