The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the
nuclear receptor family of
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s.
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
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...
, 1,25-(OH)
2vitamin D
3) 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, o ...
or
transrepression In the field of molecular biology, transrepression is a process whereby one protein represses (i.e., inhibits) the activity of a second protein through a protein-protein interaction. Since this repression occurs between two different protein mole ...
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. mi ...
-directed post transcriptional mechanisms.
In humans, the vitamin D receptor is encoded by the ''VDR''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
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
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
and
renal
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...
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 t ...
and other minerals.
Glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every verteb ...
s 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 D
2 homologue ercalcitriol, ) is also a strong activator. Other forms of vitamin D bind with lower affinity, as does the secondary
bile acid 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 hydro ...
. 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
Rickets is a condition that results in weak or soft bones in children, and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications ma ...
. 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
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling ...
) 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
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
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,
[
* 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 coa ...
,[
* ]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 c ...
,
* NCOR2,[
* NCOA2,]
* RXRA,[
* ]RUNX1
Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the ''RUNX1'' gene.
RUNX1 is a transcription factor that re ...
,[
* ]RUNX1T1
Protein CBFA2T1 is a protein that in humans is encoded by the ''RUNX1T1'' gene.
Function
The protein encoded by this gene is a putative zinc finger transcription factor and oncoprotein. In acute myeloid leukemia, especially in the M2 subtype, ...
,[
* ]SNW1
SNW domain-containing protein 1 is a protein that in humans is encoded by the ''SNW1'' gene.
Function
This gene, a member of the SNW gene family, encodes a coactivator that enhances transcription from some Pol II promoters. This coactivator can ...
,
* STAT1
Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family.
Function
All STAT molecules are phosphorylated by receptor associ ...
, and
* ZBTB16.
Interactive pathway map
References
Further reading
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External links
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Nuclear Receptor Resource
Vitamin D Receptor: Molecule of the Month
IUPHAR: Vitamin D receptor
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{{Vitamin D receptor modulators
Vitamin D
Intracellular receptors
Transcription factors