vitamin D receptor

The VDR gene encodes the nuclear hormone receptor for vitamin D. The most potent natural agonist is calcitriol ({{chem name|1,25-dihydroxycholecalciferol}}) and the vitamin D₂ homologue ercalcitriol, {{chem name|1-alpha,25-dihydroergocalciferol}}) is also a strong activator. Other forms of vitamin D bind with lower affinity, as does the secondary bile acid lithocholic acid. The receptor belongs to the family of trans-acting transcriptional regulatory factors and shows similarity of sequence to the steroid and thyroid hormone receptors.{{cite journal | vauthors = Germain P, Staels B, Dacquet C, Spedding M, Laudet V | title = Overview of nomenclature of nuclear receptors | journal = Pharmacol. Rev. | volume = 58 | issue = 4 | pages = 685–704 | date = December 2006 | pmid = 17132848 | doi = 10.1124/pr.58.4.2 | s2cid = 1190488 }}

Downstream targets of this nuclear hormone receptor include many genes involved in mineral metabolism. The receptor regulates a variety of other metabolic pathways, such as those involved in the immune response and cancer.

VDR variants that bolster vitamin-D action and that are directly correlated with AIDS progression rates and VDR association with progression to AIDS follows an additive model.{{cite journal | vauthors = Laplana M, Sánchez-de-la-Torre M, Puig T, Caruz A, Fibla J | title = Vitamin-D pathway genes and HIV-1 disease progression in injection drug users | journal = Gene | volume = 545 | issue = 1 | pages = 163–9 | date = July 2014 | pmid = 24768180 | doi = 10.1016/j.gene.2014.04.035 | hdl = 10459.1/67999 | hdl-access = free }} FokI polymorphism is a risk factor for enveloped virus infection as revealed in a meta-analysis.{{cite journal | vauthors = Laplana M, Royo L, Fibla J | title = Vitamin D Receptor polymorphisms and risk of enveloped virus infection: A meta-analysis | journal = Gene | volume = 678 | issue = | pages = 384–94 | date = December 2018 | pmid = 30092343 | doi = 10.1016/j.gene.2018.08.017 | hdl = 10459.1/68000 | s2cid = 51955566 | hdl-access = free }}

The importance of this gene has also been noted in the natural aging process were 3’UTR haplotypes of the gene showed an association with longevity.{{cite journal | vauthors = Laplana M, Sánchez-de-la-Torre M, Aguiló A, Casado I, Flores M, Sánchez-Pellicer R, Fibla J | title = Tagging long-lived individuals through vitamin-D receptor (VDR) haplotypes | journal = Biogerontology | volume = 11 | issue = 4| pages = 437–46 | date = April 2010 | pmid = 20407924 | doi = 10.1007/s10522-010-9273-8 | hdl = 10459.1/67920 | s2cid = 34809120 | hdl-access = free }}

Mutations in this gene are associated with type II vitamin D-resistant rickets. A single nucleotide polymorphism in the initiation codon results in an alternate translation start site three codons downstream. Alternative splicing results in multiple transcript variants encoding the same protein.{{cite web | title = Entrez Gene: VDR vitamin D (1,25- dihydroxyvitamin D3) receptor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7421}} VDR gene variants seem to influence many biological endpoints, including those related to osteoporosis {{cite journal | vauthors = Abouzid M, Karazniewicz-Lada M, Glowka F | title = Genetic Determinants of Vitamin D-Related Disorders; Focus on Vitamin D Receptor | journal = Current Drug Metabolism | volume = 19 | issue = 12 | pages = 1042–1052 | date = 2018-10-19 | pmid = 30039758 | doi = 10.2174/1389200219666180723143552 | s2cid = 51710351 }}

The vitamin D receptor plays an important role in regulating the hair cycle. Loss of VDR is associated with hair loss in experimental animals.{{cite journal | vauthors = Luderer HF, Demay MB | title = The vitamin D receptor, the skin and stem cells | journal = J. Steroid Biochem. Mol. Biol. | volume = 121 | issue = 1–2 | pages = 314–6 | date = July 2010 | pmid = 20138991 | doi = 10.1016/j.jsbmb.2010.01.015 | s2cid = 23876206 }} Experimental studies have shown that the unliganded VDR interacts with regulatory regions in cWnt (wnt signaling pathway) and sonic hedgehog target genes and is required for the induction of these pathways during the postnatal hair cycle.{{cite journal | vauthors = Lisse TS, Saini V, Zhao H, Luderer HF, Gori F, Demay MB | title = The Vitamin D Receptor Is Required for Activation of cWnt and Hedgehog Signaling in Keratinocytes | journal = Mol. Endocrinol. | volume = 28 | issue = 10 | pages = 1698–1706 | date = September 2014 | pmid = 25180455 | doi = 10.1210/me.2014-1043 | pmc=4179637}} These studies have revealed novel actions of the unliganded VDR in regulating the post-morphogenic hair cycle.

