scholarly journals Antagonistic Action of a 25-Carboxylic Ester Analogue of 1α,25-Dihydroxyvitamin D3Is Mediated by a Lack of Ligand-induced Vitamin D Receptor Interaction with Coactivators

2000 ◽  
Vol 275 (22) ◽  
pp. 16506-16512 ◽  
Author(s):  
Michaela Herdick ◽  
Andreas Steinmeyer ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Receptor Interaction ◽  
Antagonistic Action ◽  
Carboxylic Ester

scholarly journals Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1α,25-Dihydroxyvitamin D3Analogue toward Vitamin D Receptor Function

1999 ◽  
Vol 274 (45) ◽  
pp. 32376-32381 ◽  
Author(s):  
Keiichi Ozono ◽  
Mariko Saito ◽  
Daishiro Miura ◽  
Toshimi Michigami ◽  
Shigeo Nakajima ◽  
...  
Keyword(s):  
Vitamin D ◽  
Molecular Mechanism ◽  
Vitamin D Receptor ◽  
Receptor Function ◽  
Antagonistic Action

scholarly journals Repression of basal transcription by vitamin D receptor: evidence for interaction of unliganded vitamin D receptor with two receptor interaction domains in RIP13delta1

1998 ◽  
Vol 20 (3) ◽  
pp. 327-335 ◽  
Author(s):  
PP Dwivedi ◽  
GE Muscat ◽  
PJ Bailey ◽  
JL Omdahl ◽  
BK May
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Target Genes ◽  
Dominant Negative ◽  
Receptor Interaction ◽  
Kidney Cells ◽  
Basal Transcription ◽  
Dihydroxyvitamin D3 ◽  
Promoter Construct ◽  
Interaction Domains

Repression of basal transcription of a 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) responsive 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter construct as observed in kidney cells in the absence of ligand and this repression was dependent on a functional vitamin D response element (VDRE). Basal repression was also seen with a construct where a consensus DR-3-type VDRE was fused to the thymidine kinase promoter. Expression of a dominant negative vitamin D receptor (VDR) isoform that strongly bound to the VDRE motif in the CYP24 promoter ablated basal repression. This VDR isoform lacked sequence in the hinge- and ligand-binding domains implicating one or both of these domains in basal repression. It is well known that thyroid hormone and retinoic acid receptors silence basal transcription of target genes in the absence of ligands and this repressor function can be mediated by the nuclear receptor corepressor N-CoR. Two variants of N-CoR have been described, RIP13a and RIP13delta1. N-CoR and the variants contain two receptor interaction domains, ID-I and ID-II, which are identical except region ID-II in RIP13delta1 has an internal deletion. We have used the mammalian two hybrid system to investigate whether VDR, in the absence of ligand 1,25-(OH)2D3, can interact with these domains. The data showed that unliganded VDR does not interact with either ID-I or ID-II from RIP13a and RIP13delta1, but does interact strongly with a composite domain of ID-I and ID-II from RIP13delta1 (but not from RIP13a) and this strong interaction is abrogated in the presence of ligand. This finding implicates RIP13delta1 in VDR-dependent basal repression of the promoter constructs under investigation. However, over-expression of RIP13delta1 in kidney cell lines did not alter basal expression of the CYP24 promoter construct. It is concluded that either the level of endogenous RIP13delta1 in these kidney cells permits maximal repression or that repression occurs by a mechanism that is independent of RIP13delta1. Alternatively, repression may be dependent on RIP13delta1 but requires an additional cofactor that is limiting in these cells.

Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone

2010 ◽  
Vol 66 (8) ◽  
pp. 918-926 ◽  
Author(s):  
Shinji Kakuda ◽  
Seiichi Ishizuka ◽  
Hiroshi Eguchi ◽  
Mathew T. Mizwicki ◽  
Anthony W. Norman ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Conformational Changes ◽  
Structural Basis ◽  
Antagonist Activity ◽  
Hydrogen Bond Interaction ◽  
Antagonistic Action ◽  
Covalent Adduct ◽  
Sh Group ◽  
Agonistic Activity

TEI-9647 antagonizes vitamin D receptor (VDR) mediated genomic actions of 1α,25(OH)2D3in human cells but is agonistic in rodent cells. The presence of Cys403, Cys410 or of both residues in the C-terminal region of human VDR (hVDR) results in antagonistic action of this compound. In the complexes of TEI-9647 with wild-type hVDR (hVDRwt) and H397F hVDR, TEI-9647 functions as an antagonist and forms a covalent adduct with hVDR according to MALDI–TOF MS. The crystal structures of complexes of TEI-9647 with rat VDR (rVDR), H305F hVDR and H305F/H397F hVDR showed that the agonistic activity of TEI-9647 is caused by a hydrogen-bond interaction with His397 or Phe397 located in helix 11. Both biological activity assays and the crystal structure of H305F hVDR complexed with TEI-9647 showed that the interaction between His305 and TEI-9647 is crucial for antagonist activity. This study indicates the following stepwise mechanism for TEI-9647 antagonism. Firstly, TEI-9647 forms hydrogen bonds to His305, which promote conformational changes in hVDR and draw Cys403 or Cys410 towards the ligand. This is followed by the formation of a 1,4-Michael addition adduct between the thiol (–SH) group of Cys403 or Cys410 and theexo-methylene group of TEI-9647.

Association of vitamin D receptor genotypes with early onset rheumatoid arthritis

2001 ◽  
Vol 28 (1) ◽  
pp. 89-93 ◽  
Author(s):  
J. R. Garcia-Lozano ◽  
M. F. Gonzalez-Escribano ◽  
A. Valenzuela ◽  
A. Garcia ◽  
A. Nunez-Roldan
Keyword(s):  
Rheumatoid Arthritis ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Early Onset

803: Interactions Between Ultraviolet Radiation and Polymorphisms in the Vitamin D Receptor Gene Mediate Prostate Cancer Susceptibility

2006 ◽  
Vol 175 (4S) ◽  
pp. 260-260
Author(s):  
Nicholas J. Rukin ◽  
Samuel J. Moon ◽  
Dhaval Bodiwala ◽  
Christopher J. Luscombe ◽  
Mark F. Saxby ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Ultraviolet Radiation ◽  
Vitamin D Receptor ◽  
Cancer Susceptibility ◽  
Receptor Gene ◽  
Vitamin D Receptor Gene ◽  
Prostate Cancer Susceptibility
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