New understanding of the molecular mechanism of receptor-mediated genomic actions of the vitamin D hormone

The nuclear vitamin D receptor (VDR) binds the 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] hormone with high affinity and elicits its actions to regulate gene expression in target cells by binding to vitamin D-responsive elements (VDREs). VDREs in positively controlled genes such as osteocalcin, osteopontin, β₃-integrin, and vitamin D-24-OHase are direct hexanucleotide repeats with a spacer of three nucleotides. The VDR associates with these VDREs with the greatest affinity as a heterodimer with one of the family of retinoid X receptors (RXRs). VDR consists of an N-terminal zinc finger domain that determines DNA binding, a "hinge" segment and a C-terminal hormone binding domain which also contains two conserved regions that engage in heterodimerization with an RXR on the VDRE. The role of the 1,25(OH)₂D₃ ligand in transcriptional activation by the VDR-RXR heterodimer is to alter the conformation of the hormone-binding domain of VDR to facilitate strong dimerization with the VDRE. Thus RXR is recruited into a hetero-complex by liganded VDR. The natural ligand for the RXR coreceptor, 9-cis retinoic acid, suppresses both VDR-RXR binding to the VDRE and 1,25(OH)₂D₃-stimulated transcription, indicating that 9-cis retinoic acid diverts RXR away from being the silent partner of VDR to instead form RXR homodimers. Recent data reveal that after binding RXR, a subsequent target for VDR in the vitamin D signal transduction cascade is basal transcription factor IIB (TFIIB). VDR can be shown to bind directly to TFIIB, in vitro, and synergizes with it in transcriptional control by 1,25(OH)₂D₃ in transfected cells, thus unveiling a molecular mechanism whereby 1,25(OH)₂D₃ activates the transcription machine. Finally, natural mutations in hVDR that confer 1,25(OH)₂D₃ resistance in a number of patients have been characterized. The mutations fall into three categories: (i) DNA binding/nuclear localization; (ii) hormone binding; and (iii) RXR heterodimerization. These natural mutations are consistent with the structure/function analysis of hVDR via biochemical and molecular biological approaches and confirm the basic model of the receptor as a DNA-bound active heterodimer of liganded hVDR and unoccupied RXR.