Vitamin D receptor explained

The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors.^[1] Calcitriol (the active form of vitamin D, 1,25-(OH)₂vitamin D₃) binds to VDR, which then forms a heterodimer with the retinoid-X receptor. The VDR heterodimer then enters the nucleus and binds to Vitamin D responsive elements (VDRE) in genomic DNA. VDR binding results in expression or transrepression of many specific gene products. VDR is also involved in microRNA-directed post transcriptional mechanisms.^[2] In humans, the vitamin D receptor is encoded by the VDR gene located on chromosome 12q13.11.^[3]

VDR is expressed in most tissues of the body, and regulates transcription of genes involved in intestinal and renal transport of calcium and other minerals.^[4] Glucocorticoids decrease VDR expression.^[4] Many types of immune cells also express VDR.^[5]

Function

The VDR gene encodes the nuclear hormone receptor for vitamin D. The most potent natural agonist is calcitriol and the vitamin D₂ homologue ercalcitriol,) 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.^[6]

Downstream targets of this nuclear hormone receptor include many genes involved in mineral metabolism.^[4] The receptor regulates a variety of other metabolic pathways, such as those involved in the immune response and cancer.^[5] 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.^[7] FokI polymorphism is a risk factor for enveloped virus infection as revealed in a meta-analysis.^[8] 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.^[9]

Clinical relevance

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.^[10] VDR gene variants seem to influence many biological endpoints, including those related to osteoporosis ^[11]

The vitamin D receptor plays an important role in regulating the hair cycle. Loss of VDR is associated with hair loss in experimental animals.^[12] 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.^[13] 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^[7] and the role of FokI polymorphism as a risk factor for enveloped virus infection as revealed in a meta-analysis.^[8]

Interactions

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

• BAG1,^[14]
• CAV3,^[15]
• MED12,^[16]
• MED24,^[16]
• NCOR1,^[17]
• NCOR2,^[17]
• NCOA2^{[18] [19]}
• RXRA,
• RUNX1,
• RUNX1T1,
• SNW1,^{[20] [21]}
• STAT1,^[22] and
• ZBTB16.^{[23] [24]}

