Biology:Vitamin D receptor

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Short description: Transcription factor activated by vitamin D


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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 (1,25-dihydroxycholecalciferol) and the vitamin D2 homologue ercalcitriol, 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.[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:


Interactive pathway map

References

  1. ↑ "International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor". Pharmacol. Rev. 58 (4): 742–59. December 2006. doi:10.1124/pr.58.4.6. PMID 17132852. 
  2. ↑ "Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts". J Bone Miner Res 28 (6): 1478–14788. June 2013. doi:10.1002/jbmr.1882. PMID 23362149. 
  3. ↑ "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. doi:10.1016/0888-7543(91)90114-T. PMID 1662663. 
  4. ↑ 4.0 4.1 4.2 "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. doi:10.3109/10408363.2010.536429. PMID 21182397. 
  5. ↑ 5.0 5.1 "Vitamin D receptor agonists, cancer and the immune system: an intricate relationship". Curr Top Med Chem 6 (12): 1297–301. 2006. doi:10.2174/156802606777864890. PMID 16848743. 
  6. ↑ "Overview of nomenclature of nuclear receptors". Pharmacol. Rev. 58 (4): 685–704. December 2006. doi:10.1124/pr.58.4.2. PMID 17132848. 
  7. ↑ 7.0 7.1 "Vitamin-D pathway genes and HIV-1 disease progression in injection drug users". Gene 545 (1): 163–9. July 2014. doi:10.1016/j.gene.2014.04.035. PMID 24768180. 
  8. ↑ 8.0 8.1 "Vitamin D Receptor polymorphisms and risk of enveloped virus infection: A meta-analysis". Gene 678: 384–94. December 2018. doi:10.1016/j.gene.2018.08.017. PMID 30092343. 
  9. ↑ "Tagging long-lived individuals through vitamin-D receptor (VDR) haplotypes". Biogerontology 11 (4): 437–46. April 2010. doi:10.1007/s10522-010-9273-8. PMID 20407924. 
  10. ↑ "Entrez Gene: VDR vitamin D (1,25- dihydroxyvitamin D3) receptor". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7421. 
  11. ↑ "Genetic Determinants of Vitamin D-Related Disorders; Focus on Vitamin D Receptor". Current Drug Metabolism 19 (12): 1042–1052. 2018-10-19. doi:10.2174/1389200219666180723143552. PMID 30039758. 
  12. ↑ "The vitamin D receptor, the skin and stem cells". J. Steroid Biochem. Mol. Biol. 121 (1–2): 314–6. July 2010. doi:10.1016/j.jsbmb.2010.01.015. PMID 20138991. 
  13. ↑ "The Vitamin D Receptor Is Required for Activation of cWnt and Hedgehog Signaling in Keratinocytes". Mol. Endocrinol. 28 (10): 1698–1706. September 2014. doi:10.1210/me.2014-1043. PMID 25180455. 
  14. ↑ "BAG1L enhances trans-activation function of the vitamin D receptor". J. Biol. Chem. 275 (52): 40749–56. December 2000. doi:10.1074/jbc.M004977200. PMID 10967105. 
  15. ↑ 15.0 15.1 15.2 15.3 15.4 "The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome". Cell 113 (7): 905–17. June 2003. doi:10.1016/S0092-8674(03)00436-7. PMID 12837248. 
  16. ↑ "Membrane Localization, Caveolin-3 Association and Rapid Actions of Vitamin D Receptor in Cardiac Myocytes". Steroids 75 (8–9): 555–9. 2010. doi:10.1016/j.steroids.2009.12.001. PMID 20015453. 
  17. ↑ 17.0 17.1 17.2 "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. doi:10.1016/S1097-2765(00)80463-3. PMID 10198638. 
  18. ↑ 18.0 18.1 "The interaction of the vitamin D receptor with nuclear receptor corepressors and coactivators". Biochem. Biophys. Res. Commun. 253 (2): 358–63. December 1998. doi:10.1006/bbrc.1998.9799. PMID 9878542. 
  19. ↑ 19.0 19.1 19.2 19.3 "AML-associated translocation products block vitamin D(3)-induced differentiation by sequestering the vitamin D(3) receptor". Cancer Res. 62 (23): 7050–8. December 2002. PMID 12460926. 
  20. ↑ "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". J. Biol. Chem. 275 (22): 16506–12. June 2000. doi:10.1074/jbc.M910000199. PMID 10748178. 
  21. ↑ 21.0 21.1 21.2 "Ternary complexes and cooperative interplay between NCoA-62/Ski-interacting protein and steroid receptor coactivators in vitamin D receptor-mediated transcription". J. Biol. Chem. 276 (44): 40614–20. November 2001. doi:10.1074/jbc.M106263200. PMID 11514567. 
  22. ↑ "Electrostatic Modulation in Steroid Receptor Recruitment of LXXLL and FXXLF Motifs". Mol. Cell. Biol. 23 (6): 2135–50. March 2003. doi:10.1128/MCB.23.6.2135-2150.2003. PMID 12612084. 
  23. ↑ 23.0 23.1 "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. doi:10.1074/jbc.273.26.16434. PMID 9632709. 
  24. ↑ "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. doi:10.1128/MCB.22.8.2777-2787.2002. PMID 11909970. 
  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". Blood 98 (12): 3290–300. December 2001. doi:10.1182/blood.V98.12.3290. PMID 11719366. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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