Disease relevance of VDR

• The vitamin D3 receptor gene (VDR) contains a TaqI RFLP that is associated with increased VDR mRNA stability, increased serum levels of 1alpha,25-dihydroxyvitamin D3 (1,25-D3), and decreased risk for prostate cancer [1].
• We conclude that polymorphism in the VDR gene may influence tumor progression and tamoxifen treatment response in early-onset breast carcinomas [1].
• Here we report that stress-activated protein kinases p38 and JNK trans-activate nuclear steroid vitamin D receptor (VDR) gene and increase vitamin D(3)-dependent growth inhibition in human breast cancer cells [2].
• Chromatin immunoprecipitation studies revealed that endogenous NCoA62/SKIP associated in a 1,25-dihydroxyvitamin D3-dependent manner with VDR target genes in ROS17/2.8 osteosarcoma cells [3].
• We have localized the locus for the vitamin D receptor (VDR) responsible for hypocalcemic vitamin D-resistant rickets (HVDRR), close to the pseudovitamin D-deficient rickets (PDDR) locus, another disorder related to impaired vitamin D metabolism [4].

Psychiatry related information on VDR

• VDR genotype groups did not differ for demographics, physical activity, grip strength, personal and maternal history of fracture, and calcium intake [5].
• Previously obtained data of the nuclear vitamin D receptor (VDR) expression and this study on 1,25D3-MARRS suggest the existence of cross-talk between the genomic and nongenomic pathways during human development [6].
• The groups were similar in terms of dietary habits (protein, calcium, sodium, phosphorus intake); VDR genotypes; and family, smoking, and nutritional histories [7].
• Since grooming is an important element of animal behavior, here we studied whether genetic ablation of vitamin D receptors (VDR) in mice may be associated with altered grooming behaviors [8].

High impact information on VDR

• Furthermore, overexpression of WSTF could restore the impaired recruitment of VDR to vitamin D regulated promoters in fibroblasts from Williams syndrome patients [9].
• In human colon cancers, elevated SNAIL expression correlates with downregulation of VDR [10].
• We show that the SNAIL transcription factor represses VDR gene expression in human colon cancer cells and blocks the antitumor action of EB1089, a 1,25(OH)(2)D(3) analog, in xenografted mice [10].
• Here we report the identities of thirteen DRIPs that constitute this complex, and show that the complex has a central function in hormone-dependent transactivation by VDR on chromatin templates [11].
• DRIPs bind to several nuclear receptors and mediate ligand-dependent enhancement of transcription by VDR and the thyroid-hormone receptor in cell-free transcription assays [11].

Chemical compound and disease context of VDR

• Therefore, most forms of androgen ablation should not eliminate the utility of VDR agonist treatment in most prostate cancers [12].
• In consistent with our previous results, we found that expression of wild-type VDR in SW620 colon cancer cells, which expressed very low level of endogenous VDR, increased vitamin D3-stimulated p27Kip1 promoter activity and protein expression [13].
• In summary, these studies demonstrate transcriptional regulation of the exon 1c VDR promoter in breast cancer cells, and identify three distinct GC-rich, Sp1 consensus sites that differentially confer responsiveness to estrogen, resveratrol and 1,25(OH)(2)D(3) [14].
• We transiently transfected a VDR promoter luciferase construct into the estrogen receptor (ER) positive human breast cancer cell lines T47D and MCF-7, and treated with 0.4-4 microM resveratrol or 5-500 nM genistein [15].
• In transient transfection assays, luciferase reporter constructs containing -800 to +31 of the VDR gene exhibit basal promoter activity in T47D breast cancer cells which is enhanced by 1,25(OH)(2)D(3), estrogen and the phytoestrogen resveratrol [14].

Biological context of VDR

• Interactions between genetic and environmental factors, including lifestyle, have been investigated initially for the VDR polymorphisms in relation to the response of bone density and turnover to calcium intake and treatment with simple vitamin D and active vitamin D compounds [16].
• Common allelic variation in the VDR was the first of several genes and now chromosomal loci to be implicated in the genetic determination of bone phenotype [16].
• Irrespective of the strength or mechanism of these associations, these initial findings on the VDR stimulated the field of the genetics of osteoporosis with targeted genetic studies and now genome scan approaches [16].
• Signaling through the VDR is essential for normal calcium homeostasis and has been shown to inhibit the proliferation of cancer cells derived from a number of tissues [17].
• Therefore, phosphorylation of hVDR by CK-11 at Ser-208 specifically modulates its transcriptional capacity, suggesting that this covalent modification alters the conformation of VDR to potentiate its interaction with the machinery for DNA transcription [18].

Anatomical context of VDR

• We previously described a control element in the granulocyte-macrophage colony-stimulating factor (GM-CSF) enhancer that is necessary and sufficient to mediate both transcriptional activation in response to T-cell stimuli and transcriptional repression by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] through the vitamin D3 receptor (VDR) [19].
• Here, we tested whether the potency of one class of compounds, 20-epi analogues, to induce myeloid cell differentiation, is because of direct molecular effects on vitamin D receptor (VDR) [20].
• Compared with the interaction of VDR with RXR or GRIP-1, the differentiation dose-response most closely correlated to the ligand-dependent recruitment of the DRIP coactivator complex to VDR and to the ability of the receptor to activate transcription in a cell-free system [20].
• Transient expression of both VDR and RXR alpha, but not of a single component, was capable of inhibiting expression of a NFAT-driven reporter gene in stimulated jurkat cells in a ligand-dependent manner [21].
• Taken together, these data show that NCoA62/SKIP has properties that are consistent with those of nuclear receptor coactivators and with RNA spliceosome components, thus suggesting a potential role for NCoA62/SKIP in coupling VDR-mediated transcription to RNA splicing [3].

