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Vitamin D receptor

The vitamin D receptor ( VDR also known as the calcitriol receptor ) is a member of the nuclear receptor family of transcription factors . [ 5 ] Calcitriol (the active form of v...

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The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors.[5]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.[6] In humans, the vitamin D receptor is encoded by the VDRgene located on chromosome 12q13.11.[7]

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.[8]Glucocorticoids decrease VDR expression.[8] Many types of immune cells also express VDR.[9]

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 acidlithocholic 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.[10]

Los objetivos posteriores de este receptor de hormonas nucleares incluyen muchos genes involucrados en el metabolismo mineral. [ 8 ] El receptor regula una variedad de otras vías metabólicas, como las involucradas en la respuesta inmune y el cáncer. [ 9 ] Las variantes de VDR que refuerzan la acción de la vitamina D y que están directamente correlacionadas con las tasas de progresión del SIDA y la asociación de VDR con la progresión al SIDA sigue un modelo aditivo. [ 11 ] El polimorfismo FokI es un factor de riesgo para la infección por virus envueltos como se reveló en un metaanálisis. [ 12 ] La importancia de este gen también se ha observado en el proceso natural de envejecimiento donde los haplotipos 3'UTR del gen mostraron una asociación con la longevidad. [ 13 ]

Relevancia clínica

Las mutaciones en este gen están asociadas con el raquitismo resistente a la vitamina D de tipo II . Un polimorfismo de un solo nucleótido en el codón de iniciación da como resultado un sitio de inicio de traducción alternativo tres codones más adelante. El empalme alternativo da como resultado múltiples variantes de transcripción que codifican la misma proteína. [ 14 ] Las variantes del gen VDR parecen influir en muchos resultados biológicos, incluidos los relacionados con la osteoporosis. [ 15 ]

El receptor de vitamina D desempeña un papel importante en la regulación del ciclo capilar. La pérdida de VDR se asocia con la pérdida de cabello en animales de experimentación. [ 16 ] Estudios experimentales han demostrado que el VDR sin ligando interactúa con regiones reguladoras en cWnt ( vía de señalización Wnt ) y genes diana de Sonic hedgehog y es necesario para la inducción de estas vías durante el ciclo capilar posnatal. [ 17 ] Estos estudios han revelado nuevas acciones del VDR sin ligando en la regulación del ciclo capilar posmorfogénico.

Los investigadores han centrado sus esfuerzos en dilucidar el papel de los polimorfismos del VDR en diferentes enfermedades y fenotipos normales, como la susceptibilidad y progresión de la infección por VIH-1 o el proceso natural de envejecimiento. Entre los hallazgos más notables se incluyen el informe de variantes del VDR que potencian la acción de la vitamina D y que se correlacionan directamente con las tasas de progresión del SIDA, que la asociación del VDR con la progresión al SIDA sigue un modelo aditivo [ 11 ] y el papel del polimorfismo FokI como factor de riesgo para la infección por virus envueltos, según lo revelado en un metaanálisis [ 12 ] .

Interacciones

Se ha demostrado que el receptor de vitamina D interactúa con muchos otros factores que afectarán la activación de la transcripción:

Mapa interactivo de la ruta

Haz clic en genes, proteínas y metabolitos a continuación para acceder a los artículos correspondientes. [ § 1 ]

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Vía de síntesis de la vitamina D ( ver / editar )
  1. ↑ El mapa interactivo de la ruta metabólica se puede editar en WikiPathways: "VitaminDSynthesis_WP1531" .