Researchers have focused their efforts in elucidating the role of VDR polymorphisms in different diseases and normal phenotypes such as the HIV-1 infection susceptibility and progression or the natural aging process. The most remarkable findings include the report of VDR variants that bolster vitamin-D action and that are directly correlated with AIDS progression rates, that VDR association with progression to AIDS follows an additive model and the role of FokI polymorphism as a risk factor for enveloped virus infection as revealed in a meta-analysis.

Vitamin D receptor has been shown to interact with many other factors which will affect transcription activation:

{{div col|colwidth=20em}}

• BAG1,{{cite journal | vauthors = Guzey M, Takayama S, Reed JC | title = BAG1L enhances trans-activation function of the vitamin D receptor | journal = J. Biol. Chem. | volume = 275 | issue = 52 | pages = 40749–56 | date = December 2000 | pmid = 10967105 | doi = 10.1074/jbc.M004977200 | doi-access = free }}
• CAV3,{{cite journal | vauthors = Zhao G, Simpson RU | title = Membrane Localization, Caveolin-3 Association and Rapid Actions of Vitamin D Receptor in Cardiac Myocytes | journal = Steroids | volume = 75 | issue = 8–9 | pages = 555–9 | year = 2010 | pmid = 20015453 | pmc = 2885558 | doi = 10.1016/j.steroids.2009.12.001 }}
• MED12,{{cite journal | vauthors = Ito M, Yuan CX, Malik S, Gu W, Fondell JD, Yamamura S, Fu ZY, Zhang X, Qin J, Roeder RG | title = Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators | journal = Mol. Cell | volume = 3 | issue = 3 | pages = 361–70 | date = March 1999 | pmid = 10198638 | doi = 10.1016/S1097-2765(00)80463-3 | doi-access = free }}
• MED24,
• NCOR1,{{cite journal | vauthors = Tagami T, Lutz WH, Kumar R, Jameson JL | title = The interaction of the vitamin D receptor with nuclear receptor corepressors and coactivators | journal = Biochem. Biophys. Res. Commun. | volume = 253 | issue = 2 | pages = 358–63 | date = December 1998 | pmid = 9878542 | doi = 10.1006/bbrc.1998.9799 }}
• NCOR2,
• NCOA2{{cite journal | vauthors = Herdick M, Steinmeyer A, Carlberg C | title = Antagonistic action of a 25-carboxylic ester analogue of 1alpha, 25-dihydroxyvitamin D3 is mediated by a lack of ligand-induced vitamin D receptor interaction with coactivators | journal = J. Biol. Chem. | volume = 275 | issue = 22 | pages = 16506–12 | date = June 2000 | pmid = 10748178 | doi = 10.1074/jbc.M910000199 | doi-access = free }}{{cite journal | vauthors = He B, Wilson EM | title = Electrostatic Modulation in Steroid Receptor Recruitment of LXXLL and FXXLF Motifs | journal = Mol. Cell. Biol. | volume = 23 | issue = 6 | pages = 2135–50 | date = March 2003 | pmid = 12612084 | pmc = 149467 | doi = 10.1128/MCB.23.6.2135-2150.2003 }}
• RXRA,
• RUNX1,
• RUNX1T1,
• SNW1,{{cite journal | vauthors = Zhang C, Baudino TA, Dowd DR, Tokumaru H, Wang W, MacDonald PN | title = Ternary complexes and cooperative interplay between NCoA-62/Ski-interacting protein and steroid receptor coactivators in vitamin D receptor-mediated transcription | journal = J. Biol. Chem. | volume = 276 | issue = 44 | pages = 40614–20 | date = November 2001 | pmid = 11514567 | doi = 10.1074/jbc.M106263200 | doi-access = free}}{{cite journal | vauthors = Baudino TA, Kraichely DM, Jefcoat SC, Winchester SK, Partridge NC, MacDonald PN | title = Isolation and characterization of a novel coactivator protein, NCoA-62, involved in vitamin D-mediated transcription | journal = J. Biol. Chem. | volume = 273 | issue = 26 | pages = 16434–41 | date = June 1998 | pmid = 9632709 | doi = 10.1074/jbc.273.26.16434 | doi-access = free}}
• STAT1,{{cite journal | vauthors = Vidal M, Ramana CV, Dusso AS | title = Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription | journal = Mol. Cell. Biol. | volume = 22 | issue = 8 | pages = 2777–87 | date = April 2002 | pmid = 11909970 | pmc = 133712 | doi = 10.1128/MCB.22.8.2777-2787.2002 }} and
• ZBTB16.{{cite journal | vauthors = Puccetti E, Obradovic D, Beissert T, Bianchini A, Washburn B, Chiaradonna F, Boehrer S, Hoelzer D, Ottmann OG, Pelicci PG, Nervi C, Ruthardt M | title = AML-associated translocation products block vitamin D(3)-induced differentiation by sequestering the vitamin D(3) receptor | journal = Cancer Res. | volume = 62 | issue = 23 | pages = 7050–8 | date = December 2002 | pmid = 12460926 }}{{cite journal | vauthors = Ward JO, McConnell MJ, Carlile GW, Pandolfi PP, Licht JD, Freedman LP | title = 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 | journal = Blood | volume = 98 | issue = 12 | pages = 3290–300 | date = December 2001 | pmid = 11719366 | doi = 10.1182/blood.V98.12.3290 | doi-access = free }}

