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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.
Calcitriol Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the ...
(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 Vitamin D response element (VDRE) is a type of DNA sequence that is found in the promoter region of vitamin D regulated genes. This sequence binds the vitamin D receptor (VDR), when complexed with calcitriol (1,25(OH)2D), the active form of vitamin ...
) in genomic DNA. VDR binding results in
expression Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Fixed expression, a form of words with a specific meaning * Idiom, a type of fixed expression * Metaphorical expression, a particular word, phrase, ...
or transrepression of many specific gene products. VDR is also involved in
microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
-directed post transcriptional mechanisms. In humans, the vitamin D receptor is encoded by the ''VDR'' gene located on
chromosome 12 Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the to ...
q13.11. VDR is expressed in most tissues of the body, and regulates transcription of genes involved in intestinal and renal transport of
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
and other minerals. Glucocorticoids decrease VDR expression. Many types of immune cells also express VDR.


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 Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Primary ...
lithocholic acid Lithocholic acid, also known as 3α-hydroxy-5β-cholan-24-oic acid or LCA, is a bile acid that acts as a detergent to solubilize fats for absorption. Bacterial action in the colon produces LCA from chenodeoxycholic acid by reduction of the hydrox ...
. The receptor belongs to the family of trans-acting transcriptional regulatory factors and shows similarity of sequence to the steroid and thyroid hormone receptors. 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. FokI polymorphism is a risk factor for enveloped virus infection as revealed in a meta-analysis. 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.


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. VDR gene variants seem to influence many biological endpoints, including those related to osteoporosis The vitamin D receptor plays an important role in regulating the hair cycle. Loss of VDR is associated with hair loss in experimental animals. 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. 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.


Interactions

Vitamin D receptor has been shown to interact with many other factors which will affect transcription activation: *
BAG1 BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the ''BAG1'' gene. Function The oncogene BCL2 is a membrane protein that blocks a step in a pathway leading to apoptosis or programmed cell death. The protei ...
, *
BAZ1B Tyrosine-protein kinase, or Bromodomain adjacent to zinc finger domain, 1B (BAZ1B) is an enzyme that in humans is encoded by the ''BAZ1B'' gene. Function This gene encodes a member of the bromodomain protein family. The bromodomain is a struct ...
, * CAV3, *
MED1 Mediator of RNA polymerase II transcription subunit 1 also known as DRIP205 or Trap220 is a subunit of the Mediator complex and is a protein that in humans is encoded by the ''MED1'' gene. MED1 functions as a nuclear receptor coactivator. Fun ...
, *
MED12 Mediator of RNA polymerase II transcription, subunit 12 homolog (S. cerevisiae), also known as MED12, is a human gene found on the X chromosome. Clinical significance Mutations in ''MED12'' are responsible for at least two different forms of X- ...
, *
MED24 Mediator of RNA polymerase II transcription subunit 24 is an enzyme that in humans is encoded by the ''MED24'' gene. Function This gene encodes a component of the mediator complex (also known as TRAP, SMCC, DRIP, or ARC), a transcriptional c ...
, *
NCOR1 The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the ''NCOR1'' gene. NCOR1 is a transcriptional coregulatory protein which ...
, * NCOR2, * NCOA2, * RXRA, * RUNX1, * RUNX1T1, * SNW1, * STAT1, and * ZBTB16.


Interactive pathway map


References


Further reading

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External links

*
Nuclear Receptor ResourceVitamin D Receptor: Molecule of the Month

IUPHAR: Vitamin D receptor
* {{Vitamin D receptor modulators Vitamin D Intracellular receptors Transcription factors