Retinoic acid receptor alpha (RAR-α), also known asNR1B1 (nuclear receptor subfamily 1, group B, member 1), is anuclear receptor that in humans is encoded by theRARAgene.[5][6]
NR1B1 is a gene with a protein product and has a chromosomal location of 17q21.2.RARA codes for the nuclear hormone receptor retinoic acid receptor, alpha subtype, atranscription factor. There are another two subtypes of RARs: beta and gamma subtypes.[7][8]
Retinoic acid receptor-alpha, the protein, interacts withretinoic acid, a derivative ofvitamin A, which plays an important role in cell growth, differentiation, and the formation of organs in embryonic development.[8][10]
Once retinoic acid binds to the RAR, the heterodimer initiatestranscription and allows for its target genes to be expressed.[10]
RA signaling has been correlated with several signaling pathways in earlyembryonic development. First, it participates in the formation of theembryonic axis, which establishes symmetry in the offspring. RA also influences neural differentiation by regulating the expression of pro-neural induction factor Neurogenin 2 (Neurog2). RA affectscardiogenesis, as it plays a role specifically in the formation of theatrial chambers of the heart. RA also plays a role in the development of the pancreas, kidneys, lungs, and extremities. [10]
Translocations that always involve rearrangement of theRARA gene are a cardinal feature ofacute promyelocytic leukemia (APL; MIM 612376). The most frequent translocation is t(15,17)(q21;q22), which fuses theRARA gene with thePML gene.[11]
RARA plays an important role in the establishment of the immune system by inducingT-regulatory cells, promoting tolerance, and controlling the differentiation of immature immune cells in thebone marrow calledpromyelocytes into maturewhite blood cells.[12] The prevalence of this gene in the developing immune system leaves it subject to possible defects, the most common of which is a condition known as acute promyeloid leukemia (APL), caused by asomatic mutation described by the fusion ofRARA and thePML gene located onchromosome 15.[13] This fusion results in the formation of the protein complex PML-RARα. Under normal circumstances, PML produces a tumor suppressing protein that works by inhibiting uncontrolled rapid cell growth. When the two proteins fuse together, their normal functions are hindered, resulting in the accumulation of promyelocytes in the bone marrow unable to differentiate past this immature phase.[13] This fusion makes up for the cause of 98% of APL cases, with some other rare mutations and fusions making up the other 2%.6 Current treatment approaches includeall-trans-retinoic acid (ATRA) which works by targeting and degrading the PML-RARα protein complex, in addition tochemotherapy andplatelet transfusions.[14]
Knock-out mice studies showed that a deletion in one of the copies of the RARA gene did not create any observable defect, while deletion of both copies shows symptoms similar to that of vitamin A deficiency. This proved that all three subtypes of RARs work redundantly.[citation needed]
^Anderson LA, Friedman L, Osborne-Lawrence S, Lynch E, Weissenbach J, Bowcock A, King MC (September 1993). "High-density genetic map of the BRCA1 region of chromosome 17q12-q21".Genomics.17 (3):618–23.doi:10.1006/geno.1993.1381.PMID8244378.
^Vitoux D, Nasr R, de The H (2007). "Acute promyelocytic leukemia: new issues on pathogenesis and treatment response".The International Journal of Biochemistry & Cell Biology.39 (6):1063–70.doi:10.1016/j.biocel.2007.01.028.PMID17468032.
^Zhong S, Delva L, Rachez C, Cenciarelli C, Gandini D, Zhang H, et al. (November 1999). "A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARalpha and T18 oncoproteins".Nature Genetics.23 (3):287–95.doi:10.1038/15463.PMID10610177.S2CID23613492.
Petkovich M, Brand NJ, Krust A, Chambon P (1988). "A human retinoic acid receptor which belongs to the family of nuclear receptors".Nature.330 (6147):444–50.doi:10.1038/330444a0.PMID2825025.S2CID4271628.
Sirulnik A, Melnick A, Zelent A, Licht JD (September 2003). "Molecular pathogenesis of acute promyelocytic leukaemia and APL variants".Best Practice & Research. Clinical Haematology.16 (3):387–408.doi:10.1016/S1521-6926(03)00062-8.PMID12935958.
de Thé H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A (August 1991). "The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR".Cell.66 (4):675–84.doi:10.1016/0092-8674(91)90113-D.PMID1652369.S2CID40272758.
de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A (October 1990). "The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus".Nature.347 (6293):558–61.Bibcode:1990Natur.347..558D.doi:10.1038/347558a0.PMID2170850.S2CID4314933.
Liu W, Hellman P, Li Q, Yu WR, Juhlin C, Nordlinder H, et al. (December 1996). "Biosynthesis and function of all-trans- and 9-cis-retinoic acid in parathyroid cells".Biochemical and Biophysical Research Communications.229 (3):922–9.Bibcode:1996BBRC..229..922L.doi:10.1006/bbrc.1996.1903.PMID9005841.
