SIM2

Single-minded homolog 2 is a protein that in humans is encoded by the SIM2 gene.[5][6] It plays a major role in the development of the central nervous system midline as well as the construction of the face and head.[7]

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
Gene location (Human) Chr. Chromosome 21 (human)[1] Band 21q22.13 Start 36,699,115 bp[1] End 36,749,917 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16 C4|16 55.05 cM Start 94,084,931 bp[2] End 94,127,032 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • protein heterodimerization activity • protein dimerization activity • DNA binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • nucleoplasm • nuclear body • cell nucleus Biological process • multicellular organism development • regulation of transcription, DNA-templated • negative regulation of transcription from RNA polymerase II promoter • regulation of transcription from RNA polymerase II promoter • 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	Q61079
RefSeq (mRNA)	NM_005069 NM_009586	NM_011377
RefSeq (protein)	NP_005060 NP_033664	NP_035507
Location (UCSC)	Chr 21: 36.7 – 36.75 Mb	Chr 16: 94.08 – 94.13 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

SIM1 and SIM2 genes are Drosophila single-minded (sim) gene homologs. The Drosophila sim gene encodes a transcription factor that is a master regulator of neurogenesis of midline cells in the central nervous system. SIM2 maps within the so-called Down syndrome chromosomal region, specifically on the q arm of chromosome 21, band 22.2.[7] 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[6]

Interactions

SIM2 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator.[8][9][10][11]

When the SIM2 gene is tranfected into PC12 cells, it effects the normal cycle of cell maturation. SIM2 inhibits the expression of cyclin E, 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 p27, a growth inhibitor protein. The presence of p27 inhibits the activation of cell cycle regulatory kinases.[12]

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 the craniofacial area. Individuals with SIM2 -/- have either a full or partial secondary palate cleft and malformations in the tongue and pterygoid processes of the sphenoid bone. These malformations cause aerophagia, or the swallowing of air, and postnatal death. Severe aerophagia leads to accumulation of air in the gastrointestinal tract, causing the belly to be distended.[7] It is thought that the over-expression of the SIM2 gene brings about some of the phenotypic deformities that are characteristic of Down syndrome. The presence of SIM2 mRNA in many parts of the brain known to show deformities in individuals with Down syndrome, as well as in the palate, oral and tongue epithelia, mandibular and hyoid bones.[7]

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 in mammary gland tissue.[13] SIM2s is a splice variant which lacks exon 11 of SIM2.[14] It has been researched that SIM2s acts in mammary gland development and has tumor suppressive characteristics specifically in breast cancer.[13][15][16] 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.[16] The defects were increased cell proliferation, cellular invasion of local stroma, loss of cellular polarity, and loss of E-cadherin cellular adhesion molecules.[16] These observations suggest that SIM2s is essential for proper mammary gland development.[16] 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.[13] Reintroducing SIM2s expression in breast cancer cells showed a decrease in growth, proliferation, and invasiveness.[13] SIM2s represses the actions of the matrix metalloprotease-3 gene (MMP3) which include cell migration, cancer progression, and epithelial to mesenchymal transitions (EMT).[13] SIM2s also represses the SLUG transcription factor which in turn suppresses EMT.[16] EMT suppression allows for E-cadherin to remain and for the cell to not undergo pathological EMT associated with tumor formation.[16] 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 perform homologous recombination and eliminate the predicted start codon and the following 47 amino acids. Then the EcoRI restriction site is introduced into the chromosome.[7]

References

1. GRCh38: Ensembl release 89: ENSG00000159263 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000062713 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Muenke M, Bone LJ, Mitchell HF, Hart I, Walton K, Hall-Johnson K, Ippel EF, Dietz-Band J, Kvaløy K, Fan CM (Nov 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): 1074–9. PMC 1801356. PMID 7485157.
6. "Entrez Gene: SIM2 single-minded homolog 2 (Drosophila)".
7. Shamblott, MJ; Bugg, EM; Lawler, AM; Gearhart, JD (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.
8. Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O (Feb 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): 4451–7. doi:10.1074/jbc.272.7.4451. PMID 9020169.
9. Ooe N, Saito K, Mikami N, Nakatuka I, Kaneko H (Jan 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): 608–16. doi:10.1128/MCB.24.2.608-616.2004. PMC 343817. PMID 14701734.
10. Woods SL, Whitelaw ML (Mar 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): 10236–43. doi:10.1074/jbc.M110752200. PMID 11782478.
11. Moffett P, Reece M, Pelletier J (Sep 1997). "The murine Sim-2 gene product inhibits transcription by active repression and functional interference". Molecular and Cellular Biology. 17 (9): 4933–47. doi:10.1128/mcb.17.9.4933. PMC 232345. PMID 9271372.
12. Meng, X; Shi, J; Peng, B; Zou, X; Zhang, C (2006). "Effect of mouse Sim2 gene on the cell cycle of PC12 cell". Cell Biology International. 2006 (30): 349–353. doi:10.1016/j.cellbi.2005.11.012. PMID 16530433. S2CID 46238281.
13. Kwak, Hyeong-Il; Gustafson, Tanya; Metz, Richard P.; Laffin, Brian; Schedin, Pepper; Porter, Weston W. (July 2006). "Inhibition of breast cancer growth and invasion by single-minded 2s". Carcinogenesis. 28 (2): 259–266. doi:10.1093/carcin/bgl122. PMID 16840439.
14. Metz, Richard P.; Kwak, Hyeong-Il; Gustafson, Tanya; Laffin, Brian; Porter, Weston W. (February 2006). "Differential Transcriptional Regulation by Mouse Single-minded 2s". The Journal of Biological Chemistry. 281 (16): 10839–10848. doi:10.1074/jbc.m508858200. PMID 16484282.
15. Wellberg, Elizabeth; Metz, Richard P.; Parker, Caitlin; Porter, Weston W. (March 2010). "The bHLH/PAS transcription factor singleminded 2s promotes mammary gland lactogenic differentiation". Development. 137 (6): 945–952. doi:10.1242/dev.041657. PMC 2834457. PMID 20150276.
16. Laffin, Brian; Wellburg, Elizabeth; Kwak, Hyeong-Il; Burghardt, Robert C.; Metz, Richard P.; Gustafson, Tanya; Schedin, Pepper; Porter, Weston W. (March 2008). "Loss of Singleminded-2s in the Mouse Mammary Gland Induces an Epithelial-Mesenchymal Transition Associated with Up-Regulation of Slug and Matrix Metalloprotease 2". Molecular and Cellular Biology. 28 (6): 1936–1946. doi:10.1128/mcb.01701-07. PMC 2268409. PMID 18160708.

