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Gene Review

VDR  -  vitamin D (1,25- dihydroxyvitamin D3)...

Homo sapiens

Synonyms: 1,25-dihydroxyvitamin D3 receptor, NR1I1, Nuclear receptor subfamily 1 group I member 1, PPP1R163, Vitamin D3 receptor
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Disease relevance of VDR


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


Enzymatic interactions of VDR


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].


  1. Association of breast cancer progression with a vitamin D receptor gene polymorphism. South-East Sweden Breast Cancer Group. Lundin, A.C., Söderkvist, P., Eriksson, B., Bergman-Jungeström, M., Wingren, S. Cancer Res. (1999) [Pubmed]
  2. The p38 and JNK pathways cooperate to trans-activate vitamin D receptor via c-Jun/AP-1 and sensitize human breast cancer cells to vitamin D(3)-induced growth inhibition. Qi, X., Pramanik, R., Wang, J., Schultz, R.M., Maitra, R.K., Han, J., DeLuca, H.F., Chen, G. J. Biol. Chem. (2002) [Pubmed]
  3. Nuclear coactivator-62 kDa/Ski-interacting protein is a nuclear matrix-associated coactivator that may couple vitamin D receptor-mediated transcription and RNA splicing. Zhang, C., Dowd, D.R., Staal, A., Gu, C., Lian, J.B., van Wijnen, A.J., Stein, G.S., MacDonald, P.N. J. Biol. Chem. (2003) [Pubmed]
  4. Two hereditary defects related to vitamin D metabolism map to the same region of human chromosome 12q13-14. Labuda, M., Fujiwara, T.M., Ross, M.V., Morgan, K., Garcia-Heras, J., Ledbetter, D.H., Hughes, M.R., Glorieux, F.H. J. Bone Miner. Res. (1992) [Pubmed]
  5. Vitamin D receptor gene polymorphisms are associated with the risk of fractures in postmenopausal women, independently of bone mineral density. Garnero, P., Munoz, F., Borel, O., Sornay-Rendu, E., Delmas, P.D. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  6. Expression of a 1,25-dihydroxyvitamin D3 membrane-associated rapid-response steroid binding protein during human tooth and bone development and biomineralization. Mesbah, M., Nemere, I., Papagerakis, P., Nefussi, J.R., Orestes-Cardoso, S., Nessmann, C., Berdal, A. J. Bone Miner. Res. (2002) [Pubmed]
  7. Moderate physical activity is associated with higher bone mineral density in postmenopausal women. Hagberg, J.M., Zmuda, J.M., McCole, S.D., Rodgers, K.S., Ferrell, R.E., Wilund, K.R., Moore, G.E. Journal of the American Geriatrics Society. (2001) [Pubmed]
  8. Increased grooming behavior in mice lacking vitamin D receptors. Kalueff, A.V., Lou, Y.R., Laaksi, I., Tuohimaa, P. Physiol. Behav. (2004) [Pubmed]
  9. The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Kitagawa, H., Fujiki, R., Yoshimura, K., Mezaki, Y., Uematsu, Y., Matsui, D., Ogawa, S., Unno, K., Okubo, M., Tokita, A., Nakagawa, T., Ito, T., Ishimi, Y., Nagasawa, H., Matsumoto, T., Yanagisawa, J., Kato, S. Cell (2003) [Pubmed]
  10. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Pálmer, H.G., Larriba, M.J., García, J.M., Ordóñez-Morán, P., Peña, C., Peiró, S., Puig, I., Rodríguez, R., de la Fuente, R., Bernad, A., Pollán, M., Bonilla, F., Gamallo, C., de Herreros, A.G., Muñoz, A. Nat. Med. (2004) [Pubmed]
  11. Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Rachez, C., Lemon, B.D., Suldan, Z., Bromleigh, V., Gamble, M., Näär, A.M., Erdjument-Bromage, H., Tempst, P., Freedman, L.P. Nature (1999) [Pubmed]
  12. Androgen receptor signaling and vitamin D receptor action in prostate cancer cells. Murthy, S., Agoulnik, I.U., Weigel, N.L. Prostate (2005) [Pubmed]
  13. Functional role of VDR in the activation of p27Kip1 by the VDR/Sp1 complex. Cheng, H.T., Chen, J.Y., Huang, Y.C., Chang, H.C., Hung, W.C. J. Cell. Biochem. (2006) [Pubmed]
  14. Regulation of the human vitamin D3 receptor promoter in breast cancer cells is mediated through Sp1 sites. Wietzke, J.A., Ward, E.C., Schneider, J., Welsh, J. Mol. Cell. Endocrinol. (2005) [Pubmed]
  15. Phytoestrogen regulation of a Vitamin D3 receptor promoter and 1,25-dihydroxyvitamin D3 actions in human breast cancer cells. Wietzke, J.A., Welsh, J. J. Steroid Biochem. Mol. Biol. (2003) [Pubmed]
  16. Genetics of osteoporosis. Eisman, J.A. Endocr. Rev. (1999) [Pubmed]
  17. Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor alpha. Solomon, C., White, J.H., Kremer, R. J. Clin. Invest. (1999) [Pubmed]
  18. Human vitamin D receptor phosphorylation by casein kinase II at Ser-208 potentiates transcriptional activation. Jurutka, P.W., Hsieh, J.C., Nakajima, S., Haussler, C.A., Whitfield, G.K., Haussler, M.R. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  19. A two-hit mechanism for vitamin D3-mediated transcriptional repression of the granulocyte-macrophage colony-stimulating factor gene: vitamin D receptor competes for DNA binding with NFAT1 and stabilizes c-Jun. Towers, T.L., Staeva, T.P., Freedman, L.P. Mol. Cell. Biol. (1999) [Pubmed]
