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{{Infobox_gene}}
{{PBB_Controls
'''Single-minded homolog 2''' is a [[protein]] that in humans is encoded by the ''SIM2'' [[gene]].<ref name="pmid7485157">{{cite journal | vauthors = Muenke M, Bone LJ, Mitchell HF, Hart I, Walton K, Hall-Johnson K, Ippel EF, Dietz-Band J, Kvaløy K, Fan CM | title = 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 | journal = American Journal of Human Genetics | volume = 57 | issue = 5 | pages = 1074–9 | date = Nov 1995 | pmid = 7485157 | pmc = 1801356 | doi = }}</ref><ref name="entrez"/> It plays a major role in the development of the [[central nervous system]] midline as well as the construction of the face and head.<ref name = Shamblott/>
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| update_protein_box = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Single-minded homolog 2 (Drosophila)
| HGNCid = 10883
| Symbol = SIM2
| AltSymbols =; MGC119447; SIM
| OMIM = 600892
| ECnumber = 
| Homologene = 3716
| MGIid = 98307
| GeneAtlas_image1 = PBB_GE_SIM2_206558_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0004871 |text = signal transducer activity}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0007399 |text = nervous system development}} {{GNF_GO|id=GO:0030154 |text = cell differentiation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 6493
    | Hs_Ensembl = ENSG00000159263
    | Hs_RefseqProtein = NP_005060
    | Hs_RefseqmRNA = NM_005069
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 21
    | Hs_GenLoc_start = 36993851
    | Hs_GenLoc_end = 37044088
    | Hs_Uniprot = Q14190
    | Mm_EntrezGene = 20465
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = NM_011377
    | Mm_RefseqProtein = NP_035507
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot = 
  }}
}}
'''Single-minded homolog 2 (Drosophila)''', also known as '''SIM2''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: SIM2 single-minded homolog 2 (Drosophila)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6493| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
[[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.<ref name = Shamblott/> 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<ref name="entrez">{{cite web | title = Entrez Gene: SIM2 single-minded homolog 2 (Drosophila)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6493| accessdate = }}</ref>
{{PBB_Summary
| section_title =
| summary_text = 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 fruit fly neurogenesis. SIM2 maps within the so-called Down syndrome chromosomal region.  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<ref name="entrez">{{cite web | title = Entrez Gene: SIM2 single-minded homolog 2 (Drosophila)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6493| accessdate = }}</ref>
}}


==References==
== Interactions ==
{{reflist|2}}
 
==Further reading==
SIM2 has been shown to [[Protein-protein interaction|interact]] with [[Aryl hydrocarbon receptor nuclear translocator]].<ref name=pmid9020169>{{cite journal | vauthors = Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O | title = Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein | journal = The Journal of Biological Chemistry | volume = 272 | issue = 7 | pages = 4451–7 | date = Feb 1997 | pmid = 9020169 | doi = 10.1074/jbc.272.7.4451 }}</ref><ref name=pmid14701734>{{cite journal | vauthors = Ooe N, Saito K, Mikami N, Nakatuka I, Kaneko H | title = 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 | journal = Molecular and Cellular Biology | volume = 24 | issue = 2 | pages = 608–16 | date = Jan 2004 | pmid = 14701734 | pmc = 343817 | doi = 10.1128/MCB.24.2.608-616.2004 }}</ref><ref name=pmid11782478>{{cite journal | vauthors = Woods SL, Whitelaw ML | title = 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 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 12 | pages = 10236–43 | date = Mar 2002 | pmid = 11782478 | doi = 10.1074/jbc.M110752200 }}</ref><ref name=pmid9271372>{{cite journal | vauthors = Moffett P, Reece M, Pelletier J | title = The murine Sim-2 gene product inhibits transcription by active repression and functional interference | journal = Molecular and Cellular Biology | volume = 17 | issue = 9 | pages = 4933–47 | date = Sep 1997 | pmid = 9271372 | pmc = 232345 | doi=10.1128/mcb.17.9.4933}}</ref>
{{refbegin | 2}}
 
{{PBB_Further_reading
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 (gene)|p27]], a growth [[inhibitor protein]]. The presence of p27 inhibits the activation of cell cycle regulatory [[kinases]].<ref>{{cite journal|last1=Meng|first1=X|last2=Shi|first2=J|last3=Peng|first3=B|last4=Zou|first4=X|last5=Zhang|first5=C|title=Effect of mouse Sim2 gene on the cell cycle of PC12 cell.|journal=Cell Biology International|volume=2006|issue=30|pages=349–353|doi=10.1016/j.cellbi.2005.11.012}}</ref>
| citations =
 
