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SIM2
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<h2 id="function">Function</h2> <p><i><a href="/facts/SIM1/fo2M9mu3">SIM1</a></i> and <i>SIM2</i> genes are <i><a href="/facts/Drosophila/P4K7RkJl">Drosophila</a></i> single-minded (sim) gene homologs. The Drosophila sim gene encodes a <a href="/facts/Transcription_factor/wro0DPHe">transcription factor</a> that is a master regulator of <a href="/facts/Neurogenesis/XSteTv8s">neurogenesis</a> of midline cells in the central nervous system. SIM2 maps within the so-called <a href="/facts/Down_syndrome/Y4XEQSMS">Down syndrome</a> chromosomal region, specifically on the <a href="/facts/Q_arm/JcIT8wLm">q arm</a> of <a href="/facts/Chromosome_21/F1nQLrCp">chromosome 21</a>, band 22.2.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> Based on the mapping position, its potential function as transcriptional repressor and similarity to Drosophila sim, it is proposed that SIM2 may contribute to some specific Down syndrome phenotypes<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> </p> <h2 id="interactions">Interactions</h2> <p>SIM2 has been shown to <a href="/facts/Protein-protein_interaction/etvm9Wmg">interact</a> with <a href="/facts/Aryl_hydrocarbon_receptor_nuclear_translocator/bHrUYbde">Aryl hydrocarbon receptor nuclear translocator</a>.<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><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a><a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p><p>When the SIM2 gene is transfected into <a href="/facts/PC12_cells/BHh57yNT">PC12 cells</a>, it affects the normal cycle of cell maturation. SIM2 inhibits the expression of <a href="/facts/Cyclin_E/dRQ2EKem">cyclin E</a>, which in turn inhibits the cell's ability to pass through the G1/S checkpoint and suppresses the cell's proliferation ability. it also up-regulates the presence of <a href="/facts/P27_(gene)/PrucRk1D">p27</a>, a growth <a href="/facts/Inhibitor_protein/o9QF2LKh">inhibitor protein</a>. The presence of p27 inhibits the activation of cell cycle regulatory <a href="/facts/Kinases/dhlHpjnD">kinases</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <h2 id="disease-state">Disease state</h2> <p>There are three states of the gene: +/+, +/-, and -/-. When the gene is expressed as SIM2 -/-, it is considered disrupted and many physical malformations are seen, particularly in the <a href="/facts/Craniofacial/ANgNovfE">craniofacial</a> area. Individuals with SIM2 -/- have either a full or partial <a href="/facts/Secondary_palate/Sp8xupIl">secondary palate</a> <a href="/facts/Cleft_lip_and_palate/CoLE8Wbu">cleft</a> and malformations in the tongue and <a href="/facts/Pterygoid_processes/YpwfNENw">pterygoid processes</a> of the <a href="/facts/Sphenoid_bone/7GGt2f8s">sphenoid bone</a>. These malformations cause <a href="/facts/Aerophagia/Mcw5yDPu">aerophagia</a>, or the swallowing of air, and <a href="/facts/Postnatal/abLj2JtY">postnatal</a> death. Severe aerophagia leads to accumulation of air in the <a href="/facts/Gastrointestinal_tract/nK2zwqBS">gastrointestinal tract</a>, causing the belly to be distended.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> It is thought that the over-expression of the SIM2 gene brings about some of the phenotypic deformities that are characteristic of <a href="/facts/Down_syndrome/Y4XEQSMS">Down syndrome</a>. The presence of SIM2 <a href="/facts/MRNA/oUL6qxQn">mRNA</a> in many parts of the brain known to show deformities in individuals with Down syndrome, as well as in the <a href="/facts/Palate/o0RMlkss">palate</a>, oral and tongue <a href="/facts/Epithelia/ecKHcHC3">epithelia</a>, <a href="/facts/Mandibular/1ATEfAQa">mandibular</a> and <a href="/facts/Hyoid/yAa2Vatb">hyoid</a> bones.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h2 id="sim2-short-sim2s">SIM2 Short (SIM2s)</h2> <p>There are two known isoforms of SIM2 which play different roles in various tissues. The isoform SIM2 Short (SIM2s) has been shown to be specifically expressed in <a href="/facts/Mammary_gland/6fVBnNSA">mammary gland</a> tissue.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> SIM2s is a splice variant which lacks <a href="/facts/Exon/8KWJtLuN">exon</a> 11 of SIM2.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> It has been researched that SIM2s acts in mammary gland development and has tumor suppressive characteristics specifically in breast cancer.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> In a mouse specimen, when SIM2s was not expressed in mammary epithelial cells there were development defects leading to cancer-like characteristics in the cells.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> The defects were increased cell proliferation, cellular invasion of local stroma, loss of cellular polarity, and loss of E-cadherin cellular adhesion molecules.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> These observations suggest that SIM2s is essential for proper mammary gland development.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> Experiments reintroducing SIM2s in human breast cancer cells allowed for the tumor suppressive characteristics to be observed. Comparing normal human breast cells to human breast cancer cells with immunohistochemical staining showed that SIM2s was expressed more in the normal than the cancerous.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> Reintroducing SIM2s expression in breast cancer cells showed a decrease in growth, proliferation, and invasiveness.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> SIM2s represses the actions of the matrix metalloprotease-3 gene (MMP3) which include cell migration, cancer progression, and epithelial to mesenchymal transitions (EMT).<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> SIM2s also represses the SLUG transcription factor which in turn suppresses EMT.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> EMT suppression allows for E-cadherin to remain and for the cell to not undergo pathological EMT associated with tumor formation.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> These actions show the tumor suppressive effects of SIM2s in mammary epithelium. </p> <h2 id="knockout-model">Knockout model</h2> <p>Scientists can purposefully "knockout" or cause the gene to be disrupted. To do this, they perform <a href="/facts/Homologous_recombination/WU0IIVVv">homologous recombination</a> and eliminate the predicted start codon and the following 47 <a href="/facts/Amino_acids/WDxYwBny">amino acids</a>. Then the <a href="/facts/EcoRI/BQABUyYE">EcoRI</a> restriction site is introduced into the chromosome.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> </p> <h2 id="further-reading">Further reading</h2> <ul><li>Dahmane N, Charron G, Lopes C, Yaspo ML, Maunoury C, Decorte L, et al. (September 1995). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC40950">"Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development"</a>. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 92 (20): 9191–9195. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1995PNAS...92.9191D">1995PNAS...92.9191D</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1073%2Fpnas.92.20.9191">10.1073/pnas.92.20.9191</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC40950">40950</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/7568099">7568099</a>.</li> <li>Chen H, Chrast R, Rossier C, Gos A, Antonarakis SE, Kudoh J, et al. (May 1995). "Single-minded and Down syndrome?". <i>Nature Genetics</i>. 10 (1): 9–10. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fng0595-9">10.1038/ng0595-9</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/7647800">7647800</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:12087372">12087372</a>.</li> <li>Yamaki A, Noda S, Kudoh J, Shindoh N, Maeda H, Minoshima S, et al. (July 1996). "The mammalian single-minded (SIM) gene: mouse cDNA structure and diencephalic expression indicate a candidate gene for Down syndrome". <i>Genomics</i>. 35 (1): 136–143. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1006%2Fgeno.1996.0332">10.1006/geno.1996.0332</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8661114">8661114</a>.</li> <li>Fan CM, Kuwana E, Bulfone A, Fletcher CF, Copeland NG, Jenkins NA, et al. (January 1996). "Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome". <i>Molecular and Cellular Neurosciences</i>. 7 (1): 1–16. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1006%2Fmcne.1996.0001">10.1006/mcne.1996.0001</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8812055">8812055</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:11411254">11411254</a>.</li> <li>Osoegawa K, Okano S, Kato Y, Nishimura Y, Soeda E (June 1996). "A 19-kb CpG island associated with single-minded gene 2 in Down syndrome chromosomal region". <i>DNA Research</i>. 3 (3): 175–179. <a href="/facts/CiteSeerX_(identifier)/SceDmd3c">CiteSeerX</a> <a href="https://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.588.7194">10.1.1.588.7194</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Fdnares%2F3.3.175">10.1093/dnares/3.3.175</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8905236">8905236</a>.</li> <li>Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O (February 1997). <a href="https://doi.org/10.1074%2Fjbc.272.7.4451">"Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein"</a>. <i>The Journal of Biological Chemistry</i>. 272 (7): 4451–4457. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.272.7.4451">10.1074/jbc.272.7.4451</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9020169">9020169</a>.</li> <li>Chrast R, Scott HS, Chen H, Kudoh J, Rossier C, Minoshima S, et al. (June 1997). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC310662">"Cloning of two human homologs of the Drosophila single-minded gene SIM1 on chromosome 6q and SIM2 on 21q within the Down syndrome chromosomal region"</a>. <i>Genome Research</i>. 7 (6): 615–624. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1101%2Fgr.7.6.615">10.1101/gr.7.6.615</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC310662">310662</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9199934">9199934</a>.</li> <li>Moffett P, Reece M, Pelletier J (September 1997). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC232345">"The murine Sim-2 gene product inhibits transcription by active repression and functional interference"</a>. <i>Molecular and Cellular Biology</i>. 17 (9): 4933–4947. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1128%2Fmcb.17.9.4933">10.1128/mcb.17.9.4933</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC232345">232345</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9271372">9271372</a>.</li> <li>Dahmane N, Ghezala GA, Gosset P, Chamoun Z, Dufresne-Zacharia MC, Lopes C, et al. (February 1998). "Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome". <i>Genomics</i>. 48 (1): 12–23. