Retinoic acid receptor

Last updated
retinoic acid receptor alpha
Identifiers
SymbolRARA
NCBI gene 5914
HGNC 9864
OMIM 180240
RefSeq NM_000964
UniProt P10276
Other data
Locus Chr. 17 q21.1
Search for
Structures Swiss-model
Domains InterPro
retinoic acid receptor beta
Identifiers
SymbolRARB
NCBI gene 5915
HGNC 9865
OMIM 180220
RefSeq NM_000965
UniProt P10826
Other data
Locus Chr. 3 p24
Search for
Structures Swiss-model
Domains InterPro
retinoic acid receptor gamma
Identifiers
SymbolRARG
NCBI gene 5916
HGNC 9866
OMIM 180190
RefSeq NM_000966
UniProt P13631
Other data
Locus Chr. 12 q13
Search for
Structures Swiss-model
Domains InterPro

The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor [1] that is activated by both all-trans retinoic acid and 9-cis retinoic acid, retinoid active derivatives of Vitamin A. [2] They are typically found within the nucleus. [3] There are three retinoic acid receptors (RAR), RAR-alpha , RAR-beta , and RAR-gamma , encoded by the RARA , RARB , RARG genes, respectively. Within each RAR subtype there are various isoforms differing in their N-terminal region A. [1] Multiple splice variants have been identified in human RARs: four for RARA , five for RARB , and two for RARG . [4] As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements known as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation. [5] Both the length and magnitude of the retinoid response is dependent of the degradation of RARs and RXRs through the ubiquitin-proteasome. [3] This degradation can lead to elongation of the DNA transcription through disruption of the initiation complex or to end the response to facilitate further transcriptional programs. [3] RAR receptors are also known to exhibit many retinoid-independent effects as they bind to and regulate other nuclear receptor pathways, such as the estrogen receptor. [6]

Contents

RARs play a crucial role in embryonic development. Mice knockout studies of RARs revealed that knocking out RARs could fully replicate the spectrum of defects associated with fetal vitamin A deficiency syndrome, unveiling additional abnormalities beyond previously known vitamin A functions. Notably, double RAR mutants exhibited the most severe defects, including ocular and cardiovascular defects, indicating some level of redundancy among RARs. RXR/RAR heterodimers transmit retinoid signals in diverse ways to control the expression of networks of retinoic acid (RA) target genes. This process plays a crucial role in shaping both the axial and limb patterning during early embryo development, as well as influencing various aspects of organ formation in later stages of development. [7] [8]

See also

Related Research Articles

A hormone receptor is a receptor molecule that binds to a specific hormone. Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and Vitamin D, and a variety of other receptors for various ligands, such as fatty acids and prostaglandins. Hormone receptors are of mainly two classes. Receptors for peptide hormones tend to be cell surface receptors built into the plasma membrane of cells and are thus referred to as trans membrane receptors. An example of this is Actrapid. Receptors for steroid hormones are usually found within the protoplasm and are referred to as intracellular or nuclear receptors, such as testosterone. Upon hormone binding, the receptor can initiate multiple signaling pathways, which ultimately leads to changes in the behavior of the target cells.

<span class="mw-page-title-main">Retinoic acid</span> Metabolite of vitamin A

Retinoic acid (simplified nomenclature for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-trans-retinoic acid is required for chordate animal development, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages. In adult tissues, the activity of endogenous retinoic acid appears limited to immune function. and male fertility. Retinoic acid administered as a drug (see tretinoin and alitretinoin) causes significant toxicity that is distinct from normal retinoid biology.

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.

The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-cis-13,14-dihydroretinoic acid, which may be an endogenous mammalian RXR-selective agonist. Bexarotene is the only specific activator of the RXRs which does not activate the Retinoic Acid Receptors.

<span class="mw-page-title-main">Nuclear receptor</span> Protein

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 expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.

Retinoid receptors are type II nuclear receptors that bind to retinoids. When bound to a retinoid, they act as transcription factors, altering the expression of genes with corresponding response elements.

<span class="mw-page-title-main">Nuclear receptor coactivator 2</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor coactivator 2 also known as NCoA-2 is a protein that in humans is encoded by the NCOA2 gene. NCoA-2 is also frequently called glucocorticoid receptor-interacting protein 1 (GRIP1), steroid receptor coactivator-2 (SRC-2), or transcriptional mediators/intermediary factor 2 (TIF2).

<span class="mw-page-title-main">Nuclear receptor co-repressor 2</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor co-repressor 2 (NCOR2) is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target gene expression. NCOR2 is also referred to as a silencing mediator for retinoid or thyroid-hormone receptors (SMRT) or T3 receptor-associating cofactor 1 (TRAC-1).

<span class="mw-page-title-main">Small heterodimer partner</span> Protein found in humans

The small heterodimer partner (SHP) also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.

<span class="mw-page-title-main">Retinoid X receptor alpha</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.