Further reading

• Hosoi T . [Polymorphisms of vitamin D receptor gene] . Nippon Rinsho . 60 . 106–10 . 2002 . Suppl 3 . 11979895 .
• Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP . Genetics and biology of vitamin D receptor polymorphisms . Gene . 338 . 2 . 143–56 . 2004 . 15315818 . 10.1016/j.gene.2004.05.014 . 1765/73442 . 11023870 . free .
• Norman AW . Minireview: vitamin D receptor: new assignments for an already busy receptor . Endocrinology . 147 . 12 . 5542–8 . 2007 . 16946007 . 10.1210/en.2006-0946 . free .
• Bollag WB . Differentiation of human keratinocytes requires the vitamin d receptor and its coactivators . J. Invest. Dermatol. . 127 . 4 . 748–50 . 2007 . 17363957 . 10.1038/sj.jid.5700692 . free .
• Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG . RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors . EMBO J. . 11 . 4 . 1409–18 . 1992 . 1314167 . 556590 . 10.1002/j.1460-2075.1992.tb05186.x.
• Goto H, Chen KS, Prahl JM, DeLuca HF . A single receptor identical with that from intestine/T47D cells mediates the action of 1,25-dihydroxyvitamin D-3 in HL-60 cells . Biochim. Biophys. Acta . 1132 . 1 . 103–8 . 1992 . 1324736 . 10.1016/0167-4781(92)90063-6 .
• Saijo T, Ito M, Takeda E, Huq AH, Naito E, Yokota I, Sone T, Pike JW, Kuroda Y . A unique mutation in the vitamin D receptor gene in three Japanese patients with vitamin D-dependent rickets type II: utility of single-strand conformation polymorphism analysis for heterozygous carrier detection . Am. J. Hum. Genet. . 49 . 3 . 668–73 . 1991 . 1652893 . 1683124 .
• Szpirer J, Szpirer C, Riviere M, Levan G, Marynen P, Cassiman JJ, Wiese R, DeLuca HF . The Sp1 transcription factor gene (SP1) and the 1,25-dihydroxyvitamin D3 receptor gene (VDR) are colocalized on human chromosome arm 12q and rat chromosome 7 . Genomics . 11 . 1 . 168–73 . 1992 . 1662663 . 10.1016/0888-7543(91)90114-T .
• Yu XP, Mocharla H, Hustmyer FG, Manolagas SC . Vitamin D receptor expression in human lymphocytes. Signal requirements and characterization by western blots and DNA sequencing . J. Biol. Chem. . 266 . 12 . 7588–95 . 1991 . 10.1016/S0021-9258(20)89488-5 . 1850412 . free .
• Malloy PJ, Hochberg Z, Tiosano D, Pike JW, Hughes MR, Feldman D . The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families . J. Clin. Invest. . 86 . 6 . 2071–9 . 1991 . 2174914 . 329846 . 10.1172/JCI114944 .
• Sone T, Marx SJ, Liberman UA, Pike JW . A unique point mutation in the human vitamin D receptor chromosomal gene confers hereditary resistance to 1,25-dihydroxyvitamin D3 . Mol. Endocrinol. . 4 . 4 . 623–31 . 1991 . 2177843 . 10.1210/mend-4-4-623 . free .
• Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike JW, Shine J, O'Malley BW . Cloning and expression of full-length cDNA encoding human vitamin D receptor . Proc. Natl. Acad. Sci. U.S.A. . 85 . 10 . 3294–8 . 1988 . 2835767 . 280195 . 10.1073/pnas.85.10.3294 . 1988PNAS...85.3294B . free .
• Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, O'Malley BW . Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets . Science . 242 . 4886 . 1702–5 . 1989 . 2849209 . 10.1126/science.2849209 .
• Rut AR, Hewison M, Kristjansson K, Luisi B, Hughes MR, O'Riordan JL . Two mutations causing vitamin D resistant rickets: modelling on the basis of steroid hormone receptor DNA-binding domain crystal structures . Clin. Endocrinol. . 41 . 5 . 581–90 . 1995 . 7828346 . 10.1111/j.1365-2265.1994.tb01822.x . 40851942 .
• Malloy PJ, Weisman Y, Feldman D . Hereditary 1 alpha,25-dihydroxyvitamin D-resistant rickets resulting from a mutation in the vitamin D receptor deoxyribonucleic acid-binding domain . J. Clin. Endocrinol. Metab. . 78 . 2 . 313–6 . 1994 . 10.1210/jcem.78.2.8106618 . 8106618 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Yagi H, Ozono K, Miyake H, Nagashima K, Kuroume T, Pike JW . A new point mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor in a kindred with hereditary 1,25-dihydroxyvitamin D-resistant rickets . J. Clin. Endocrinol. Metab. . 76 . 2 . 509–12 . 1993 . 10.1210/jcem.76.2.8381803 . 8381803 .
• Kristjansson K, Rut AR, Hewison M, O'Riordan JL, Hughes MR . Two mutations in the hormone binding domain of the vitamin D receptor cause tissue resistance to 1,25 dihydroxyvitamin D3 . J. Clin. Invest. . 92 . 1 . 12–6 . 1993 . 8392085 . 293517 . 10.1172/JCI116539 .
• Jurutka PW, Hsieh JC, Nakajima S, Haussler CA, Whitfield GK, Haussler MR . Human vitamin D receptor phosphorylation by casein kinase II at Ser-208 potentiates transcriptional activation . Proc. Natl. Acad. Sci. U.S.A. . 93 . 8 . 3519–24 . 1996 . 8622969 . 39642 . 10.1073/pnas.93.8.3519 . 1996PNAS...93.3519J . free .
• Lin NU, Malloy PJ, Sakati N, al-Ashwal A, Feldman D . A novel mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets . J. Clin. Endocrinol. Metab. . 81 . 7 . 2564–9 . 1996 . 10.1210/jcem.81.7.8675579 . 8675579 . 46366654 . free .