*{{cite journal  | author=Muenke M, Bone LJ, Mitchell HF, ''et al.'' |title=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. |journal=Am. J. Hum. Genet. |volume=57 |issue= 5 |pages= 1074-9 |year= 1995 |pmid= 7485157 |doi= }}
== Disease state ==
*{{cite journal | author=Dahmane N, Charron G, Lopes C, ''et al.'' |title=Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 20 |pages= 9191-5 |year= 1995 |pmid= 7568099 |doi= }}
 
*{{cite journal  | author=Chen H, Chrast R, Rossier C, ''et al.'' |title=Single-minded and Down syndrome? |journal=Nat. Genet. |volume=10 |issue= 1 |pages= 9-10 |year= 1995 |pmid= 7647800 |doi= 10.1038/ng0595-9 }}
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 lip and 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.<ref name=Shamblott>{{cite journal|last1=Shamblott|first1=MJ|last2=Bugg|first2=EM|last3=Lawler|first3=AM|last4=Gearhart|first4=JD|title=Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene.|journal=Developmental Dynamics|date=2002|volume=224|pages=373–380|doi=10.1002/dvdy.10116|pmid=12203729}}</ref>
*{{cite journal | author=Yamaki A, Noda S, Kudoh J, ''et al.'' |title=The mammalian single-minded (SIM) gene: mouse cDNA structure and diencephalic expression indicate a candidate gene for Down syndrome. |journal=Genomics |volume=35 |issue= 1 |pages= 136-43 |year= 1996 |pmid= 8661114 |doi= 10.1006/geno.1996.0332 }}
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.<ref name=Shamblott/>
*{{cite journal  | author=Fan CM, Kuwana E, Bulfone A, ''et al.'' |title=Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome. |journal=Mol. Cell. Neurosci. |volume=7 |issue= 1 |pages= 1-16 |year= 1996 |pmid= 8812055 |doi= 10.1006/mcne.1996.0001 }}
 
*{{cite journal  | author=Osoegawa K, Okano S, Kato Y, ''et al.'' |title=A 19-kb CpG island associated with single-minded gene 2 in Down syndrome chromosomal region. |journal=DNA Res. |volume=3 |issue= 3 |pages= 175-9 |year= 1997 |pmid= 8905236 |doi= }}
== SIM2 Short (SIM2s) ==
*{{cite journal  | author=Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O |title=Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein. |journal=J. Biol. Chem. |volume=272 |issue= 7 |pages= 4451-7 |year= 1997 |pmid= 9020169 |doi= }}
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.<ref name=":0">{{Cite journal|last=Kwak|first=Hyeong-Il|last2=Gustafson|first2=Tanya|last3=Metz|first3=Richard P.|last4=Laffin|first4=Brian|last5=Schedin|first5=Pepper|last6=Porter|first6=Weston W.|date=July 2006|title=Inhibition of breast cancer growth and invasion by single-minded 2s|url=https://academic.oup.com/carcin/article/28/2/259/2476216/Inhibition-of-breast-cancer-growth-and-invasion-by|journal=Carcinogenesis|volume=28|pages=259–266|doi=10.1093/carcin/bgl122}}</ref> SIM2s is a splice variant which lacks exon 11 of SIM2.<ref>{{Cite journal|last=Metz|first=Richard P.|last2=Kwak|first2=Hyeong-Il|last3=Gustafson|first3=Tanya|last4=Laffin|first4=Brian|last5=Porter|first5=Weston W.|date=February 2006|title=Differential Transcriptional Regulation by Mouse Single-minded 2s|url=http://www.jbc.org/content/281/16/10839.long|journal=The Journal of Biological Chemistry|volume=281|pages=10839–10848|doi=10.1074/jbc.m508858200}}</ref> It has been researched that SIM2s acts in mammary gland development and has tumor suppressive characteristics specifically in breast cancer.<ref name=":0" /><ref>{{Cite journal|last=Wellberg|first=Elizabeth|last2=Metz|first2=Richard P.|last3=Parker|first3=Caitlin|last4=Porter|first4=Weston W.|date=March 2010|title=The bHLH/PAS transcription factor singleminded 2s promotes mammary gland lactogenic differentiation|journal=Development|volume=137|pages=945–952|doi=10.1242/dev.041657|pmc=2834457|pmid=20150276}}</ref><ref name=":1">{{Cite journal|last=Laffin|first=Brian|last2=Wellburg|first2=Elizabeth|last3=Kwak|first3=Hyeong-Il|last4=Burghardt|first4=Robert C.|last5=Metz|first5=Richard P.|last6=Gustafson|first6=Tanya|last7=Schedin|first7=Pepper|last8=Porter|first8=Weston W.|date=March 2008|title=Loss of Singleminded-2s in the Mouse Mammary Gland Induces an Epithelial-Mesenchymal Transition Associated with Up-Regulation of Slug and Matrix Metalloprotease 2|url=http://mcb.asm.org/content/28/6/1936.full|journal=Molecular and Cellular Biology|volume=28|pages=1936–1946|doi=10.1128/mcb.01701-07|pmc=2268409}}</ref> 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.<ref name=":1" /> The defects were increased cell proliferation, cellular invasion of local stroma, loss of cellular polarity, and loss of E-cadherin cellular adhesion molecules.<ref name=":1" /> These observations suggest that SIM2s is essential for proper mammary gland development.<ref name=":1" /> 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.<ref name=":0" /> Reintroducing SIM2s expression in breast cancer cells showed a decrease in growth, proliferation, and invasiveness.<ref name=":0" /> SIM2s represses the actions of the matrix metalloprotease-3 gene (MMP3) which include cell migration, cancer progression, and epithelial to mesenchymal transitions (EMT).<ref name=":0" /> SIM2s also represses the SLUG transcription factor which in turn suppresses EMT.<ref name=":1" /> EMT suppression allows for E-cadherin to remain and for the cell to not undergo pathological EMT associated with tumor formation.<ref name=":1" /> These actions show the tumor suppressive effects of SIM2s in mammary epithelium.
*{{cite journal  | author=Chrast R, Scott HS, Chen H, ''et al.'' |title=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. |journal=Genome Res. |volume=7 |issue= 6 |pages= 615-24 |year= 1997 |pmid= 9199934 |doi=  }}
 
