The retinoid X receptor ligand restores defective signalling by the vitamin D receptor.
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.
Sánchez-Martínez
Ruth
R
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Arturo Duperier 4, Madrid 28029, Spain.
Castillo
Ana I
AI
Steinmeyer
Andreas
A
Aranda
Ana
A
D000077556:Alitretinoin; D002454:Cell Differentiation / Q000187:drug effects; D019281:Dimerization; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D050505:Mutant Proteins / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D008024:Ligands; D050505:Mutant Proteins; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538866:NCOA3 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3