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

M. R. Haussler, P. W. Jurutka, J. C. Hsieh, P. D. Thompson, S. H. Selznick, C. A. Haussler, G. K. Whitfield

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)S33-S38
JournalBone
Volume17
Issue number2 SUPPL. 1
DOIs
StatePublished - Aug 1995

Keywords

  • 1,25-Dihydroxyvitamin D
  • Hereditary hypocalcemic vitamin D-resistant rickets
  • Retinoid X receptors
  • Transcriptional control
  • Vitamin D receptor
  • Vitamin D-responsive element

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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