Referencias

  1. 1 2 3 GRCh38: Versión 89 de Ensembl: ENSG00000111424 – Ensembl , mayo de 2017
  2. 1 2 3 GRCm38: Versión 89 de Ensembl: ENSMUSG00000022479 – Ensembl , mayo de 2017
  3. ↑ "Referencia humana de PubMed:" . Centro Nacional de Información Biotecnológica, Biblioteca Nacional de Medicina de EE. UU .
  4. ↑ "Referencia de PubMed sobre el ratón:" . Centro Nacional de Información Biotecnológica, Biblioteca Nacional de Medicina de EE . UU .
  5. ↑ Moore DD, Kato S, Xie W, Mangelsdorf DJ, Schmidt DR, Xiao R, Kliewer SA (diciembre de 2006). "Unión Internacional de Farmacología. LXII. Los receptores NR1H y NR1I: receptor de androstano constitutivo, receptor X de pregneno, receptor X farnesoide alfa, receptor X farnesoide beta, receptor X hepático alfa, receptor X hepático beta y receptor de vitamina D". Pharmacol . Rev. 58 ( 4): 742– 59. doi : 10.1124/pr.58.4.6 . PMID 17132852. S2CID 85996383 .  
  6. ↑Lisse TS, Chun RF, Rieger S, Adams JS, Hewison M (June 2013). "Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts". J Bone Miner Res. 28 (6): 1478–14788. doi:10.1002/jbmr.1882. PMC 3663893. PMID 23362149.
  7. ↑Szpirer J, Szpirer C, Riviere M, Levan G, Marynen P, Cassiman JJ, Wiese R, DeLuca HF (September 1991). "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. doi:10.1016/0888-7543(91)90114-T. PMID 1662663.
  8. 123Fleet JC, Schoch RD (August 2010). "Molecular Mechanisms for Regulation of Intestinal Calcium Absorption by Vitamin D and Other Factors". Crit Rev Clin Lab Sci. 47 (4): 181–195. doi:10.3109/10408363.2010.536429. PMC 3235806. PMID 21182397.
  9. 12Adorini L, Daniel KC, Penna G (2006). "Vitamin D receptor agonists, cancer and the immune system: an intricate relationship". Curr Top Med Chem. 6 (12): 1297–301. doi:10.2174/156802606777864890. PMID 16848743.
  10. ↑Germain P, Staels B, Dacquet C, Spedding M, Laudet V (December 2006). "Overview of nomenclature of nuclear receptors". Pharmacol. Rev. 58 (4): 685–704. doi:10.1124/pr.58.4.2. PMID 17132848. S2CID 1190488.
  11. 12Laplana M, Sánchez-de-la-Torre M, Puig T, Caruz A, Fibla J (July 2014). "Vitamin-D pathway genes and HIV-1 disease progression in injection drug users". Gene. 545 (1): 163–9. doi:10.1016/j.gene.2014.04.035. hdl:10459.1/67999. PMID 24768180.
  12. 12Laplana M, Royo L, Fibla J (December 2018). "Vitamin D Receptor polymorphisms and risk of enveloped virus infection: A meta-analysis". Gene. 678: 384–94. doi:10.1016/j.gene.2018.08.017. hdl:10459.1/68000. PMID 30092343. S2CID 51955566.
  13. ↑Laplana M, Sánchez-de-la-Torre M, Aguiló A, Casado I, Flores M, Sánchez-Pellicer R, Fibla J (April 2010). "Tagging long-lived individuals through vitamin-D receptor (VDR) haplotypes". Biogerontology. 11 (4): 437–46. doi:10.1007/s10522-010-9273-8. hdl:10459.1/67920. PMID 20407924. S2CID 34809120.
  14. ↑"Entrez Gene: VDR vitamin D (1,25- dihydroxyvitamin D3) receptor".
  15. ↑Abouzid M, Karazniewicz-Lada M, Glowka F (2018-10-19). "Genetic Determinants of Vitamin D-Related Disorders; Focus on Vitamin D Receptor". Current Drug Metabolism. 19 (12): 1042–1052. doi:10.2174/1389200219666180723143552. PMID 30039758. S2CID 51710351.