<span class="mw-page-title-main">Retinoic acid receptor alpha</span> Protein found in humans

Retinoic acid receptor alpha (RAR-α), also known as NR1B1, is a nuclear receptor that in humans is encoded by the RARA gene.

<span class="mw-page-title-main">Retinoid X receptor gamma</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor gamma (RXR-gamma), also known as NR2B3 is a nuclear receptor that in humans is encoded by the RXRG gene.

<span class="mw-page-title-main">Retinoid X receptor beta</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.

<span class="mw-page-title-main">Retinoic acid receptor beta</span> Protein-coding gene in the species Homo sapiens

Retinoic acid receptor beta (RAR-beta), also known as NR1B2 is a nuclear receptor that in humans is encoded by the RARB gene.

<span class="mw-page-title-main">Retinoic acid receptor gamma</span> Protein-coding gene in the species Homo sapiens

Retinoic acid receptor gamma (RAR-γ), also known as NR1B3 is a nuclear receptor encoded by the RARG gene. Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma and its agonism of the gamma subtype is largely responsible for adapalene's observed effects.

<span class="mw-page-title-main">CRABP2</span> Protein-coding gene in the species Homo sapiens

Cellular retinoic acid-binding protein 2 is a cytoplasmic binding protein that in humans is encoded by the CRABP2 gene.

<span class="mw-page-title-main">TRIM24</span> Protein-coding gene in the species Homo sapiens

Tripartite motif-containing 24 (TRIM24) also known as transcriptional intermediary factor 1α (TIF1α) is a protein that, in humans, is encoded by the TRIM24 gene.

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 D, and so regulates the expression of many genes.

Dino Moras, born on 23 November 1944, is a French biochemist, research director at the CNRS and co-director of the Institute of Genetics and Molecular and Cellular Biology (IGBMC) in Illkirch-Graffenstaden until 2010.

Microphthalmia, syndromic 12 (MCOPS12) is an ultra-rare and complex neurological disease. It is caused by a single-point missense mutation in the retinoic acid receptor beta (RARB) gene. The most common disease symptoms are microphthalmia, severe (progressive) movement disorders and intellectual disability. Movement disorders may include spasticity, dystonia and chorea. In addition, malformations such as incomplete lung development, defects of the cerebellum, and a defect/hole in the diaphragm have been observed.

References

  1. 1 2 Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, et al. (December 2006). "International Union of Pharmacology. LX. Retinoic acid receptors". Pharmacological Reviews. 58 (4): 712–725. doi:10.1124/pr.58.4.4. PMID   17132850. S2CID   7483165.
  2. ↑ Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, et al. (January 1993). "Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids". Proceedings of the National Academy of Sciences of the United States of America. 90 (1): 30–34. Bibcode:1993PNAS...90...30A. doi: 10.1073/pnas.90.1.30 . PMC   45593 . PMID   8380496.
  3. 1 2 3 Bastien J, Rochette-Egly C (March 2004). "Nuclear retinoid receptors and the transcription of retinoid-target genes". Gene. 328: 1–16. doi:10.1016/j.gene.2003.12.005. PMID   15019979.
  4. ↑ di Masi A, Leboffe L, De Marinis E, Pagano F, Cicconi L, Rochette-Egly C, et al. (February 2015). "Retinoic acid receptors: from molecular mechanisms to cancer therapy". Molecular Aspects of Medicine. 41: 1–115. doi:10.1016/j.mam.2014.12.003. PMID   25543955.
  5. ↑ Rotondo JC, Borghi A, Selvatici R, Mazzoni E, Bononi I, Corazza M, et al. (July 2018). "Association of Retinoic Acid Receptor β Gene With Onset and Progression of Lichen Sclerosus-Associated Vulvar Squamous Cell Carcinoma". JAMA Dermatology. 154 (7): 819–823. doi:10.1001/jamadermatol.2018.1373. PMC   6128494 . PMID   29898214.
  6. ↑ Ross-Innes, Caryn S.; Stark, Rory; Holmes, Kelly A.; Schmidt, Dominic; Spyrou, Christiana; Russell, Roslin; Massie, Charlie E.; Vowler, Sarah L.; Eldridge, Matthew; Carroll, Jason S. (2010-01-15). "Cooperative interaction between retinoic acid receptor-α and estrogen receptor in breast cancer". Genes & Development. 24 (2): 171–182. doi:10.1101/gad.552910. ISSN   0890-9369. PMC   2807352 . PMID   20080953.
  7. ↑ Petkovich, Martin; Chambon, Pierre (2022-11-01). "Retinoic acid receptors at 35 years". Journal of Molecular Endocrinology. 69 (4): T13–T24. doi:10.1530/JME-22-0097. ISSN   1479-6813. PMID   36149754.
  8. ↑ Giguère, Vincent; Evans, Ronald M (2022-11-01). "Chronicle of a discovery: the retinoic acid receptor". Journal of Molecular Endocrinology. 69 (4): T1–T11. doi:10.1530/JME-22-0117. ISSN   0952-5041. PMID   35900848.
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