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1006%2Fgeno.1997.5146">10.1006/geno.1997.5146</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9503011">9503011</a>.</li> <li>Ema M, Ikegami S, Hosoya T, Mimura J, Ohtani H, Nakao K, et al. (August 1999). <a href="https://doi.org/10.1093%2Fhmg%2F8.8.1409">"Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome"</a>. <i>Human Molecular Genetics</i>. 8 (8): 1409–1415. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Fhmg%2F8.8.1409">10.1093/hmg/8.8.1409</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10400987">10400987</a>.</li> <li>Yamaki A, Tochigi J, Kudoh J, Minoshima S, Shimizu N, Shimizu Y (May 2001). "Molecular mechanisms of human single-minded 2 (SIM2) gene expression: identification of a promoter site in the SIM2 genomic sequence". <i>Gene</i>. 270 (1–2): 265–275. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0378-1119%2801%2900450-4">10.1016/S0378-1119(01)00450-4</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11404025">11404025</a>.</li> <li>Woods SL, Whitelaw ML (March 2002). <a href="https://doi.org/10.1074%2Fjbc.M110752200">"Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors"</a>. <i>The Journal of Biological Chemistry</i>. 277 (12): 10236–10243. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M110752200">10.1074/jbc.M110752200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11782478">11782478</a>.</li> <li>Deyoung MP, Scheurle D, Damania H, Zylberberg C, Narayanan R (2003). "Down's syndrome-associated single minded gene as a novel tumor marker". <i>Anticancer Research</i>. 22 (6A): 3149–3157. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12530058">12530058</a>.</li> <li>DeYoung MP, Tress M, Narayanan R (April 2003). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC153629">"Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors"</a>. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 100 (8): 4760–4765. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/2003PNAS..100.4760D">2003PNAS..100.4760D</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1073%2Fpnas.0831000100">10.1073/pnas.0831000100</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC153629">153629</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/12676991">12676991</a>.</li> <li>DeYoung MP, Tress M, Narayanan R (October 2003). "Down's syndrome-associated Single Minded 2 gene as a pancreatic cancer drug therapy target". <i>Cancer Letters</i>. 200 (1): 25–31. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0304-3835%2803%2900409-9">10.1016/S0304-3835(03)00409-9</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/14550949">14550949</a>.</li> <li>Yamaki A, Kudoh J, Shimizu N, Shimizu Y (January 2004). <a href="https://doi.org/10.1016%2Fj.bbrc.2003.11.168">"A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2"</a>. <i>Biochemical and Biophysical Research Communications</i>. 313 (3): 482–488. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2Fj.bbrc.2003.11.168">10.1016/j.bbrc.2003.11.168</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/14697214">14697214</a>.</li> <li>Ooe N, Saito K, Mikami N, Nakatuka I, Kaneko H (January 2004). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC343817">"Identification of a novel basic helix-loop-helix-PAS factor, NXF, reveals a Sim2 competitive, positive regulatory role in dendritic-cytoskeleton modulator drebrin gene expression"</a>. <i>Molecular and Cellular Biology</i>. 24 (2): 608–616. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1128%2FMCB.24.2.608-616.2004">10.1128/MCB.24.2.608-616.2004</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC343817">343817</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/14701734">14701734</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Muenke M, Bone LJ, Mitchell HF, Hart I, Walton K, Hall-Johnson K, et al. (November 1995). "Physical mapping of the holoprosencephaly critical region in 21q22.3, exclusion of SIM2 as a candidate gene for holoprosencephaly, and mapping of SIM2 to a region of chromosome 21 important for Down syndrome". American Journal of Human Genetics. 57 (5): 1074–1079. PMC 1801356. PMID 7485157. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1801356" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1801356</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>"Entrez Gene: SIM2 single-minded homolog 2 (Drosophila)". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6493" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6493</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Shamblott MJ, Bugg EM, Lawler AM, Gearhart JD (August 2002). "Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene". Developmental Dynamics. 224 (4): 373–380. doi:10.1002/dvdy.10116. PMID 12203729. S2CID 22828235. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Shamblott MJ, Bugg EM, Lawler AM, Gearhart JD (August 2002). "Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene". Developmental Dynamics. 224 (4): 373–380. doi:10.1002/dvdy.10116. PMID 12203729. S2CID 22828235. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>"Entrez Gene: SIM2 single-minded homolog 2 (Drosophila)". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6493" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6493</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O (February 1997). "Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein". The Journal of Biological Chemistry. 272 (7): 4451–4457. doi:10.1074/jbc.272.7.4451. 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