*{{cite journal  | author=Moffett P, Reece M, Pelletier J |title=The murine Sim-2 gene product inhibits transcription by active repression and functional interference. |journal=Mol. Cell. Biol. |volume=17 |issue= 9 |pages= 4933-47 |year= 1997 |pmid= 9271372 |doi= }}
== Knockout model ==
*{{cite journal  | author=Dahmane N, Ghezala GA, Gosset P, ''et al.'' |title=Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome. |journal=Genomics |volume=48 |issue= 1 |pages= 12-23 |year= 1998 |pmid= 9503011 |doi= 10.1006/geno.1997.5146 }}
 
*{{cite journal | author=Ema M, Ikegami S, Hosoya T, ''et al.'' |title=Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome. |journal=Hum. Mol. Genet. |volume=8 |issue= 8 |pages= 1409-15 |year= 1999 |pmid= 10400987 |doi= }}
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.<ref name=Shamblott/>
*{{cite journal  | author=Hattori M, Fujiyama A, Taylor TD, ''et al.'' |title=The DNA sequence of human chromosome 21. |journal=Nature |volume=405 |issue= 6784 |pages= 311-9 |year= 2000 |pmid= 10830953 |doi= 10.1038/35012518 }}
 
*{{cite journal | author=Yamaki A, Tochigi J, Kudoh J, ''et al.'' |title=Molecular mechanisms of human single-minded 2 (SIM2) gene expression: identification of a promoter site in the SIM2 genomic sequence. |journal=Gene |volume=270 |issue= 1-2 |pages= 265-75 |year= 2001 |pmid= 11404025 |doi=  }}
== References ==
*{{cite journal | author=Woods SL, Whitelaw ML |title=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. |journal=J. Biol. Chem. |volume=277 |issue= 12 |pages= 10236-43 |year= 2002 |pmid= 11782478 |doi= 10.1074/jbc.M110752200 }}
{{reflist|33em}}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
 
*{{cite journal  | author=Deyoung MP, Scheurle D, Damania H, ''et al.'' |title=Down's syndrome-associated single minded gene as a novel tumor marker. |journal=Anticancer Res. |volume=22 |issue= 6A |pages= 3149-57 |year= 2003 |pmid= 12530058 |doi= }}
== Further reading ==
*{{cite journal  | author=DeYoung MP, Tress M, Narayanan R |title=Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue= 8 |pages= 4760-5 |year= 2003 |pmid= 12676991 |doi= 10.1073/pnas.0831000100 }}
{{refbegin|33em}}
*{{cite journal | author=DeYoung MP, Tress M, Narayanan R |title=Down's syndrome-associated Single Minded 2 gene as a pancreatic cancer drug therapy target. |journal=Cancer Lett. |volume=200 |issue= 1 |pages= 25-31 |year= 2003 |pmid= 14550949 |doi= }}
* {{cite journal | vauthors = Dahmane N, Charron G, Lopes C, Yaspo ML, Maunoury C, Decorte L, Sinet PM, Bloch B, Delabar JM | title = Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 20 | pages = 9191–5 | date = Sep 1995 | pmid = 7568099 | pmc = 40950 | doi = 10.1073/pnas.92.20.9191 }}
*{{cite journal | author=Yamaki A, Kudoh J, Shimizu N, Shimizu Y |title=A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2. |journal=Biochem. Biophys. Res. Commun. |volume=313 |issue= 3 |pages= 482-8 |year= 2004 |pmid= 14697214 |doi= }}
* {{cite journal | vauthors = Chen H, Chrast R, Rossier C, Gos A, Antonarakis SE, Kudoh J, Yamaki A, Shindoh N, Maeda H, Minoshima S | title = Single-minded and Down syndrome? | journal = Nature Genetics | volume = 10 | issue = 1 | pages = 9–10 | date = May 1995 | pmid = 7647800 | doi = 10.1038/ng0595-9 }}
*{{cite journal | author=Ooe N, Saito K, Mikami N, ''et al.'' |title=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. |journal=Mol. Cell. Biol. |volume=24 |issue= 2 |pages= 608-16 |year= 2004 |pmid= 14701734 |doi= }}
* {{cite journal | vauthors = Yamaki A, Noda S, Kudoh J, Shindoh N, Maeda H, Minoshima S, Kawasaki K, Shimizu Y, Shimizu N | title = The mammalian single-minded (SIM) gene: mouse cDNA structure and diencephalic expression indicate a candidate gene for Down syndrome | journal = Genomics | volume = 35 | issue = 1 | pages = 136–43 | date = Jul 1996 | pmid = 8661114 | doi = 10.1006/geno.1996.0332 }}
}}
* {{cite journal | vauthors = Fan CM, Kuwana E, Bulfone A, Fletcher CF, Copeland NG, Jenkins NA, Crews S, Martinez S, Puelles L, Rubenstein JL, Tessier-Lavigne M | title = Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome | journal = Molecular and Cellular Neurosciences | volume = 7 | issue = 1 | pages = 1–16 | date = Jan 1996 | pmid = 8812055 | doi = 10.1006/mcne.1996.0001 }}
* {{cite journal | vauthors = Osoegawa K, Okano S, Kato Y, Nishimura Y, Soeda E | title = A 19-kb CpG island associated with single-minded gene 2 in Down syndrome chromosomal region | journal = DNA Research | volume = 3 | issue = 3 | pages = 175–9 | date = Jun 1996 | pmid = 8905236 | doi = 10.1093/dnares/3.3.175 }}
* {{cite journal | vauthors = Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O | title = Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein | journal = The Journal of Biological Chemistry | volume = 272 | issue = 7 | pages = 4451–7 | date = Feb 1997 | pmid = 9020169 | doi = 10.1074/jbc.272.7.4451 }}
* {{cite journal | vauthors = Chrast R, Scott HS, Chen H, Kudoh J, Rossier C, Minoshima S, Wang Y, Shimizu N, Antonarakis SE | title = 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 | journal = Genome Research | volume = 7 | issue = 6 | pages = 615–24 | date = Jun 1997 | pmid = 9199934 | pmc = 310662 | doi = 10.1101/gr.7.6.615 }}
* {{cite journal | vauthors = Moffett P, Reece M, Pelletier J | title = The murine Sim-2 gene product inhibits transcription by active repression and functional interference | journal = Molecular and Cellular Biology | volume = 17 | issue = 9 | pages = 4933–47 | date = Sep 1997 | pmid = 9271372 | pmc = 232345 | doi =  10.1128/mcb.17.9.4933}}
* {{cite journal | vauthors = 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 | title = Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome | journal = Genomics | volume = 48 | issue = 1 | pages = 12–23 | date = Feb 1998 | pmid = 9503011 | doi = 10.1006/geno.1997.5146 }}
* {{cite journal | vauthors = Ema M, Ikegami S, Hosoya T, Mimura J, Ohtani H, Nakao K, Inokuchi K, Katsuki M, Fujii-Kuriyama Y | title = Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome | journal = Human Molecular Genetics | volume = 8 | issue = 8 | pages = 1409–15 | date = Aug 1999 | pmid = 10400987 | doi = 10.1093/hmg/8.8.1409 }}
* {{cite journal | vauthors = Yamaki A, Tochigi J, Kudoh J, Minoshima S, Shimizu N, Shimizu Y | title = Molecular mechanisms of human single-minded 2 (SIM2) gene expression: identification of a promoter site in the SIM2 genomic sequence | journal = Gene | volume = 270 | issue = 1–2 | pages = 265–75 | date = May 2001 | pmid = 11404025 | doi = 10.1016/S0378-1119(01)00450-4 }}
* {{cite journal | vauthors = Woods SL, Whitelaw ML | title = 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 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 12 | pages = 10236–43 | date = Mar 2002 | pmid = 11782478 | doi = 10.1074/jbc.M110752200 }}
* {{cite journal | vauthors = Deyoung MP, Scheurle D, Damania H, Zylberberg C, Narayanan R | title = Down's syndrome-associated single minded gene as a novel tumor marker | journal = Anticancer Research | volume = 22 | issue = 6A | pages = 3149–57 | year = 2003 | pmid = 12530058 | doi =  }}
* {{cite journal | vauthors = DeYoung MP, Tress M, Narayanan R | title = Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 8 | pages = 4760–5 | date = Apr 2003 | pmid = 12676991 | pmc = 153629 | doi = 10.1073/pnas.0831000100 }}
* {{cite journal | vauthors = DeYoung MP, Tress M, Narayanan R | title = Down's syndrome-associated Single Minded 2 gene as a pancreatic cancer drug therapy target | journal = Cancer Letters | volume = 200 | issue = 1 | pages = 25–31 | date = Oct 2003 | pmid = 14550949 | doi = 10.1016/S0304-3835(03)00409-9 }}
* {{cite journal | vauthors = Yamaki A, Kudoh J, Shimizu N, Shimizu Y | title = A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2 | journal = Biochemical and Biophysical Research Communications | volume = 313 | issue = 3 | pages = 482–8 | date = Jan 2004 | pmid = 14697214 | doi = 10.1016/j.bbrc.2003.11.168 }}
* {{cite journal | vauthors = Ooe N, Saito K, Mikami N, Nakatuka I, Kaneko H | title = 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 | journal = Molecular and Cellular Biology | volume = 24 | issue = 2 | pages = 608–16 | date = Jan 2004 | pmid = 14701734 | pmc = 343817 | doi = 10.1128/MCB.24.2.608-616.2004 }}
{{refend}}
{{refend}}


