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Retinoic acid receptor alpha
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<h2 id="function">Function</h2> <p><a href="/facts/Retinoid/0TyyRMxr">Retinoid</a> signaling is <a href="/facts/Signal_transduction/1bs0Me6w">transduced</a> by two families of nuclear receptors, retinoic acid receptor (<a href="/facts/Retinoic_acid_receptor/YCYeUb6t">RAR</a>) and retinoid X receptor (<a href="/facts/Retinoid_X_receptor/VhHIuyLy">RXR</a>), which form RXR/RAR <a href="/facts/Heterodimer/c8LwFJPG">heterodimers</a>. In the absence of ligand, DNA-bound <a href="/facts/Retinoid_X_receptor_gamma/govb9v94">RXR</a>/RARA <a href="/facts/Repressor/qGBBQwqS">represses transcription</a> by recruiting the <a href="/facts/Corepressor/2C1GqzD0">corepressors</a> <a href="/facts/Nuclear_receptor_co-repressor_1/s9ytQSwA">NCOR1</a>, SMRT (<a href="/facts/Nuclear_receptor_co-repressor_2/hyspxexv">NCOR2</a>), and <a href="/facts/Histone_deacetylase/P38q78aV">histone deacetylase</a>. When ligand binds to the complex, it induces a conformational change allowing the recruitment of <a href="/facts/Coactivator/0lVABmQx">coactivators</a>, <a href="/facts/Histone_acetyltransferase/gIzJY5fn">histone acetyltransferases</a>, and the basic transcription machinery.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> </p><p>Retinoic acid receptor-alpha, the protein, interacts with <a href="/facts/Retinoic_acid/tlyLyvCT">retinoic acid</a>, a derivative of <a href="/facts/Vitamin_A/5ewDf9LF">vitamin A</a>, which plays an important role in cell growth, differentiation, and the formation of organs in embryonic development.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p><p>Once retinoic acid binds to the RAR, the heterodimer initiates <a href="/facts/Transcription_(biology)/bDgp9HDN">transcription</a> and allows for its target genes to be expressed. <a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <h2 id="clinical-significance">Clinical significance</h2> <p>RA signaling has been correlated with several signaling pathways in early <a href="/facts/Embryonic_development/1lFY4EoW">embryonic development</a>. 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 (<a href="/facts/Neurogenin-2/c4hY1z22">Neurog2</a>). RA affects <a href="/facts/Cardiogenesis/wL9UQjsb">cardiogenesis</a>, as it plays a role specifically in the formation of the <a href="/facts/Atrium_(heart)/eYNg8Vw2">atrial chambers</a> of the heart. RA also plays a role in the development of the pancreas, kidneys, lungs, and extremities. <a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p><p><a href="/facts/Translocations/MKEwqpQw">Translocations</a> that always involve rearrangement of the <i>RARA</i> gene are a cardinal feature of <a href="/facts/Acute_promyelocytic_leukemia/dFxwxHoX">acute promyelocytic leukemia</a> (APL; MIM 612376). The most frequent translocation is t(15,17)(q21;q22), which fuses the <i>RARA</i> gene with the <i><a href="/facts/Promyelocytic_leukemia_protein/QdCl05AJ">PML</a></i> gene.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <h2 id="acute-promyeloid-leukemia">Acute promyeloid leukemia</h2> <p>RARA plays an important role in the establishment of the immune system by inducing <a href="/facts/T-regulatory_cell/1ECRAGMg">T-regulatory cells</a>, promoting tolerance, and controlling the differentiation of immature immune cells in the <a href="/facts/Bone_marrow/4dfudk0H">bone marrow</a> called <a href="/facts/Promyelocyte/SdvC8MHT">promyelocytes</a> into mature <a href="/facts/White_blood_cell/vsDunUK0">white blood cells</a>.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> 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 <a href="/facts/Somatic_mutation/VpVSmN9y">somatic mutation</a> described by the fusion of <i>RARA</i> and the <i>PML</i> gene located on <a href="/facts/Chromosome_15/5omtrEyl">chromosome 15</a>.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> 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.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> 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 <a href="/facts/All-trans-retinoic_acid/DjthvC01">all-trans-retinoic acid</a> (ATRA) which works by targeting and degrading the PML-RARα protein complex, in addition to <a href="/facts/Chemotherapy/fWTLbaUT">chemotherapy</a> and <a href="/facts/Platelet_transfusion/gW8kQnDn">platelet transfusions</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h2 id="interactions">Interactions</h2> <p>Retinoic acid receptor alpha has been shown to <a href="/facts/Protein-protein_interaction/etvm9Wmg">interact</a> with: </p> <ul><li><a href="/facts/BAG1/VE1afUuC">BAG1</a>,<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a></li> <li><a href="/facts/CLOCK/lhutPKq1">CLOCK</a>,<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a></li> <li><a href="/facts/Cyclin_D3/eWasw7CL">CCND3</a>,<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a></li> <li><a href="/facts/NCOA6/zqUpCwbH">NCOA6</a>,<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a></li> <li><a href="/facts/Nuclear_receptor_co-repressor_1/s9ytQSwA">NCOR1</a>,<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a></li> <li><a href="/facts/Nuclear_receptor_co-repressor_2/hyspxexv">NCOR2</a>,<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a></li> <li><a href="/facts/NPAS2/Lg9NhkDc">NPAS2</a>,<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a></li> <li><a href="/facts/NRIP1/gIgg3yJm">NRIP1</a>,<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a></li> <li><a href="/facts/Small_heterodimer_partner/CnBNGHjs">NR0B2</a>,<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a></li> <li><a href="/facts/Nuclear_receptor_related_1_protein/SjGTW9oN">NR4A2</a>,<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a></li> <li><a href="/facts/Promyelocytic_leukemia_protein/QdCl05AJ">PML</a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a></li> <li><a href="/facts/Retinoid_X_receptor_alpha/y69mBhSt">RXRA</a>.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a></li> <li><a href="/facts/Src_(gene)/5SCJqCU4">Src</a>,<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a><a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a></li> <li><a href="/facts/TADA3L/WvB1AnTF">TADA3L</a>,<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> and</li> <li><a href="/facts/Zinc_finger_and_BTB_domain-containing_protein_16/8ScfHtFk">ZBTB16</a>.