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, 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 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 RXR, which results in ligand-enhanced association with the VDRE. Thus RXR is recruited into a heterocomplex 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).(ABSTRACT TRUNCATED AT 250 WORDS)
Haussler
M R
MR
Department of Biochemistry, College of Medicine, University of Arizona, Tucson 85724, USA.
Jurutka
P W
PW
Hsieh
J C
JC
Thompson
P D
PD
Selznick
S H
SH
Haussler
C A
CA
Whitfield
G K
GK
D000818:Animals; D001483:Base Sequence; D002117:Calcitriol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002645:Chickens; D003577:Cytochrome P-450 Enzyme System; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D016023:Integrins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D015675:Osteocalcin / Q000235:genetics; D053495:Osteopontin; D051381:Rats; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D012795:Sialoglycoproteins / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D014212:Tretinoin / Q000378:metabolism; D014807:Vitamin D / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D065668:Vitamin D3 24-Hydroxylase
D016023:Integrins; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D014157:Transcription Factors; D015675:Osteocalcin; D053495:Osteopontin; D014807:Vitamin D; D014212:Tretinoin; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol