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 D -3 [1,25(OH)(2)D-3] hormone with high affinity and elicits its actions to regulate gene expression in target cells by binding to vitamin D-r esponsive elements (VDREs), VDREs in positively controlled genes such as osteocalcin, osteopontin, beta(3)-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 he terodimer with one of the family of retinoid X receptors (RXRs), VDR c onsists of an N-terminal zinc finger domain that determines DNA bindin g, a ''hinge'' segment and a C-terminal hormone binding domain which a lso contains two conserved regions that engage in heterodimerization w ith an RXR on the VDRE, The role of the 1,25(OH)(2)D-3 ligand in trans criptional activation by the VDR-RXR heterodimer is to alter the confo rmation of the hormone-binding domain of VDR to facilitate strong dime rization with RXR, which results in ligand-enhanced association with t he VDRE, Thus RXR is recruited into a heterocomplex by liganded VDR, T he natural ligand for the RXR coreceptor, 9-cis retinoic acid, suppres ses both VDR-RXR binding to the VDRE and 1,25(OH)(2)D-3-stimulated tra nscription, 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 th e 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)(2)D-3 in tr ansfected cells, thus unveiling a molecular mechanism whereby 1,25(OH) (2)D-3 activates the transcription machine, Finally, natural mutations in hVDR that confer 1,25(OH)(2)D-3 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) RX R heterodimerization, These natural mutations are consistent with the structure/function analysis of hVDR via biochemical and molecular biol ogical approaches and confirm the basic model of the receptor as a DNA -bound active heterodimer of liganded hVDR and unoccupied RXR.