Retinoid X receptor

retinoid X receptor alpha
Identifiers
SymbolRXRA
NCBI gene6256
HGNC10477
OMIM180245
RefSeqNM_002957
UniProtP19793
Other data
LocusChr. 9 q34
Search for
StructuresSwiss-model
DomainsInterPro
retinoid X receptor beta
Identifiers
SymbolRXRB
NCBI gene6257
HGNC10478
OMIM180246
RefSeqNM_021976
UniProtP28702
Other data
LocusChr. 6 p21.3
Search for
StructuresSwiss-model
DomainsInterPro
retinoid X receptor gamma
Identifiers
SymbolRXRG
NCBI gene6258
HGNC10479
OMIM180247
RefSeqNM_006917
UniProtP48443
Other data
LocusChr. 1 q22-q23
Search for
StructuresSwiss-model
DomainsInterPro

The retinoid X receptor (RXR)[1] is an important family of transcription factors that can combine with various nuclear receptors to form a protein dimer, which is often needed for those receptors to perform their functions. It is also a nuclear receptor which is activated by 9-cis retinoic acid, but whether its role as a direct endogenous receptor is important biologically is controversial.[2][3] It can also bind to 9-cis-13,14-dihydroretinoic acid, which may be an endogenous mammalian RXR-selective agonist.[4] Bexarotene is the only FDA-approved medication that selectively activates the RXRs while exhibiting negligible activity toward the retinoic acid receptors.[5]

There are three retinoic X receptors (RXR): RXR-alpha, RXR-beta, and RXR-gamma, encoded by the RXRA, RXRB, RXRG genes, respectively.

RXR heterodimerizes with multiple nuclear receptors including CAR, FXR, LXR, PPAR,[6] PXR, RAR, TR, ER and VDR. RXRs are permissive co-receptors as only one of six alleles is needed for normal development and health.[7] Given this, it is difficult to extrapolate whether the RXR pathway has its own endogenous activity driven by 9-cis retinoic acid species or whether it merely participates in other pathways, predominantly the retinoic nuclear receptor pathway. Genomic knockout of the RXRs results in obesity resistance[8] while bexarotene treatment causes severe hypothyroidism,[9] suggesting that the RXR pathway functions at least to regulate the thyroid hormone receptor pathway.

Pharmacology

The retinoid X receptors are selectively targeted by certain pharmaceutical retinoids, in particular as part of cancer treatments or to treat severe hand eczema. These including bexarotene and alitretinoin (synthetic 9-cis-retinoic acid), though with the caveat that alitretinoin also has some affinity for the Retinoic Acid Receptors (RARs).[10]

References

  1. ^ Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, et al. (December 2006). "International Union of Pharmacology. LXIII. Retinoid X receptors". Pharmacological Reviews. 58 (4): 760–772. doi:10.1124/pr.58.4.7. PMID 17132853. S2CID 1476000.
  2. ^ de Lera ÁR, Krezel W, Rühl R (May 2016). "An Endogenous Mammalian Retinoid X Receptor Ligand, At Last!". ChemMedChem. 11 (10): 1027–1037. doi:10.1002/cmdc.201600105. PMID 27151148. S2CID 269196.
  3. ^ 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.
  4. ^ Rühl R, Krzyżosiak A, Niewiadomska-Cimicka A, Rochel N, Szeles L, Vaz B, et al. (June 2015). "9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice". PLOS Genetics. 11 (6) e1005213. doi:10.1371/journal.pgen.1005213. PMC 4451509. PMID 26030625.
  5. ^ Panchal MR, Scarisbrick JJ (3 February 2015). "The utility of bexarotene in mycosis fungoides and Sézary syndrome". OncoTargets and Therapy. 8: 367–373. doi:10.2147/OTT.S61308. PMC 4322887. PMID 25678803.
  6. ^ Plutzky J (April 2011). "The PPAR-RXR transcriptional complex in the vasculature: energy in the balance". Circulation Research. 108 (8): 1002–1016. doi:10.1161/CIRCRESAHA.110.226860. PMID 21493923.
  7. ^ Krezel W, Dupé V, Mark M, Dierich A, Kastner P, Chambon P (August 1996). "RXR gamma null mice are apparently normal and compound RXR alpha ±/RXR beta -/-/RXR gamma -/- mutant mice are viable". Proceedings of the National Academy of Sciences of the United States of America. 93 (17): 9010–9014. doi:10.1073/pnas.93.17.9010. PMC 38586. PMID 8799145.
  8. ^ Haugen BR, Jensen DR, Sharma V, Pulawa LK, Hays WR, Krezel W, et al. (August 2004). "Retinoid X receptor gamma-deficient mice have increased skeletal muscle lipoprotein lipase activity and less weight gain when fed a high-fat diet". Endocrinology. 145 (8): 3679–3685. doi:10.1210/en.2003-1401. PMID 15087432.
  9. ^ Esposito M, Amory JK, Kang Y (September 2024). "The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes". The Journal of Experimental Medicine. 221 (9) e20240519. doi:10.1084/jem.20240519. PMC 11318670. PMID 39133222.
  10. ^ Dawson MI, Xia Z (1 January 2012). "The retinoid X receptors and their ligands". Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 1821 (1): 21-56. doi:10.1016/j.bbalip.2011.09.014.
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