External links

• • Nuclear Receptor Resource
• Vitamin D Receptor: Molecule of the Month
• IUPHAR: Vitamin D receptor

Notes and References

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3. Szpirer J, Szpirer C, Riviere M, Levan G, Marynen P, Cassiman JJ, Wiese R, DeLuca HF . The Sp1 transcription factor gene (SP1) and the 1,25-dihydroxyvitamin D3 receptor gene (VDR) are colocalized on human chromosome arm 12q and rat chromosome 7 . Genomics . 11 . 1 . 168–73 . September 1991 . 1662663 . 10.1016/0888-7543(91)90114-T .
4. Fleet JC, Schoch RD . Molecular Mechanisms for Regulation of Intestinal Calcium Absorption by Vitamin D and Other Factors . Crit Rev Clin Lab Sci . 47 . 4 . 181–195 . August 2010 . 21182397 . 10.3109/10408363.2010.536429 . 3235806.
5. Adorini L, Daniel KC, Penna G . Vitamin D receptor agonists, cancer and the immune system: an intricate relationship . Curr Top Med Chem . 6 . 12 . 1297–301 . 2006 . 16848743 . 10.2174/156802606777864890 .
6. Germain P, Staels B, Dacquet C, Spedding M, Laudet V . Overview of nomenclature of nuclear receptors . Pharmacol. Rev. . 58 . 4 . 685–704 . December 2006 . 17132848 . 10.1124/pr.58.4.2 . 1190488 .
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8. Laplana M, Royo L, Fibla J . Vitamin D Receptor polymorphisms and risk of enveloped virus infection: A meta-analysis . Gene . 678 . 384–94 . December 2018 . 30092343 . 10.1016/j.gene.2018.08.017 . 10459.1/68000 . 51955566 . free .
9. Laplana M, Sánchez-de-la-Torre M, Aguiló A, Casado I, Flores M, Sánchez-Pellicer R, Fibla J . Tagging long-lived individuals through vitamin-D receptor (VDR) haplotypes . Biogerontology . 11 . 4. 437–46 . April 2010 . 20407924 . 10.1007/s10522-010-9273-8 . 10459.1/67920 . 34809120 . free .
10. Web site: Entrez Gene: VDR vitamin D (1,25- dihydroxyvitamin D3) receptor.
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13. Lisse TS, Saini V, Zhao H, Luderer HF, Gori F, Demay MB . The Vitamin D Receptor Is Required for Activation of cWnt and Hedgehog Signaling in Keratinocytes . Mol. Endocrinol. . 28 . 10 . 1698–1706 . September 2014 . 25180455 . 10.1210/me.2014-1043 . 4179637.
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16. Ito M, Yuan CX, Malik S, Gu W, Fondell JD, Yamamura S, Fu ZY, Zhang X, Qin J, Roeder RG . Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators . Mol. Cell . 3 . 3 . 361–70 . March 1999 . 10198638 . 10.1016/S1097-2765(00)80463-3 . free .
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21. Baudino TA, Kraichely DM, Jefcoat SC, Winchester SK, Partridge NC, MacDonald PN . Isolation and characterization of a novel coactivator protein, NCoA-62, involved in vitamin D-mediated transcription . J. Biol. Chem. . 273 . 26 . 16434–41 . June 1998 . 9632709 . 10.1074/jbc.273.26.16434 . free.
22. Vidal M, Ramana CV, Dusso AS . Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription . Mol. Cell. Biol. . 22 . 8 . 2777–87 . April 2002 . 11909970 . 133712 . 10.1128/MCB.22.8.2777-2787.2002 .
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