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a></li></ul> <h2 id="genetic-studies">Genetic studies</h2> <p>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. </p> <h2 id="ligands">Ligands</h2> Antagonists <ul><li>BMS-189453 (non selective)</li> <li><a href="/facts/YCT529/vwy55Qkw">YCT529</a> (selective for RAR-α)</li></ul> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Retinoic_acid_receptor/YCYeUb6t">Retinoic acid receptor</a></li> <li><a href="/facts/Retinoid_X_receptor/VhHIuyLy">Retinoic X receptor</a></li> <li><a href="/facts/Acute_promyelocytic_leukemia/dFxwxHoX">Acute promyelocytic leukemia</a></li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Petkovich M, Brand NJ, Krust A, Chambon P (1988). "A human retinoic acid receptor which belongs to the family of nuclear receptors". <i>Nature</i>. 330 (6147): 444–50. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2F330444a0">10.1038/330444a0</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/2825025">2825025</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:4271628">4271628</a>.</li> <li>Sirulnik A, Melnick A, Zelent A, Licht JD (September 2003). "Molecular pathogenesis of acute promyelocytic leukaemia and APL variants". <i>Best Practice & Research. Clinical Haematology</i>. 16 (3): 387–408. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS1521-6926%2803%2900062-8">10.1016/S1521-6926(03)00062-8</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12935958">12935958</a>.</li> <li>Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM (January 1992). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159885">"Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling"</a>. <i>Nature</i>. 355 (6359): 446–9. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1992Natur.355..446K">1992Natur.355..446K</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2F355446a0">10.1038/355446a0</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159885">6159885</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/1310351">1310351</a>.</li> <li>Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub MP, Durand B, et al. (February 1992). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556495">"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"</a>. <i>The EMBO Journal</i>. 11 (2): 629–42. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2Fj.1460-2075.1992.tb05095.x">10.1002/j.1460-2075.1992.tb05095.x</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556495">556495</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/1311253">1311253</a>.</li> <li>Baniahmad A, Köhne AC, Renkawitz R (March 1992). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556542">"A transferable silencing domain is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor"</a>. <i>The EMBO Journal</i>. 11 (3): 1015–23. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2Fj.1460-2075.1992.tb05140.x">10.1002/j.1460-2075.1992.tb05140.x</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556542">556542</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/1347744">1347744</a>.</li> <li>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". <i>Cell</i>. 66 (4): 675–84. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2F0092-8674%2891%2990113-D">10.1016/0092-8674(91)90113-D</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/1652369">1652369</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:40272758">40272758</a>.</li> <li>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". <i>Nature</i>. 347 (6293): 558–61. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1990Natur.347..558D">1990Natur.347..558D</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2F347558a0">10.1038/347558a0</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/2170850">2170850</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:4314933">4314933</a>.</li> <li>Brand NJ, Petkovich M, Chambon P (December 1990). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC332734">"Characterization of a functional promoter for the human retinoic acid receptor-alpha (hRAR-alpha)"</a>. <i>Nucleic Acids Research</i>. 18 (23): 6799–806. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Fnar%2F18.23.6799">10.1093/nar/18.23.6799</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC332734">332734</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/2175878">2175878</a>.</li> <li>Borrow J, Goddard AD, Sheer D, Solomon E (September 1990). "Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17". <i>Science</i>. 249 (4976): 1577–80. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1990Sci...249.1577B">1990Sci...249.1577B</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1126%2Fscience.2218500">10.1126/science.2218500</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/2218500">2218500</a>.</li> <li>Arveiler B, Petkovich M, Mandel JL, Chambon P (July 1988). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC336887">"A PstI RFLP for the human retinoic acid receptor in 17q21"</a>. <i>Nucleic Acids Research</i>. 16 (13): 6252. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Fnar%2F16.13.6252">10.1093/nar/16.13.6252</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC336887">336887</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/2899875">2899875</a>.</li> <li>Chen JD, Evans RM (October 1995). "A transcriptional co-repressor that interacts with nuclear hormone receptors". <i>Nature</i>. 377 (6548): 454–7. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1995Natur.377..454C">1995Natur.377..454C</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2F377454a0">10.1038/377454a0</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/7566127">7566127</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:4361329">4361329</a>.</li> <li>Fisher GJ, Talwar HS, Xiao JH, Datta SC, Reddy AP, Gaub MP, et al. (August 1994). <a href="https://doi.org/10.1016%2FS0021-9258%2817%2932039-2">"Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin"</a>. <i>The Journal of Biological Chemistry</i>. 269 (32): 20629–35. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0021-9258%2817%2932039-2">10.1016/S0021-9258(17)32039-2</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8051161">8051161</a>.</li> <li>Chen Z, Guidez F, Rousselot P, Agadir A, Chen SJ, Wang ZY, et al. 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