Retinoic acid receptor alpha
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Location (UCSC) | Chr 17: 40.31 – 40.36 Mb | Chr 11: 98.82 – 98.87 Mb | |||||||
PubMed search | [3] | [4] |
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Retinoic acid receptor alpha (RAR-α), also known as NR1B1 (nuclear receptor subfamily 1, group B, member 1) is a nuclear receptor that in humans is encoded by the RARA gene.[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, a transcription factor. There are another two subtypes of RARs: beta and gamma subtypes.[7][8]
Function
Retinoid signaling is transduced by 2 families of nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR), which form RXR/RAR heterodimers. In the absence of ligand, DNA-bound RXR/RARA represses transcription by recruiting the corepressors NCOR1, SMRT (NCOR2), and histone deacetylase. When ligand binds to the complex, it induces a conformational change allowing the recruitment of coactivators, histone acetyltransferases, and the basic transcription machinery.[9]
Retinoic acid receptor-alpha, the protein, interacts with retinoic acid, a derivative of vitamin 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 initiates transcription and allows for its target genes to be expressed. [10]
Clinical significance
RA signaling has been correlated with several signaling pathways in early
Acute promyeloid leukemia
RARA plays an important role in the establishment of the immune system by inducing T-regulatory cells, promoting tolerance, and controlling the differentiation of immature immune cells in the bone marrow called promyelocytes into mature white 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 a somatic mutation described by the fusion of RARA and the PML gene located on chromosome 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 include all-trans-retinoic acid (ATRA) which works by targeting and degrading the PML-RARα protein complex, in addition to chemotherapy and platelet transfusions.[14]
Interactions
Retinoic acid receptor alpha has been shown to
Genetic studies
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 3 subtypes of RARs work redundantly.[citation needed]
Ligands
- Antagonists
- BMS-189453 (non selective)
- YCT529 (selective for RAR-α)
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000131759 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037992 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 4308015.
- PMID 8244378.
- ^ "Gene symbol report | HUGO Gene Nomenclature Committee". www.genenames.org. Retrieved 2021-04-27.
- ^ a b "OMIM Entry - * 180240 - RETINOIC ACID RECEPTOR, ALPHA; RARA". www.omim.org. Retrieved 2021-04-27.
- ^ "Entrez Gene: retinoic acid receptor".
- ^ PMID 22439772.
- PMID 17468032.
- PMID 19172691.
- ^ PMID 32182684.
- PMID 31842650.
- PMID 9642262.
- ^ S2CID 6251321.
- PMID 12482873.
- PMID 11158331.
- PMID 10567404.
- PMID 10823961.
- PMID 10336495.
- PMID 9531570.
- PMID 11929748.
- PMID 9256429.
- PMID 14581481.
- PMID 12549917.
- PMID 8887632.
- S2CID 32853062.
- PMID 9773978.
- PMID 7705655.
- S2CID 23613492.
- PMID 12052862.
- PMID 1314167.
- PMID 10454579.
- PMID 12612084.
- PMID 12235159.
- PMID 14521715.
Further reading
- 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. S2CID 4271628.
- 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. PMID 12935958.
- Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM (January 1992). "Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling". Nature. 355 (6359): 446–9. PMID 1310351.
- Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub MP, Durand B, et al. (February 1992). "Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins". The EMBO Journal. 11 (2): 629–42. PMID 1311253.
- Baniahmad A, Köhne AC, Renkawitz R (March 1992). "A transferable silencing domain is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor". The EMBO Journal. 11 (3): 1015–23. PMID 1347744.
- 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. S2CID 40272758.
- 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. S2CID 4314933.
- Brand NJ, Petkovich M, Chambon P (December 1990). "Characterization of a functional promoter for the human retinoic acid receptor-alpha (hRAR-alpha)". Nucleic Acids Research. 18 (23): 6799–806. PMID 2175878.
- Borrow J, Goddard AD, Sheer D, Solomon E (September 1990). "Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17". Science. 249 (4976): 1577–80. PMID 2218500.
- Arveiler B, Petkovich M, Mandel JL, Chambon P (July 1988). "A PstI RFLP for the human retinoic acid receptor in 17q21". Nucleic Acids Research. 16 (13): 6252. PMID 2899875.
- Chen JD, Evans RM (October 1995). "A transcriptional co-repressor that interacts with nuclear hormone receptors". Nature. 377 (6548): 454–7. S2CID 4361329.
- Fisher GJ, Talwar HS, Xiao JH, Datta SC, Reddy AP, Gaub MP, et al. (August 1994). "Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin". The Journal of Biological Chemistry. 269 (32): 20629–35. PMID 8051161.
- Chen Z, Guidez F, Rousselot P, Agadir A, Chen SJ, Wang ZY, et al. (February 1994). "PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors". Proceedings of the National Academy of Sciences of the United States of America. 91 (3): 1178–82. PMID 8302850.
- Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ (February 1996). "The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion". Blood. 87 (3): 882–6. PMID 8562957.
- Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, et al. (May 1996). "A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors". Cell. 85 (3): 403–14. S2CID 16273727.
- 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. PMID 9005841.
- Thénot S, Henriquet C, Rochefort H, Cavaillès V (May 1997). "Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1". The Journal of Biological Chemistry. 272 (18): 12062–8. PMID 9115274.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.