![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 57, Issue 6, 1206-1217, June 2000
Institut für Physiologische Chemie I and Biomedizinisches
Forschungszentrum, Heinrich-Heine-Universität, Düsseldorf,
Germany (M.H., Y.B., M.Q., P.P., C.C.); and Hoffmann-La Roche Inc.,
Nutley, New Jersey (M.R.U.)
The vitamin D receptor (VDR) is the nuclear receptor for
1,25-dihydroxyvitamin D3
[1
,25(OH)2D3] that acts as a
ligand-dependent transcription factor via combined contact with
coactivator proteins (steroid receptor coactivator-1, transcriptional
intermediary factor 2, and receptor associated coactivator 3) and
specific DNA binding sites [vitamin D response elements (VDREs)].
Ligand-mediated conformational changes of the VDR contribute to the key
mechanisms in this nuclear hormone signaling process.
1,25(OH)2D3, MC1288 [20-epi-1,25(OH)2D3], ZK161422
[20-methyl-1,25(OH)2D3], and Ro27-2310
(also called Gemini, having two side chains at carbon 20) were used as
model VDR agonists. The analysis of agonist-induced VDR conformations
and coactivator interactions were found to be insufficient for
extrapolating in vivo activities. In DNA-independent assays, such as
classical limited protease digestions and glutathione S-transferase pull downs, Gemini seemed to be up to
10,000-fold and the other VDR agonists 10- to 100-fold weaker than in
functional in vivo assays. A more accurate description of the gene
regulatory potential of VDR agonists was obtained with all tested VDR
agonists by analyzing VDR conformations in the context of VDRE-bound
VDR-retinoid X receptor heterodimers, in such assays as gel supershift,
gel shift clipping, and limited protease digestion in the presence of
DNA and cofactor. Coactivators were found to shift the ligand sensitivity (by a factor of 4 for Gemini) and the ratio of VDR conformations in the presence of DNA toward the high-affinity ligand
binding conformation (c1LPD). In conclusion, the induction of response element- and coactivator-modulated VDR conformations appears to be a key step for the gene regulatory function of a VDR
agonist. The quantification of these effects would be of central importance for the evaluation of the cell-specific efficacy of systemically applied 1,25(OH)2D3 analogs.
This article has been cited by other articles:
|
|
 |
|
  J. Nevado, S. P Tenbaum, A. I. Castillo, A. Sanchez-Pacheco, and A. Aranda Activation of the human immunodeficiency virus type I long terminal repeat by 1{alpha},25-dihydroxyvitamin D3 J. Mol. Endocrinol., June 1, 2007; 38(6): 587 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. I. Castillo, R. Sanchez-Martinez, A. M. Jimenez-Lara, A. Steinmeyer, U. Zugel, and A. Aranda Characterization of Vitamin D Receptor Ligands with Cell-Specific and Dissociated Activity Mol. Endocrinol., December 1, 2006; 20(12): 3093 - 3104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Molnar, M. Perakyla, and C. Carlberg Vitamin D Receptor Agonists Specifically Modulate the Volume of the Ligand-binding Pocket J. Biol. Chem., April 14, 2006; 281(15): 10516 - 10526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Perakyla, M. Malinen, K.-H. Herzig, and C. Carlberg Gene Regulatory Potential of Nonsteroidal Vitamin D Receptor Ligands Mol. Endocrinol., August 1, 2005; 19(8): 2060 - 2073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Molnar, M. Matilainen, and C. Carlberg Structural Determinants of the Agonist-independent Association of Human Peroxisome Proliferator-activated Receptors with Coactivators J. Biol. Chem., July 15, 2005; 280(28): 26543 - 26556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Masuyama, N. Suwaki, Y. Tateishi, H. Nakatsukasa, T. Segawa, and Y. Hiramatsu The Pregnane X Receptor Regulates