The retinoid X receptor ligand restores defective signalling by the vitamin D receptor
Open Access
- 25 August 2006
- journal article
- Published by Springer Nature in EMBO Reports
- Vol. 7 (10) , 1030-1034
- https://doi.org/10.1038/sj.embor.7400776
Abstract
It is assumed that the retinoid X receptor (RXR) acts as a silent partner to the vitamin D receptor (VDR) with its only function to increase affinity of VDR/RXR to its DNA recognition site. In this study, we show that the RXR ligand 9‐cis‐retinoic acid (9‐cis‐RA) induces recruitment of coactivators by the DNA‐bound heterodimer and potentiates vitamin D‐dependent transcriptional responses. The presence of 9‐cis‐RA increases induction of cyp24 transcripts and differentiation of colon cancer cells by vitamin D, confers significant agonistic activity to a VDR ligand with very low agonistic activity and can even restore transcriptional activity of an AF‐2 mutant VDR that causes hereditary rickets. This study shows that, in VDR/RXR heterodimers, allosteric communication triggered by the RXR ligand has a previously unrecognized role in vitamin D signalling, with important physiological and therapeutic implications.Keywords
This publication has 14 references indexed in Scilit:
- Molecular Mechanism of the Vitamin D Antagonistic Actions of (23S)-25-Dehydro-1α-Hydroxyvitamin D3-26,23-Lactone Depends on the Primary Structure of the Carboxyl-Terminal Region of the Vitamin D ReceptorMolecular Endocrinology, 2005
- Crystal Structures of the Vitamin D Nuclear Receptor Liganded with the Vitamin D Side Chain Analogues Calcipotriol and Seocalcitol, Receptor Agonists of Clinical Importance. Insights into a Structural Basis for the Switching of Calcipotriol to a Receptor Antagonist by Further Side Chain ModificationJournal of Medicinal Chemistry, 2004
- Molecular Structure of the Rat Vitamin D Receptor Ligand Binding Domain Complexed with 2-Carbon-Substituted Vitamin D3 Hormone Analogues and a LXXLL-Containing Coactivator Peptide,Biochemistry, 2004
- Structural Determinants of Allosteric Ligand Activation in RXR HeterodimersCell, 2004
- Retinoid X Receptor Is a Nonsilent Major Contributor to Vitamin D Receptor-Mediated Transcriptional ActivationMolecular Endocrinology, 2003
- A Novel Mutation in Helix 12 of the Vitamin D Receptor Impairs Coactivator Interaction and Causes Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets without AlopeciaMolecular Endocrinology, 2002
- Co-regulator recruitment and the mechanism of retinoic acid receptor synergyNature, 2002
- Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signalingThe Journal of cell biology, 2001
- Nuclear Hormone Receptors and Gene ExpressionPhysiological Reviews, 2001
- Antagonistic Action of a 25-Carboxylic Ester Analogue of 1α,25-Dihydroxyvitamin D3 Is Mediated by a Lack of Ligand-induced Vitamin D Receptor Interaction with CoactivatorsPublished by Elsevier ,2000