imported>Citation bot: Altered issue. Formatted dashes. | Use this bot. Report bugs. | Suggested by Boghog | #UCB_webform

2024-08-09T09:09:02Z

Altered issue. Formatted dashes. | Use this bot. Report bugs. | Suggested by Boghog | #UCB_webform

New page

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox_gene}}
'''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 = 1074–1079 | date = November 1995 | pmid = 7485157 | pmc = 1801356 }}</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/>

== 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.<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}}</ref>

== Interactions ==

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 = 4451–4457 | date = February 1997 | pmid = 9020169 | doi = 10.1074/jbc.272.7.4451 | doi-access = free }}</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 = 608–616 | date = January 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 = 10236–10243 | date = March 2002 | pmid = 11782478 | doi = 10.1074/jbc.M110752200 | doi-access = free }}</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 = 4933–4947 | date = September 1997 | pmid = 9271372 | pmc = 232345 | doi = 10.1128/mcb.17.9.4933 }}</ref>

When the SIM2 gene is transfected into [[PC12 cells]], it affects 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 | vauthors = Meng X, Shi J, Peng B, Zou X, Zhang C | title = Effect of mouse Sim2 gene on the cell cycle of PC12 cells | journal = Cell Biology International | volume = 30 | issue = 4 | pages = 349–353 | date = April 2006 | pmid = 16530433 | doi = 10.1016/j.cellbi.2005.11.012 | s2cid = 46238281 }}</ref>

== 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 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 | vauthors = Shamblott MJ, Bugg EM, Lawler AM, Gearhart JD | title = Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene | journal = Developmental Dynamics | volume = 224 | issue = 4 | pages = 373–380 | date = August 2002 | pmid = 12203729 | doi = 10.1002/dvdy.10116 | s2cid = 22828235 | doi-access = }}</ref>
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/>

== 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.<ref name=":0">{{cite journal | vauthors = Kwak HI, Gustafson T, Metz RP, Laffin B, Schedin P, Porter WW | title = Inhibition of breast cancer growth and invasion by single-minded 2s | journal = Carcinogenesis | volume = 28 | issue = 2 | pages = 259–266 | date = February 2007 | pmid = 16840439 | doi = 10.1093/carcin/bgl122 | doi-access = free }}</ref> SIM2s is a splice variant which lacks [[exon]] 11 of SIM2.<ref>{{cite journal | vauthors = Metz RP, Kwak HI, Gustafson T, Laffin B, Porter WW | title = Differential transcriptional regulation by mouse single-minded 2s | journal = The Journal of Biological Chemistry | volume = 281 | issue = 16 | pages = 10839–10848 | date = April 2006 | pmid = 16484282 | doi = 10.1074/jbc.m508858200 | doi-access = free }}</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 | vauthors = Wellberg E, Metz RP, Parker C, Porter WW | title = The bHLH/PAS transcription factor singleminded 2s promotes mammary gland lactogenic differentiation | journal = Development | volume = 137 | issue = 6 | pages = 945–952 | date = March 2010 | pmid = 20150276 | pmc = 2834457 | doi = 10.1242/dev.041657 }}</ref><ref name=":1">{{cite journal | vauthors = Laffin B, Wellberg E, Kwak HI, Burghardt RC, Metz RP, Gustafson T, Schedin P, Porter WW | 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 | journal = Molecular and Cellular Biology | volume = 28 | issue = 6 | pages = 1936–1946 | date = March 2008 | pmid = 18160708 | pmc = 2268409 | doi = 10.1128/mcb.01701-07 }}</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.

== 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.<ref name=Shamblott/>

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{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 = 9191–9195 | date = September 1995 | pmid = 7568099 | pmc = 40950 | doi = 10.1073/pnas.92.20.9191 | doi-access = free | bibcode = 1995PNAS...92.9191D }}
* {{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 | s2cid = 12087372 }}
* {{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 = 136–143 | date = July 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 = January 1996 | pmid = 8812055 | doi = 10.1006/mcne.1996.0001 | s2cid = 11411254 }}
* {{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 = 175–179 | date = June 1996 | pmid = 8905236 | doi = 10.1093/dnares/3.3.175 | citeseerx = 10.1.1.588.7194 }}
* {{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 = 4451–4457 | date = February 1997 | pmid = 9020169 | doi = 10.1074/jbc.272.7.4451 | doi-access = free }}
* {{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 = 615–624 | date = June 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 = 4933–4947 | date = September 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 = February 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 = 1409–1415 | date = August 1999 | pmid = 10400987 | doi = 10.1093/hmg/8.8.1409 | doi-access = free }}
* {{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 = 265–275 | 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 = 10236–10243 | date = March 2002 | pmid = 11782478 | doi = 10.1074/jbc.M110752200 | doi-access = free }}
* {{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 = 3149–3157 | year = 2003 | pmid = 12530058 }}
* {{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 = 4760–4765 | date = April 2003 | pmid = 12676991 | pmc = 153629 | doi = 10.1073/pnas.0831000100 | doi-access = free | bibcode = 2003PNAS..100.4760D }}
* {{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 = October 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 = 482–488 | date = January 2004 | pmid = 14697214 | doi = 10.1016/j.bbrc.2003.11.168 | doi-access = free }}
* {{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 = 608–616 | date = January 2004 | pmid = 14701734 | pmc = 343817 | doi = 10.1128/MCB.24.2.608-616.2004 }}
{{refend}}

{{Transcription factors|g1}}

[[Category:PAS-domain-containing proteins]]

SIM2 - Revision history

imported>Citation bot: Altered issue. Formatted dashes. | Use this bot. Report bugs. | Suggested by Boghog | #UCB_webform