SIM2

SIM2
Identifiers
Aliases	SIM2,HMC13F06, HMC29C01, SIM, bHLHe15, single-minded family bHLH transcription factor 2, SIM bHLH transcription factor 2
External IDs	OMIM:600892;MGI:98307;HomoloGene:3716;GeneCards:SIM2;OMA:SIM2 - orthologs
Gene location (Human) Chr. Chromosome 21 (human) Band 21q22.13 Start 36,699,115bp End 36,749,917bp
RNA expressionpattern Bgee Human Mouse(ortholog) Top expressed in renal medulla buccal mucosa cell oral cavity amniotic fluid vastus lateralis muscle human kidney superior surface of tongue tibia testicle nipple Top expressed in esophagus trachea soleus muscle submandibular gland triceps brachii muscle molar vastus lateralis muscle knee joint gastrocnemius muscle main bronchus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA-binding transcription factor activity protein heterodimerization activity protein dimerization activity DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component nucleoplasm nuclear body nucleus Biological process multicellular organism development regulation of transcription, DNA-templated negative regulation of transcription by RNA polymerase II regulation of transcription by RNA polymerase II cell differentiation embryonic pattern specification transcription, DNA-templated lung development negative regulation of transcription, DNA-templated nervous system development Sources:Amigo/QuickGO
Orthologs Species Human Mouse Entrez 6493 20465 Ensembl ENSG00000159263 ENSMUSG00000062713 UniProt Q14190 n/a RefSeq (mRNA) NM_005069 NM_009586 NM_011377 RefSeq (protein) NP_005060 NP_033664 n/a Location (UCSC) Chr 21: 36.7 – 36.75 Mb n/a PubMedsearch
Wikidata
View/Edit Human View/Edit Mouse

Single-minded homolog 2is aproteinthat in humans is encoded by theSIM2gene.It plays a major role in the development of thecentral nervous systemmidline as well as the construction of the face and head.

Function

SIM1andSIM2genes areDrosophilasingle-minded (sim) gene homologs. The Drosophila sim gene encodes atranscription factorthat is a master regulator ofneurogenesisof midline cells in the central nervous system. SIM2 maps within the so-calledDown syndromechromosomal region, specifically on theq armofchromosome 21,band 22.2.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

Interactions

SIM2 has been shown tointeractwithAryl hydrocarbon receptor nuclear translocator.

When the SIM2 gene is transfected intoPC12 cells,it affects the normal cycle of cell maturation. SIM2 inhibits the expression ofcyclin E,which in turn inhibits the cell's ability to pass through theG1/Scheckpoint and suppresses the cell's proliferation ability. it also up-regulates the presence ofp27,a growthinhibitor protein.The presence of p27 inhibits the activation of cell cycle regulatorykinases.

Disease state

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 thecraniofacialarea. Individuals with SIM2 -/- have either a full or partialsecondary palatecleftand malformations in the tongue andpterygoid processesof thesphenoid bone.These malformations causeaerophagia,or the swallowing of air, andpostnataldeath. Severe aerophagia leads to accumulation of air in thegastrointestinal tract,causing the belly to be distended. It is thought that the over-expression of the SIM2 gene brings about some of the phenotypic deformities that are characteristic ofDown syndrome.The presence of SIM2mRNAin many parts of the brain known to show deformities in individuals with Down syndrome, as well as in thepalate,oral and tongueepithelia,mandibularandhyoidbones.

SIM2 Short (SIM2s)

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 inmammary glandtissue.SIM2s is a splice variant which lacksexon11 of SIM2.It has been researched that SIM2s acts in mammary gland development and has tumor suppressive characteristics specifically in breast cancer.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.The defects were increased cell proliferation, cellular invasion of local stroma, loss of cellular polarity, and loss of E-cadherin cellular adhesion molecules.These observations suggest that SIM2s is essential for proper mammary gland development.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.Reintroducing SIM2s expression in breast cancer cells showed a decrease in growth, proliferation, and invasiveness.SIM2s represses the actions of the matrix metalloprotease-3 gene (MMP3) which include cell migration, cancer progression, and epithelial to mesenchymal transitions (EMT).SIM2s also represses the SLUG transcription factor which in turn suppresses EMT.EMT suppression allows for E-cadherin to remain and for the cell to not undergo pathological EMT associated with tumor formation.These actions show the tumor suppressive effects of SIM2s in mammary epithelium.