Further reading

• Dahmane N, Charron G, Lopes C, Yaspo ML, Maunoury C, Decorte L, Sinet PM, Bloch B, Delabar JM (Sep 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): 9191–5. Bibcode:1995PNAS...92.9191D. doi:10.1073/pnas.92.20.9191. PMC 40950. PMID 7568099.
• Chen H, Chrast R, Rossier C, Gos A, Antonarakis SE, Kudoh J, Yamaki A, Shindoh N, Maeda H, Minoshima S (May 1995). "Single-minded and Down syndrome?". Nature Genetics. 10 (1): 9–10. doi:10.1038/ng0595-9. PMID 7647800. S2CID 12087372.
• Yamaki A, Noda S, Kudoh J, Shindoh N, Maeda H, Minoshima S, Kawasaki K, Shimizu Y, Shimizu N (Jul 1996). "The mammalian single-minded (SIM) gene: mouse cDNA structure and diencephalic expression indicate a candidate gene for Down syndrome". Genomics. 35 (1): 136–43. doi:10.1006/geno.1996.0332. PMID 8661114.
• Fan CM, Kuwana E, Bulfone A, Fletcher CF, Copeland NG, Jenkins NA, Crews S, Martinez S, Puelles L, Rubenstein JL, Tessier-Lavigne M (Jan 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. PMID 8812055. S2CID 11411254.
• Osoegawa K, Okano S, Kato Y, Nishimura Y, Soeda E (Jun 1996). "A 19-kb CpG island associated with single-minded gene 2 in Down syndrome chromosomal region". DNA Research. 3 (3): 175–9. CiteSeerX 10.1.1.588.7194. doi:10.1093/dnares/3.3.175. PMID 8905236.
• Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O (Feb 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): 4451–7. doi:10.1074/jbc.272.7.4451. PMID 9020169.
• Chrast R, Scott HS, Chen H, Kudoh J, Rossier C, Minoshima S, Wang Y, Shimizu N, Antonarakis SE (Jun 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): 615–24. doi:10.1101/gr.7.6.615. PMC 310662. PMID 9199934.
• Moffett P, Reece M, Pelletier J (Sep 1997). "The murine Sim-2 gene product inhibits transcription by active repression and functional interference". Molecular and Cellular Biology. 17 (9): 4933–47. doi:10.1128/mcb.17.9.4933. PMC 232345. PMID 9271372.
• Dahmane N, Ghezala GA, Gosset P, Chamoun Z, Dufresne-Zacharia MC, Lopes C, Rabatel N, Gassanova-Maugenre S, Chettouh Z, Abramowski V, Fayet E, Yaspo ML, Korn B, Blouin JL, Lehrach H, Poutska A, Antonarakis SE, Sinet PM, Créau N, Delabar JM (Feb 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. PMID 9503011.
• Ema M, Ikegami S, Hosoya T, Mimura J, Ohtani H, Nakao K, Inokuchi K, Katsuki M, Fujii-Kuriyama Y (Aug 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): 1409–15. doi:10.1093/hmg/8.8.1409. PMID 10400987.
• 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): 265–75. doi:10.1016/S0378-1119(01)00450-4. PMID 11404025.
• Woods SL, Whitelaw ML (Mar 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): 10236–43. doi:10.1074/jbc.M110752200. PMID 11782478.
• 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): 3149–57. PMID 12530058.
• DeYoung MP, Tress M, Narayanan R (Apr 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): 4760–5. Bibcode:2003PNAS..100.4760D. doi:10.1073/pnas.0831000100. PMC 153629. PMID 12676991.
• DeYoung MP, Tress M, Narayanan R (Oct 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. PMID 14550949.
• Yamaki A, Kudoh J, Shimizu N, Shimizu Y (Jan 2004). "A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2". Biochemical and Biophysical Research Communications. 313 (3): 482–8. doi:10.1016/j.bbrc.2003.11.168. PMID 14697214.
• Ooe N, Saito K, Mikami N, Nakatuka I, Kaneko H (Jan 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): 608–16. doi:10.1128/MCB.24.2.608-616.2004. PMC 343817. PMID 14701734.