  16. ↑Luderer HF, Demay MB (July 2010). "The vitamin D receptor, the skin and stem cells". J. Steroid Biochem. Mol. Biol. 121 (1–2): 314–6. doi:10.1016/j.jsbmb.2010.01.015. PMID 20138991. S2CID 23876206.
  17. ↑Lisse TS, Saini V, Zhao H, Luderer HF, Gori F, Demay MB (September 2014). "The Vitamin D Receptor Is Required for Activation of cWnt and Hedgehog Signaling in Keratinocytes". Mol. Endocrinol. 28 (10): 1698–1706. doi:10.1210/me.2014-1043. PMC 4179637. PMID 25180455.
  18. ↑Guzey M, Takayama S, Reed JC (December 2000). "BAG1L enhances trans-activation function of the vitamin D receptor". J. Biol. Chem. 275 (52): 40749–56. doi:10.1074/jbc.M004977200. PMID 10967105.
  19. ↑Zhao G, Simpson RU (2010). "Membrane Localization, Caveolin-3 Association and Rapid Actions of Vitamin D Receptor in Cardiac Myocytes". Steroids. 75 (8–9): 555–9. doi:10.1016/j.steroids.2009.12.001. PMC 2885558. PMID 20015453.
  20. 12Ito M, Yuan CX, Malik S, Gu W, Fondell JD, Yamamura S, Fu ZY, Zhang X, Qin J, Roeder RG (March 1999). "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. doi:10.1016/S1097-2765(00)80463-3. PMID 10198638.
  21. 12Tagami T, Lutz WH, Kumar R, Jameson JL (December 1998). "The interaction of the vitamin D receptor with nuclear receptor corepressors and coactivators". Biochem. Biophys. Res. Commun. 253 (2): 358–63. Bibcode:1998BBRC..253..358T. doi:10.1006/bbrc.1998.9799. PMID 9878542.
  22. 1234Puccetti E, Obradovic D, Beissert T, Bianchini A, Washburn B, Chiaradonna F, Boehrer S, Hoelzer D, Ottmann OG, Pelicci PG, Nervi C, Ruthardt M (December 2002). "AML-associated translocation products block vitamin D(3)-induced differentiation by sequestering the vitamin D(3) receptor". Cancer Res. 62 (23): 7050–8. PMID 12460926.
  23. ↑Herdick M, Steinmeyer A, Carlberg C (June 2000). "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. doi:10.1074/jbc.M910000199. PMID 10748178.
  24. 123Zhang C, Baudino TA, Dowd DR, Tokumaru H, Wang W, MacDonald PN (November 2001). "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. doi:10.1074/jbc.M106263200. PMID 11514567.
  25. ↑He B, Wilson EM (March 2003). "Electrostatic Modulation in Steroid Receptor Recruitment of LXXLL and FXXLF Motifs". Mol. Cell. Biol. 23 (6): 2135–50. doi:10.1128/MCB.23.6.2135-2150.2003. PMC 149467. PMID 12612084.
  26. 12Baudino TA, Kraichely DM, Jefcoat SC, Winchester SK, Partridge NC, MacDonald PN (June 1998). "Isolation and characterization of a novel coactivator protein, NCoA-62, involved in vitamin D-mediated transcription". J. Biol. Chem. 273 (26): 16434–41. doi:10.1074/jbc.273.26.16434. PMID 9632709.
  27. ↑Vidal M, Ramana CV, Dusso AS (April 2002). "Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription". Mol. Cell. Biol. 22 (8): 2777–87. doi:10.1128/MCB.22.8.2777-2787.2002. PMC 133712. PMID 11909970.
  28. ↑Ward JO, McConnell MJ, Carlile GW, Pandolfi PP, Licht JD, Freedman LP (December 2001). "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. doi:10.1182/blood.V98.12.3290. PMID 11719366.