Associations of VDR with chemical compounds

• This DNA element is a composite site that is recognized by both Fos-Jun and NFAT1; it is directly bound by VDR in the absence of a retinoid X receptor as an apparent monomer, and it is bound in a unique tertiary conformation [19].
• These results establish a signaling connection between the stress MAPK pathways and steroid hormone receptor VDR expression and thereby offer new insights into regulation of cell growth by the MAPK pathways through regulation of vitamin D(3)/VDR activity [2].
• VDR and C/EBP-alpha associated endogenously as a DNA-dependent, coimmunoprecipitable complex, which was detected at a markedly higher level in 1,25-(OH)2D3-treated cells [22].
• Collectively, our results suggest that VDR is involved in the induction of p27Kip1 by vitamin D3 and may interact with Sp1 to modulate the expression of target genes that lack VDR response element (VDRE) in their promoters [23].
• An intron fragment 3' of exon 1C conferred retinoic acid responsivity when fused to a reporter gene plasmid, suggesting a molecular mechanism for the previously observed ability of retinoic acid to induce the VDR [24].

Physical interactions of VDR

• It was found that PLZF interacts directly with VDR [25].
• Vitamin D3 receptor/Sp1 complex is required for the induction of p27Kip1 expression by vitamin D3 [23].
• The liganded VDR also formed a ternary complex with NCoA-62/SKIP and SRC proteins in vitro [26].
• The steroid receptor coactivator (SRC) proteins are coactivators that interact with the AF-2 domain of VDR to augment 1,25-dihydroxyvitamin D3-dependent transcription [26].
• Cyclin D3 interacted with VDR in a ligand-independent manner, but treatment of the ligand, 1,25-dihydroxyvitamin D3, strengthened the interaction [27].

Enzymatic interactions of VDR

• The human 1,25-dihydroxyvitamin D3 receptor (hVDR) has been recently shown to be phosphorylated in vitro by casein kinase-II [28].

Regulatory relationships of VDR

• Recently, it was demonstrated that the vitamin D receptor (VDR) regulates 1,25(OH)(2)D(3)-induced CYP3A4 gene expression through the xenobiotic-responsive element and the vitamin D-responsive element located on the 5'-flanking region of the CYP3A4 gene [29].
• (III) Expression of VDR in ovarian carcinomas is independently regulated from the expression of ER and PR [30].
• Human vitamin D receptor (hVDR) also upregulated hSULT2A1 gene expression while human pregnane X receptor (hPXR) downregulated it [31].
• Moreover, stimulation of the endogenous stress pathways by adenovirus-mediated delivery of recombinant MAPK kinase 6 also activates VDR and sensitizes MCF-7 cells to vitamin D(3)-dependent growth inhibition [2].
• The purpose of this paper is to briefly review salient features of the coactivators involved in VDR-activated transcription and to focus on our current understanding of NCoA-62 and its interplay with other nuclear receptor coactivator proteins [32].
• Our results indicate that VDR is regulated by p63 and p73 and that the induction of VDR expression upon DNA damage is p73-dependent [33].

Other interactions of VDR

• The identification of RXR alpha as a dimerization partner for the RARs, T3Rs and VD3R has important implications as to the function of these receptors and their ligands in development, homeostasis and neoplasia [34].
• Moreover, PLZF altered the mobility of VDR derived from nuclear extracts when bound to its cognate binding site, forming a slowly migrating DNA-protein complex [25].
• The mechanism through which NCoA62/SKIP functions in VDR-activated transcription is unknown [3].
• In conclusion, this work suggests that VDR, PXR, and CAR control the basal and inducible expression of several CYP genes through competitive interaction with the same battery of responsive elements [35].
• We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals [36].
• Nuclear receptor cofactors NCoR1 and SRC1 that could potentially affect VDR action were also low in both MDA-MB231 and S30 cells in comparison with ER-positive, vitamin D-sensitive BT474 cells [37].

Analytical, diagnostic and therapeutic context of VDR

• The VDR polymorphisms have an effect weaker than originally reported, and part of the allelic effects may be mediated by effects on body size and development and even other hormonal regulators such as PTH or insulin [16].
• VDR alleles were typed by a polymerase chain reaction (PCR) assay based on a polymorphic BsmI restriction site [38].
• The functional basis for the transcriptional synergism appears to be at the level of cooperative DNA binding, at least for VDR alone and VDR-Oct-1, as demonstrated in vitro by gel mobility shift assays using purified factors [39].
• We can conclude that the VDR genotype polymorphism affects bone density of renal transplant recipients via its effects on the severity of SHPT [38].
• Here we report on the assignment of VDR to 12q13-14 by in situ hybridization and by linkage analysis [4].

References