  20. 20-Epi analogues of 1,25-dihydroxyvitamin D3 are highly potent inducers of DRIP coactivator complex binding to the vitamin D3 receptor. Yang, W., Freedman, L.P. J. Biol. Chem. (1999) [Pubmed]
  21. Nuclear factor of activated T cells (NFAT) as a molecular target for 1alpha,25-dihydroxyvitamin D3-mediated effects. Takeuchi, A., Reddy, G.S., Kobayashi, T., Okano, T., Park, J., Sharma, S. J. Immunol. (1998) [Pubmed]
  22. An essential role of the CAAT/enhancer binding protein-alpha in the vitamin D-induced expression of the human steroid/bile acid-sulfotransferase (SULT2A1). Song, C.S., Echchgadda, I., Seo, Y.K., Oh, T., Kim, S., Kim, S.A., Cho, S., Shi, L., Chatterjee, B. Mol. Endocrinol. (2006) [Pubmed]
  23. Vitamin D3 receptor/Sp1 complex is required for the induction of p27Kip1 expression by vitamin D3. Huang, Y.C., Chen, J.Y., Hung, W.C. Oncogene (2004) [Pubmed]
  24. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Miyamoto, K., Kesterson, R.A., Yamamoto, H., Taketani, Y., Nishiwaki, E., Tatsumi, S., Inoue, Y., Morita, K., Takeda, E., Pike, J.W. Mol. Endocrinol. (1997) [Pubmed]
  25. The acute promyelocytic leukemia-associated protein, promyelocytic leukemia zinc finger, regulates 1,25-dihydroxyvitamin D(3)-induced monocytic differentiation of U937 cells through a physical interaction with vitamin D(3) receptor. Ward, J.O., McConnell, M.J., Carlile, G.W., Pandolfi, P.P., Licht, J.D., Freedman, L.P. Blood (2001) [Pubmed]
  26. Ternary complexes and cooperative interplay between NCoA-62/Ski-interacting protein and steroid receptor coactivators in vitamin D receptor-mediated transcription. Zhang, C., Baudino, T.A., Dowd, D.R., Tokumaru, H., Wang, W., MacDonald, P.N. J. Biol. Chem. (2001) [Pubmed]
  27. Cyclin D3 interacts with vitamin D receptor and regulates its transcription activity. Jian, Y., Yan, J., Wang, H., Chen, C., Sun, M., Jiang, J., Lu, J., Yang, Y., Gu, J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  28. Vitamin D receptor phosphorylation in transfected ROS 17/2.8 cells is localized to the N-terminal region of the hormone-binding domain. Jones, B.B., Jurutka, P.W., Haussler, C.A., Haussler, M.R., Whitfield, G.K. Mol. Endocrinol. (1991) [Pubmed]
  29. C-jun N-terminal kinase modulates 1,25-dihydroxyvitamin D3-induced cytochrome P450 3A4 gene expression. Yasunami, Y., Hara, H., Iwamura, T., Kataoka, T., Adachi, T. Drug Metab. Dispos. (2004) [Pubmed]
  30. Immunohistochemical analysis of 1,25-dihydroxyvitamin-D3-receptors, estrogen and progesterone receptors and Ki-67 in ovarian carcinoma. Villena-Heinsen, C., Meyberg, R., Axt-Fliedner, R., Reitnauer, K., Reichrath, J., Friedrich, M. Anticancer Res. (2002) [Pubmed]
  31. Nuclear receptor interactions in methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1). Chen, X., Maiti, S., Zhang, J., Chen, G. J. Biochem. Mol. Toxicol. (2006) [Pubmed]
  32. Vitamin D receptor and nuclear receptor coactivators: crucial interactions in vitamin D-mediated transcription. MacDonald, P.N., Baudino, T.A., Tokumaru, H., Dowd, D.R., Zhang, C. Steroids (2001) [Pubmed]
  33. Differential regulation of vitamin D receptor (VDR) by the p53 Family: p73-dependent induction of VDR upon DNA damage. Kommagani, R., Payal, V., Kadakia, M.P. J. Biol. Chem. (2007) [Pubmed]
  34. RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors. Bugge, T.H., Pohl, J., Lonnoy, O., Stunnenberg, H.G. EMBO J. (1992) [Pubmed]
  35. Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. Drocourt, L., Ourlin, J.C., Pascussi, J.M., Maurel, P., Vilarem, M.J. J. Biol. Chem. (2002) [Pubmed]
  36. Genetic control of bone density and turnover: role of the collagen 1alpha1, estrogen receptor, and vitamin D receptor genes. Brown, M.A., Haughton, M.A., Grant, S.F., Gunnell, A.S., Henderson, N.K., Eisman, J.A. J. Bone Miner. Res. (2001) [Pubmed]
  37. Overexpression of ER and VDR is not sufficient to make ER-negative MDA-MB231 breast cancer cells responsive to 1alpha-hydroxyvitamin D5. Peng, X., Jhaveri, P., Hussain-Hakimjee, E.A., Mehta, R.G. Carcinogenesis (2007) [Pubmed]
  38. The effects of vitamin D receptor polymorphism on secondary hyperparathyroidism and bone density after renal transplantation. Giannini, S., D'Angelo, A., Nobile, M., Carraro, G., Rigotti, P., Silva-Netto, F., Pavan, S., Marchini, F., Zaninotto, M., Dalle Carbonare, L., Sartori, L., Crepaldi, G. J. Bone Miner. Res. (2002) [Pubmed]
  39. Transcriptional synergism between the vitamin D3 receptor and other nonreceptor transcription factors. Liu, M., Freedman, L.P. Mol. Endocrinol. (1994) [Pubmed]
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