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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alitretinoin
-
Cell Differentiation / drug effects
-
Dimerization
-
Histone Acetyltransferases / metabolism
-
Humans
-
Ligands*
-
Mutant Proteins / metabolism
-
Nuclear Receptor Coactivator 1
-
Nuclear Receptor Coactivator 2 / metabolism
-
Nuclear Receptor Coactivator 3
-
Protein Binding
-
Receptors, Calcitriol / metabolism*
-
Retinoid X Receptors / agonists
-
Retinoid X Receptors / metabolism*
-
Signal Transduction*
-
Trans-Activators / metabolism
-
Transcription Factors / metabolism
-
Transcriptional Activation
-
Tretinoin / pharmacology
-
Tumor Cells, Cultured
Substances
-
Ligands
-
Mutant Proteins
-
NCOA2 protein, human
-
Nuclear Receptor Coactivator 2
-
Receptors, Calcitriol
-
Retinoid X Receptors
-
Trans-Activators
-
Transcription Factors
-
Alitretinoin
-
Tretinoin
-
Histone Acetyltransferases
-
NCOA1 protein, human
-
NCOA3 protein, human
-
Nuclear Receptor Coactivator 1
-
Nuclear Receptor Coactivator 3