{{gene-21-stub}}
{{Transcription factors|g1}}
{{WikiDoc Sources}}
 
[[Category:PAS-domain-containing proteins]]

Latest revision as of 09:11, 9 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
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View/Edit Human

Single-minded homolog 2 is a protein that in humans is encoded by the SIM2 gene.[1][2] It plays a major role in the development of the central nervous system midline as well as the construction of the face and head.[3]

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.[3] 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[2]

Interactions

SIM2 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator.[4][5][6][7]

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.[8]

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.[3] 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.[3]

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.[9] SIM2s is a splice variant which lacks exon 11 of SIM2.[10] It has been researched that SIM2s acts in mammary gland development and has tumor suppressive characteristics specifically in breast cancer.[9][11][12] 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.[12] The defects were increased cell proliferation, cellular invasion of local stroma, loss of cellular polarity, and loss of E-cadherin cellular adhesion molecules.[12] These observations suggest that SIM2s is essential for proper mammary gland development.[12] 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.[9] Reintroducing SIM2s expression in breast cancer cells showed a decrease in growth, proliferation, and invasiveness.[9] SIM2s represses the actions of the matrix metalloprotease-3 gene (MMP3) which include cell migration, cancer progression, and epithelial to mesenchymal transitions (EMT).[9] SIM2s also represses the SLUG transcription factor which in turn suppresses EMT.[12] EMT suppression allows for E-cadherin to remain and for the cell to not undergo pathological EMT associated with tumor formation.[12] 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.[3]

References

  1. 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.
  2. 2.0 2.1 "Entrez Gene: SIM2 single-minded homolog 2 (Drosophila)".
  3. 3.0 3.1 3.2 3.3 3.4 Shamblott, MJ; Bugg, EM; Lawler, AM; Gearhart, JD (2002). "Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene". Developmental Dynamics. 224: 373–380. doi:10.1002/dvdy.10116. PMID 12203729.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Meng, X; Shi, J; Peng, B; Zou, X; Zhang, C. "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.
  9. 9.0 9.1 9.2 9.3 9.4 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: 259–266. doi:10.1093/carcin/bgl122.
  10. 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: 10839–10848. doi:10.1074/jbc.m508858200.
  11. 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: 945–952. doi:10.1242/dev.041657. PMC 2834457. PMID 20150276.
  12. 12.0 12.1 12.2 12.3 12.4 12.5 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: 1936–1946. doi:10.1128/mcb.01701-07. PMC 2268409.

Further reading