Further reading

  • Hosoi T (2002). "[Polymorphisms of vitamin D receptor gene]". Nippon Rinsho. 60 (Suppl 3): 106–10. PMID 11979895.
  • Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP (2004). "Genetics and biology of vitamin D receptor polymorphisms". Gene. 338 (2): 143–56. doi:10.1016/j.gene.2004.05.014. hdl:1765/73442. PMID 15315818. S2CID 11023870.
  • Norman AW (2007). "Minireview: vitamin D receptor: new assignments for an already busy receptor". Endocrinology. 147 (12): 5542–8. doi:10.1210/en.2006-0946. PMID 16946007.
  • Bollag WB (2007). "Differentiation of human keratinocytes requires the vitamin d receptor and its coactivators". J. Invest. Dermatol. 127 (4): 748–50. doi:10.1038/sj.jid.5700692. PMID 17363957.
  • Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG (1992). "RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors". EMBO J. 11 (4): 1409–18. doi:10.1002/j.1460-2075.1992.tb05186.x. PMC 556590. PMID 1314167.
  • Goto H, Chen KS, Prahl JM, DeLuca HF (1992). "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. doi:10.1016/0167-4781(92)90063-6. PMID 1324736.
  • Saijo T, Ito M, Takeda E, Huq AH, Naito E, Yokota I, Sone T, Pike JW, Kuroda Y (1991). "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. PMC 1683124. PMID 1652893.
  • Szpirer J, Szpirer C, Riviere M, Levan G, Marynen P, Cassiman JJ, Wiese R, DeLuca HF (1992). "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. doi:10.1016/0888-7543(91)90114-T. PMID 1662663.
  • Yu XP, Mocharla H, Hustmyer FG, Manolagas SC (1991). "Vitamin D receptor expression in human lymphocytes. Signal requirements and characterization by western blots and DNA sequencing". J. Biol. Chem. 266 (12): 7588–95. doi:10.1016/S0021-9258(20)89488-5. PMID 1850412.
  • Malloy PJ, Hochberg Z, Tiosano D, Pike JW, Hughes MR, Feldman D (1991). "The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families". J. Clin. Invest. 86 (6): 2071–9. doi:10.1172/JCI114944. PMC 329846. PMID 2174914.
  • Sone T, Marx SJ, Liberman UA, Pike JW (1991). "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. doi:10.1210/mend-4-4-623. PMID 2177843.
  • Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike JW, Shine J, O'Malley BW (1988). "Cloning and expression of full-length cDNA encoding human vitamin D receptor". Proc. Natl. Acad. Sci. U.S.A. 85 (10): 3294–8. Bibcode:1988PNAS...85.3294B. doi:10.1073/pnas.85.10.3294. PMC 280195. PMID 2835767.
  • Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, O'Malley BW (1989). "Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets". Science. 242 (4886): 1702–5. doi:10.1126/science.2849209. PMID 2849209.
  • Rut AR, Hewison M, Kristjansson K, Luisi B, Hughes MR, O'Riordan JL (1995). "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. doi:10.1111/j.1365-2265.1994.tb01822.x. PMID 7828346. S2CID 40851942.
  • Malloy PJ, Weisman Y, Feldman D (1994). "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. doi:10.1210/jcem.78.2.8106618. PMID 8106618.
  • Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
  • Yagi H, Ozono K, Miyake H, Nagashima K, Kuroume T, Pike JW (1993). "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. doi:10.1210/jcem.76.2.8381803. PMID 8381803.
  • Kristjansson K, Rut AR, Hewison M, O'Riordan JL, Hughes MR (1993). "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. doi:10.1172/JCI116539. PMC 293517. PMID 8392085.
  • Jurutka PW, Hsieh JC, Nakajima S, Haussler CA, Whitfield GK, Haussler MR (1996). "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. Bibcode:1996PNAS...93.3519J. doi:10.1073/pnas.93.8.3519. PMC 39642. PMID 8622969.
  • Lin NU, Malloy PJ, Sakati N, al-Ashwal A, Feldman D (1996). "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. doi:10.1210/jcem.81.7.8675579. PMID 8675579. S2CID 46366654.
  • Calcitriol+Receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • Nuclear Receptor ResourceArchived 2024-06-05 at the Wayback Machine
  • Vitamin D Receptor: Molecule of the MonthArchived 2015-10-16 at the Wayback Machine
  • IUPHAR: Vitamin D receptor
  • Overview of all the structural information available in the PDB for UniProt: P11473 (Vitamin D3 receptor) at the PDBe-KB.

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