The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the ex ...

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 (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

Calcitriol Calcitriol is a hormone and the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the exp ...

(the active form of

vitamin D Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...

, 1,25-(OH)₂vitamin D₃) binds to VDR, which then forms a

heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

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 Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

. VDR binding results in expression 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 molecu ...

of many specific gene products. VDR is also involved in

microRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...

-directed post transcriptional mechanisms. In humans, the vitamin D receptor is encoded by the ''VDR''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

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 tot ...

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 tract is the largest of the body's systems, after the cardiovascular system. T ...

and

renal In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retrop ...

transport of

calcium Calcium is a chemical element; it has 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 to it ...

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 vertebra ...

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 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 in peroxisomes. Bile acids are conjugated with taurine or glycine residues to give anions called bile ...

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 Rickets, scientific nomenclature: rachitis (from Greek , meaning 'in or of the spine'), is a condition that results in weak or soft bones in children and may have either dietary deficiency or genetic causes. Symptoms include bowed legs, stun ...

. 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 In cellular biology, 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, pronounced "wint", is a portmanteau created from the ...

) and

sonic hedgehog Sonic hedgehog protein (SHH) is a major signaling molecule of embryonic development in humans and animals, encoded by the ''SHH'' gene. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organoge ...

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 protein ...

, * CAV3, *

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 co ...

, * NCOR1, * 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) and it is a protein that is encoded by the ''RUNX1'' gene, in humans. RUNX1 is a transcription facto ...

, *

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, *

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

External links