Retinoic acid receptor alpha explained

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.^{[1] [2]}

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.^{[3] [4]}

Function

Retinoid signaling is transduced by two 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.^[5]

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.^[6]

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.^[7]

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.^[8] 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.^[9] 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.^[9] 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.^[10]

Interactions

Retinoic acid receptor alpha has been shown to interact with:

• BAG1,^[11]
• CLOCK,^[12]
• CCND3,^[13]
• NCOA6,^{[14] [15] [16]}
• NCOR1,^{[17] [18]}
• NCOR2,^{[19] [20]}
• NPAS2,^[12]
• NRIP1,^{[21] [22] [23]}
• NR0B2,^{[24] [25]}
• NR4A2,^[26]
• PML^[27]
• RXRA.^{[28] [29]}
• Src,^{[30] [31]}
• TADA3L,^[32] and
• ZBTB16.^[33]

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 three 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

• Petkovich M, Brand NJ, Krust A, Chambon P . A human retinoic acid receptor which belongs to the family of nuclear receptors . Nature . 330 . 6147 . 444–50 . 1988 . 2825025 . 10.1038/330444a0 . 4271628 .
• Sirulnik A, Melnick A, Zelent A, Licht JD . Molecular pathogenesis of acute promyelocytic leukaemia and APL variants . Best Practice & Research. Clinical Haematology . 16 . 3 . 387–408 . September 2003 . 12935958 . 10.1016/S1521-6926(03)00062-8 .
• Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM . Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling . Nature . 355 . 6359 . 446–9 . January 1992 . 1310351 . 6159885 . 10.1038/355446a0 . 1992Natur.355..446K .
• Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub MP, Durand B, Lanotte M, Berger R, Chambon P . 6 . 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 . 1311253 . 556495 . 10.1002/j.1460-2075.1992.tb05095.x .
• Baniahmad A, Köhne AC, Renkawitz R . 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 . 1347744 . 556542 . 10.1002/j.1460-2075.1992.tb05140.x .
• de Thé H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A . 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 . 1652369 . 10.1016/0092-8674(91)90113-D . 40272758 .
• de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A . 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 . 2170850 . 10.1038/347558a0 . 4314933 . 1990Natur.347..558D .
• Brand NJ, Petkovich M, Chambon P . Characterization of a functional promoter for the human retinoic acid receptor-alpha (hRAR-alpha) . Nucleic Acids Research . 18 . 23 . 6799–806 . December 1990 . 2175878 . 332734 . 10.1093/nar/18.23.6799 .
• Borrow J, Goddard AD, Sheer D, Solomon E . Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17 . Science . 249 . 4976 . 1577–80 . September 1990 . 2218500 . 10.1126/science.2218500 . 1990Sci...249.1577B .
• Arveiler B, Petkovich M, Mandel JL, Chambon P . A PstI RFLP for the human retinoic acid receptor in 17q21 . Nucleic Acids Research . 16 . 13 . 6252 . July 1988 . 2899875 . 336887 . 10.1093/nar/16.13.6252 .
• Chen JD, Evans RM . A transcriptional co-repressor that interacts with nuclear hormone receptors . Nature . 377 . 6548 . 454–7 . October 1995 . 7566127 . 10.1038/377454a0 . 4361329 . 1995Natur.377..454C .
• Fisher GJ, Talwar HS, Xiao JH, Datta SC, Reddy AP, Gaub MP, Rochette-Egly C, Chambon P, Voorhees JJ . 6 . 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 . 10.1016/S0021-9258(17)32039-2 . 8051161 . free .
• Chen Z, Guidez F, Rousselot P, Agadir A, Chen SJ, Wang ZY, Degos L, Zelent A, Waxman S, Chomienne C . 6 . 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 . 8302850 . 521477 . 10.1073/pnas.91.3.1178 . 1994PNAS...91.1178C . free .
• Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ . The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion . Blood . 87 . 3 . 882–6 . February 1996 . 8562957 . 10.1182/blood.V87.3.882.bloodjournal873882 . free .
• Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, Rosenfeld MG . 6 . A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors . Cell . 85 . 3 . 403–14 . May 1996 . 8616895 . 10.1016/S0092-8674(00)81118-6 . 16273727 . free .
• Liu W, Hellman P, Li Q, Yu WR, Juhlin C, Nordlinder H, Rollman O, Akerström G, Törmä H, Melhus H . 6 . 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 . 9005841 . 10.1006/bbrc.1996.1903 .
• Thénot S, Henriquet C, Rochefort H, Cavaillès V . Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1 . The Journal of Biological Chemistry . 272 . 18 . 12062–8 . May 1997 . 9115274 . 10.1074/jbc.272.18.12062 . free .

Notes and References

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3. Web site: Gene symbol report HUGO Gene Nomenclature Committee. 2021-04-27. www.genenames.org.
4. Web site: OMIM Entry - * 180240 - RETINOIC ACID RECEPTOR, ALPHA; RARA. 2021-04-27. www.omim.org.
5. Web site: Entrez Gene: retinoic acid receptor.
6. Kam RK, Deng Y, Chen Y, Zhao H . Retinoic acid synthesis and functions in early embryonic development . Cell & Bioscience . 2 . 1 . 11 . March 2012 . 22439772 . 3325842 . 10.1186/2045-3701-2-11 . free .
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