Retinoic acid receptor

{{Short description|Type of nuclear receptor}}

{{infobox protein

| Name = retinoic acid receptor alpha

| caption =

| image =

| width =

| HGNCid = 9864

| Symbol = RARA

| AltSymbols =

| EntrezGene = 5914

| OMIM = 180240

| RefSeq = NM_000964

| UniProt = P10276

| PDB =

| ECnumber =

| Chromosome = 17

| Arm = q

| Band = 21.1

| LocusSupplementaryData =

}}

{{infobox protein

| Name = retinoic acid receptor beta

| caption =

| image =

| width =

| HGNCid = 9865

| Symbol = RARB

| AltSymbols =

| EntrezGene = 5915

| OMIM = 180220

| RefSeq = NM_000965

| UniProt = P10826

| PDB =

| ECnumber =

| Chromosome = 3

| Arm = p

| Band = 24

| LocusSupplementaryData =

}}

{{infobox protein

| Name = retinoic acid receptor gamma

| caption =

| image =

| width =

| HGNCid = 9866

| Symbol = RARG

| AltSymbols =

| EntrezGene = 5916

| OMIM = 180190

| RefSeq = NM_000966

| UniProt = P13631

| PDB =

| ECnumber =

| Chromosome = 12

| Arm = q

| Band = 13

| LocusSupplementaryData =

}}

The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor{{cite journal | vauthors = Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H | display-authors = 6 | title = International Union of Pharmacology. LX. Retinoic acid receptors | journal = Pharmacological Reviews | volume = 58 | issue = 4 | pages = 712–725 | date = December 2006 | pmid = 17132850 | doi = 10.1124/pr.58.4.4 | s2cid = 7483165 }} that is activated by both all-trans retinoic acid and 9-cis retinoic acid, retinoid active derivatives of Vitamin A.{{cite journal | vauthors = Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF, Chambon P | display-authors = 6 | title = Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 1 | pages = 30–34 | date = January 1993 | pmid = 8380496 | pmc = 45593 | doi = 10.1073/pnas.90.1.30 | doi-access = free | bibcode = 1993PNAS...90...30A }} They are typically found within the nucleus. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the {{gene|RARA}}, {{gene|RARB}}, {{gene|RARG}} genes, respectively. Within each RAR subtype there are various isoforms differing in their N-terminal region A. Multiple splice variants have been identified in human RARs: four for {{gene|RARA}}, five for {{gene|RARB}}, and two for {{gene|RARG}}.{{cite journal | vauthors = di Masi A, Leboffe L, De Marinis E, Pagano F, Cicconi L, Rochette-Egly C, Lo-Coco F, Ascenzi P, Nervi C | display-authors = 6 | title = Retinoic acid receptors: from molecular mechanisms to cancer therapy | journal = Molecular Aspects of Medicine | volume = 41 | issue = | pages = 1–115 | date = February 2015 | pmid = 25543955 | doi = 10.1016/j.mam.2014.12.003 }} 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.{{cite journal | vauthors = Rotondo JC, Borghi A, Selvatici R, Mazzoni E, Bononi I, Corazza M, Kussini J, Montinari E, Gafà R, Tognon M, Martini F | display-authors = 6 | title = Association of Retinoic Acid Receptor β Gene With Onset and Progression of Lichen Sclerosus-Associated Vulvar Squamous Cell Carcinoma | journal = JAMA Dermatology | volume = 154 | issue = 7 | pages = 819–823 | date = July 2018 | pmid = 29898214 | pmc = 6128494 | doi = 10.1001/jamadermatol.2018.1373 }} Both the length and magnitude of the retinoid response is dependent of the degradation of RARs and RXRs through the ubiquitin-proteasome.{{cite journal | vauthors = Bastien J, Rochette-Egly C | title = Nuclear retinoid receptors and the transcription of retinoid-target genes | journal = Gene | volume = 328 | pages = 1–16 | date = March 2004 | pmid = 15019979 | doi = 10.1016/j.gene.2003.12.005 }} 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. 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.{{Cite journal |last1=Ross-Innes |first1=Caryn S. |last2=Stark |first2=Rory |last3=Holmes |first3=Kelly A. |last4=Schmidt |first4=Dominic |last5=Spyrou |first5=Christiana |last6=Russell |first6=Roslin |last7=Massie |first7=Charlie E. |last8=Vowler |first8=Sarah L. |last9=Eldridge |first9=Matthew |last10=Carroll |first10=Jason S. |date=2010-01-15 |title=Cooperative interaction between retinoic acid receptor-α and estrogen receptor in breast cancer |journal=Genes & Development |volume=24 |issue=2 |pages=171–182 |doi=10.1101/gad.552910 |issn=0890-9369 |pmc=2807352 |pmid=20080953}}

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.{{Cite journal |last1=Petkovich |first1=Martin |last2=Chambon |first2=Pierre |date=2022-11-01 |title=Retinoic acid receptors at 35 years |url=https://jme.bioscientifica.com/view/journals/jme/69/4/JME-22-0097.xml |journal=Journal of Molecular Endocrinology |language=en |volume=69 |issue=4 |pages=T13–T24 |doi=10.1530/JME-22-0097 |pmid=36149754 |issn=1479-6813}}{{Cite journal |last1=Giguère |first1=Vincent |last2=Evans |first2=Ronald M |date=2022-11-01 |title=Chronicle of a discovery: the retinoic acid receptor |url=https://jme.bioscientifica.com/view/journals/jme/69/4/JME-22-0117.xml |journal=Journal of Molecular Endocrinology |volume=69 |issue=4 |pages=T1–T11 |doi=10.1530/JME-22-0117 |pmid=35900848 |issn=0952-5041}}