Knockout model

Scientists can purposefully "knockout" or cause the gene to be disrupted. To do this, they performhomologous recombinationand eliminate the predicted start codon and the following 47amino acids.Then theEcoRIrestriction site is introduced into the chromosome.

Further reading

• Dahmane N, Charron G, Lopes C, Yaspo ML, Maunoury C, Decorte L, et al. (September 1995)."Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development".Proceedings of the National Academy of Sciences of the United States of America.92(20): 9191–9195.Bibcode:1995PNAS...92.9191D.doi:10.1073/pnas.92.20.9191.PMC40950.PMID7568099.
• Chen H, Chrast R, Rossier C, Gos A, Antonarakis SE, Kudoh J, et al. (May 1995). "Single-minded and Down syndrome?".Nature Genetics.10(1): 9–10.doi:10.1038/ng0595-9.PMID7647800.S2CID12087372.
• 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".Genomics.35(1): 136–143.doi:10.1006/geno.1996.0332.PMID8661114.
• 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".Molecular and Cellular Neurosciences.7(1): 1–16.doi:10.1006/mcne.1996.0001.PMID8812055.S2CID11411254.
• 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".DNA Research.3(3): 175–179.CiteSeerX10.1.1.588.7194.doi:10.1093/dnares/3.3.175.PMID8905236.
• 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.PMID9020169.
• Chrast R, Scott HS, Chen H, Kudoh J, Rossier C, Minoshima S, et al. (June 1997)."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".Genome Research.7(6): 615–624.doi:10.1101/gr.7.6.615.PMC310662.PMID9199934.
• Moffett P, Reece M, Pelletier J (September 1997)."The murine Sim-2 gene product inhibits transcription by active repression and functional interference".Molecular and Cellular Biology.17(9): 4933–4947.doi:10.1128/mcb.17.9.4933.PMC232345.PMID9271372.
• 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".Genomics.48(1): 12–23.doi:10.1006/geno.1997.5146.PMID9503011.
• Ema M, Ikegami S, Hosoya T, Mimura J, Ohtani H, Nakao K, et al. (August 1999)."Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome".Human Molecular Genetics.8(8): 1409–1415.doi:10.1093/hmg/8.8.1409.PMID10400987.
• 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".Gene.270(1–2): 265–275.doi:10.1016/S0378-1119(01)00450-4.PMID11404025.
• Woods SL, Whitelaw ML (March 2002)."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".The Journal of Biological Chemistry.277(12): 10236–10243.doi:10.1074/jbc.M110752200.PMID11782478.
• Deyoung MP, Scheurle D, Damania H, Zylberberg C, Narayanan R (2003). "Down's syndrome-associated single minded gene as a novel tumor marker".Anticancer Research.22(6A): 3149–3157.PMID12530058.
• DeYoung MP, Tress M, Narayanan R (April 2003)."Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors".Proceedings of the National Academy of Sciences of the United States of America.100(8): 4760–4765.Bibcode:2003PNAS..100.4760D.doi:10.1073/pnas.0831000100.PMC153629.PMID12676991.
• DeYoung MP, Tress M, Narayanan R (October 2003). "Down's syndrome-associated Single Minded 2 gene as a pancreatic cancer drug therapy target".Cancer Letters.200(1): 25–31.doi:10.1016/S0304-3835(03)00409-9.PMID14550949.
• Yamaki A, Kudoh J, Shimizu N, Shimizu Y (January 2004)."A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2".Biochemical and Biophysical Research Communications.313(3): 482–488.doi:10.1016/j.bbrc.2003.11.168.PMID14697214.
• Ooe N, Saito K, Mikami N, Nakatuka I, Kaneko H (January 2004)."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".Molecular and Cellular Biology.24(2): 608–616.doi:10.1128/MCB.24.2.608-616.2004.PMC343817.PMID14701734.