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Molecular Mechanism of the Vitamin D Antagonistic Actions of (23S)-25-Dehydro-1-Hydroxyvitamin D₃-26,23-Lactone Depends on the Primary Structure of the Carboxyl-Terminal Region of the Vitamin D Receptor

Teijin Institute for Bio-Medical Research (E.O., D.M., H.E., S.O., K.T., Y.A., T.K., S.I.), Hino, Tokyo 191-8512, Japan; and Department of Biochemistry (A.W.N.) and Division of Biomedical Sciences, University of California, Riverside, California 92521

Address all correspondence and requests for reprints to: Dr. Anthony W. Norman, Department of Biochemistry University of California Riverside, California 92521 E-mail: Anthony.Norman{at}ucr.edu.

We reported that (23S)-25-dehydro-1-hydroxyvitamin D₃-26,23-lactone (TEI-9647) antagonizes vitamin D receptor (VDR)-mediated genomic actions of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] in human cells but is agonistic in rodent cells. Human and rat VDR ligand-binding domains are similar, but differences in the C-terminal region are important for ligand binding and transactivation and might determine the agonistic/antagonistic effects of TEI-9647. We tested TEI-9647 on 1,25(OH)₂D₃ transactivation using SaOS-2 cells (human osteosarcoma) or ROS 24/1 cells (rat osteosarcoma) cotransfected with human or rodent VDR and a reporter. In both cell lines, TEI-9647 was antagonistic with wild-type human (h)VDR, but agonistic with overexpressed wild-type rat (r)VDR. VDR chimeras substituting the hVDR C-terminal region (activation function 2 domain) with corresponding rVDR residues diminished antagonism and increased agonism of TEI-9647. However, substitution of 25 C-terminal rVDR residues with corresponding hVDR residues diminished agonism and increased antagonism of TEI-9647. hVDR mutants (C403S, C410N) demonstrated that Cys403 and/or 410 was necessary for TEI-9647 antagonism of 1,25(OH)₂D₃ transactivation. These results suggest that species specificity of VDR, especially in the C-terminal region, determines the agonistic/antagonistic effects of TEI-9647 that determine, in part, VDR interactions with coactivators and emphasize the critical interaction between TEI-9647 and the two C-terminal hVDR Cys residues to mediate the antagonistic effect of TEI-9647.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR  |  RXRα

Coregulators:   SRC-1  |  GRIP1

Ligands:   Calcitriol

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