Gene Expression in a Ligand- and Promoter- Selective Fashion Mol. Endocrinol., May 1, 2005; 19(5): 1170 - 1180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ochiai, D. Miura, H. Eguchi, S. Ohara, K. Takenouchi, Y. Azuma, T. Kamimura, A. W. Norman, and S. Ishizuka Molecular Mechanism of the Vitamin D Antagonistic Actions of (23S)-25-Dehydro-1{alpha}-Hydroxyvitamin D3-26,23-Lactone Depends on the Primary Structure of the Carboxyl-Terminal Region of the Vitamin D Receptor Mol. Endocrinol., May 1, 2005; 19(5): 1147 - 1157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Frank, F. Molnar, M. Matilainen, H. Lempiainen, and C. Carlberg Agonist-dependent and Agonist-independent Transactivations of the Human Constitutive Androstane Receptor Are Modulated by Specific Amino Acid Pairs J. Biol. Chem., August 6, 2004; 279(32): 33558 - 33566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Wang, J. A. Blackford Jr., L.-N. Song, Y. Huang, S. Cho, and S. S. Simons Jr. Equilibrium Interactions of Corepressors and Coactivators with Agonist and Antagonist Complexes of Glucocorticoid Receptors Mol. Endocrinol., June 1, 2004; 18(6): 1376 - 1395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Frank, M. M. Gonzalez, C. Oinonen, T. W. Dunlop, and C. Carlberg Characterization of DNA Complexes Formed by the Nuclear Receptor Constitutive Androstane Receptor J. Biol. Chem., October 31, 2003; 278(44): 43299 - 43310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Gonzalez, P. Samenfeld, M. Perakyla, and C. Carlberg Corepressor Excess Shifts the Two-Side Chain Vitamin D Analog Gemini from an Agonist to an Inverse Agonist of the Vitamin D Receptor Mol. Endocrinol., October 1, 2003; 17(10): 2028 - 2038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yamamoto, N. K. Shevde, A. Warrier, L. A. Plum, H. F. DeLuca, and J. W. Pike 2-Methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 Potently Stimulates Gene-specific DNA Binding of the Vitamin D Receptor in Osteoblasts J. Biol. Chem., August 22, 2003; 278(34): 31756 - 31765. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Vaisanen, M. Perakyla, J. I. Karkkainen, M. R. Uskokovic, and C. Carlberg Structural Evaluation of the Agonistic Action of a Vitamin D Analog with Two Side Chains Binding to the Nuclear Vitamin D Receptor Mol. Pharmacol., June 1, 2003; 63(6): 1230 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Andersin, S. Vaisanen, and C. Carlberg The Critical Role of Carboxy-Terminal Amino Acids in Ligand-Dependent and -Independent Transactivation of the Constitutive Androstane Receptor Mol. Endocrinol., February 1, 2003; 17(2): 234 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vaisanen, S. Ryhanen, J. T. A. Saarela, M. Perakyla, T. Andersin, and P. H. Maenpaa Structurally and Functionally Important Amino Acids of the Agonistic Conformation of the Human Vitamin D Receptor Mol. Pharmacol., October 1, 2002; 62(4): 788 - 794. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Gonzalez and C. Carlberg Cross-repression, a Functional Consequence of the Physical Interaction of Non-liganded Nuclear Receptors and POU Domain Transcription Factors J. Biol. Chem., May 17, 2002; 277(21): 18501 - 18509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Toell, M. M. Gonzalez, D. Ruf, A. Steinmeyer, S. Ishizuka, and C. Carlberg Different Molecular Mechanisms of Vitamin D3 Receptor Antagonists Mol. Pharmacol., June 1, 2001; 59(6): 1478 - 1485. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Bury, A. Steinmeyer, and C. Carlberg Structure Activity Relationship of Carboxylic Ester Antagonists of the Vitamin D3 Receptor Mol. Pharmacol., November 1, 2000; 58(5): 1067 - 1074. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