{{Div col end}}

{{VitaminDSynthesis_WP1531|highlight=Calcidiol|align=left|width=600|height=300}}

{{reflist}}

{{refbegin |35em}}

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• {{cite journal | vauthors = Goto H, Chen KS, Prahl JM, DeLuca HF | title = A single receptor identical with that from intestine/T47D cells mediates the action of 1,25-dihydroxyvitamin D-3 in HL-60 cells | journal = Biochim. Biophys. Acta | volume = 1132 | issue = 1 | pages = 103–8 | year = 1992 | pmid = 1324736 | doi = 10.1016/0167-4781(92)90063-6 }}
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• {{cite journal | vauthors = Sone T, Marx SJ, Liberman UA, Pike JW | title = A unique point mutation in the human vitamin D receptor chromosomal gene confers hereditary resistance to 1,25-dihydroxyvitamin D3 | journal = Mol. Endocrinol. | volume = 4 | issue = 4 | pages = 623–31 | year = 1991 | pmid = 2177843 | doi = 10.1210/mend-4-4-623 | doi-access = free }}
• {{cite journal | vauthors = Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike JW, Shine J, O'Malley BW | title = Cloning and expression of full-length cDNA encoding human vitamin D receptor | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 10 | pages = 3294–8 | year = 1988 | pmid = 2835767 | pmc = 280195 | doi = 10.1073/pnas.85.10.3294 | bibcode = 1988PNAS...85.3294B | doi-access = free }}
• {{cite journal | vauthors = Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, O'Malley BW | title = Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets | journal = Science | volume = 242 | issue = 4886 | pages = 1702–5 | year = 1989 | pmid = 2849209 | doi = 10.1126/science.2849209 }}
• {{cite journal | vauthors = Rut AR, Hewison M, Kristjansson K, Luisi B, Hughes MR, O'Riordan JL | title = Two mutations causing vitamin D resistant rickets: modelling on the basis of steroid hormone receptor DNA-binding domain crystal structures | journal = Clin. Endocrinol. | volume = 41 | issue = 5 | pages = 581–90 | year = 1995 | pmid = 7828346 | doi = 10.1111/j.1365-2265.1994.tb01822.x | s2cid = 40851942 }}
• {{cite journal | vauthors = Malloy PJ, Weisman Y, Feldman D | title = Hereditary 1 alpha,25-dihydroxyvitamin D-resistant rickets resulting from a mutation in the vitamin D receptor deoxyribonucleic acid-binding domain | journal = J. Clin. Endocrinol. Metab. | volume = 78 | issue = 2 | pages = 313–6 | year = 1994 | doi = 10.1210/jcem.78.2.8106618 | pmid = 8106618 }}
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• {{cite journal | vauthors = Kristjansson K, Rut AR, Hewison M, O'Riordan JL, Hughes MR | title = Two mutations in the hormone binding domain of the vitamin D receptor cause tissue resistance to 1,25 dihydroxyvitamin D3 | journal = J. Clin. Invest. | volume = 92 | issue = 1 | pages = 12–6 | year = 1993 | pmid = 8392085 | pmc = 293517 | doi = 10.1172/JCI116539 }}
• {{cite journal | vauthors = Jurutka PW, Hsieh JC, Nakajima S, Haussler CA, Whitfield GK, Haussler MR | title = Human vitamin D receptor phosphorylation by casein kinase II at Ser-208 potentiates transcriptional activation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 8 | pages = 3519–24 | year = 1996 | pmid = 8622969 | pmc = 39642 | doi = 10.1073/pnas.93.8.3519 | bibcode = 1996PNAS...93.3519J | doi-access = free }}
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{{refend}}

• {{MeshName|Calcitriol+Receptors}}
• [http://nrresource.org Nuclear Receptor Resource]
• [http://www.rcsb.org/pdb/101/motm.do?momID=155 Vitamin D Receptor: Molecule of the Month] {{Webarchive|url=https://web.archive.org/web/20151016005029/http://www.rcsb.org/pdb/101/motm.do?momID=155 |date=2015-10-16 }}
• [http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=605 IUPHAR: Vitamin D receptor]
• {{PDBe-KB2|P11473|Vitamin D3 receptor}}

{{NLM content}}

{{PDB Gallery|geneid=7421}}

{{Transcription factors|g2}}

{{Vitamin D receptor modulators}}

Category:Vitamin D

Category:Intracellular receptors

Category:Transcription factors