Biology:Retinoic acid receptor alpha

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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.

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.

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.

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.

Once retinoic acid binds to the RAR, the heterodimer initiates transcription and allows for its target genes to be expressed.  

Clinical significance

RA signaling has been correlated with several signaling pathways in early embryonic development. First, it participates in the formation of the embryonic 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 affects cardiogenesis, as it plays a role specifically in the formation of the atrial chambers of the heart. RA also plays a role in the development of the pancreas, kidneys, lungs, and extremities.  

Translocations that always involve rearrangement of the RARA gene are a cardinal feature of acute promyelocytic leukemia (APL; MIM 612376). The most frequent translocation is t(15,17)(q21;q22), which fuses the RARA gene with the PML gene.

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. 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. 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. 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.

Interactions

Retinoic acid receptor alpha has been shown to interact with:

• BAG1,
• CLOCK,
• CCND3,
• NCOA6,
• NCOR1,
• NCOR2,
• NPAS2,
• NRIP1,
• NR0B2,
• NR4A2,
• PML
• RXRA.
• Src,
• TADA3L, and
• ZBTB16.

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.

Ligands

Antagonists

• BMS-189453 (non selective)
• YCT529 (selective for RAR-α)

See also

• Retinoic acid receptor
• Retinoic X Receptor
• Acute promyelocytic leukemia

Further reading

• "A human retinoic acid receptor which belongs to the family of nuclear receptors". Nature 330 (6147): 444–50. 1988. doi:10.1038/330444a0. PMID 2825025. 
• "Molecular pathogenesis of acute promyelocytic leukaemia and APL variants". Best Practice & Research. Clinical Haematology 16 (3): 387–408. September 2003. doi:10.1016/S1521-6926(03)00062-8. PMID 12935958. 
• "Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling". Nature 355 (6359): 446–9. January 1992. doi:10.1038/355446a0. PMID 1310351. Bibcode: 1992Natur.355..446K. 
• "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. February 1992. doi:10.1002/j.1460-2075.1992.tb05095.x. PMID 1311253. 
• "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. March 1992. doi:10.1002/j.1460-2075.1992.tb05140.x. PMID 1347744. 
• "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. August 1991. doi:10.1016/0092-8674(91)90113-D. PMID 1652369. 
• "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. October 1990. doi:10.1038/347558a0. PMID 2170850. Bibcode: 1990Natur.347..558D. 
• "Characterization of a functional promoter for the human retinoic acid receptor-alpha (hRAR-alpha)". Nucleic Acids Research 18 (23): 6799–806. December 1990. doi:10.1093/nar/18.23.6799. PMID 2175878. 
• "Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17". Science 249 (4976): 1577–80. September 1990. doi:10.1126/science.2218500. PMID 2218500. Bibcode: 1990Sci...249.1577B. 
• "A PstI RFLP for the human retinoic acid receptor in 17q21". Nucleic Acids Research 16 (13): 6252. July 1988. doi:10.1093/nar/16.13.6252. PMID 2899875. 
• "A transcriptional co-repressor that interacts with nuclear hormone receptors". Nature 377 (6548): 454–7. October 1995. doi:10.1038/377454a0. PMID 7566127. Bibcode: 1995Natur.377..454C. 
• "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. August 1994. doi:10.1016/S0021-9258(17)32039-2. PMID 8051161. 
• "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. February 1994. doi:10.1073/pnas.91.3.1178. PMID 8302850. Bibcode: 1994PNAS...91.1178C. 
• "The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion". Blood 87 (3): 882–6. February 1996. doi:10.1182/blood.V87.3.882.bloodjournal873882. PMID 8562957. 
• "A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors". Cell 85 (3): 403–14. May 1996. doi:10.1016/S0092-8674(00)81118-6. PMID 8616895. https://escholarship.org/uc/item/2cr6b7v8. 
• "Biosynthesis and function of all-trans- and 9-cis-retinoic acid in parathyroid cells". Biochemical and Biophysical Research Communications 229 (3): 922–9. December 1996. doi:10.1006/bbrc.1996.1903. PMID 9005841. 
• "Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1". The Journal of Biological Chemistry 272 (18): 12062–8. May 1997. doi:10.1074/jbc.272.18.12062. PMID 9115274. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.