Single-minded homolog 2 is a protein that in humans is encoded by the SIM2 gene.[1][2] It plays a mojor role in the development of the CNS 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]
Single-minded family bHLH transcription factor 2 | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||||||
Symbols | SIM2 ; HMC13F06; HMC29C01; SIM; bHLHe15 | ||||||||||||
External IDs | OMIM: 600892 MGI: 98307 HomoloGene: 3716 GeneCards: SIM2 Gene | ||||||||||||
|
|||||||||||||
RNA expression pattern | |||||||||||||
![]() |
|||||||||||||
More reference expression data | |||||||||||||
Orthologs | |||||||||||||
Species | Human | Mouse | |||||||||||
Entrez | 6493 | 20465 | |||||||||||
Ensembl | ENSG00000159263 | ENSMUSG00000062713 | |||||||||||
UniProt | Q14190 | Q61079 | |||||||||||
RefSeq (mRNA) | NM_005069 | NM_011377 | |||||||||||
RefSeq (protein) | NP_005060 | NP_035507 | |||||||||||
Location (UCSC) | Chr 21: 38.07 – 38.12 Mb |
Chr 16: 94.09 – 94.13 Mb |
|||||||||||
PubMed search | [1] | [2] | |||||||||||
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]
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
- ^ Muenke M, Bone LJ, Mitchell HF, Hart I, Walton K, Hall-Johnson K, Ippel EF, Dietz-Band J, Kvaloy K, Fan CM 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". Am J Hum Genet 57 (5): 1074–9. PMC 1801356. PMID 7485157.
- ^ a b "Entrez Gene: SIM2 single-minded homolog 2 (Drosophila)".
- ^ a b c d e Shamblott, MJ; Bugg, EM; Lawler, AM; Gearhart, JD (2002). "Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene.". Developmental Dynamics 2002 (224): 373–380.
- ^ Probst, M R; Fan C M; 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". J. Biol. Chem. (UNITED STATES) 272 (7): 4451–7. doi:10.1074/jbc.272.7.4451. ISSN 0021-9258. PMID 9020169.
- ^ Ooe, Norihisa; Saito Koichi; Mikami Nobuyoshi; Nakatuka Iwao; Kaneko Hideo (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". Mol. Cell. Biol. (United States) 24 (2): 608–16. doi:10.1128/MCB.24.2.608-616.2004. ISSN 0270-7306. PMC 343817. PMID 14701734.
- ^ Woods, Susan L; Whitelaw Murray L (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". J. Biol. Chem. (United States) 277 (12): 10236–43. doi:10.1074/jbc.M110752200. ISSN 0021-9258. PMID 11782478.
- ^ Moffett, P; Reece M; Pelletier J (September 1997). "The murine Sim-2 gene product inhibits transcription by active repression and functional interference". Mol. Cell. Biol. (UNITED STATES) 17 (9): 4933–47. ISSN 0270-7306. PMC 232345. PMID 9271372.
- ^ 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.
Further reading
- Dahmane N, Charron G, Lopes C et al. (1995). "Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development". Proc. Natl. Acad. Sci. U.S.A. 92 (20): 9191–5. doi:10.1073/pnas.92.20.9191. PMC 40950. PMID 7568099.
- Chen H, Chrast R, Rossier C et al. (1995). "Single-minded and Down syndrome?". Nat. Genet. 10 (1): 9–10. doi:10.1038/ng0595-9. PMID 7647800.
- Yamaki A, Noda S, Kudoh J et al. (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 et al. (1996). "Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome". Mol. Cell. Neurosci. 7 (1): 1–16. doi:10.1006/mcne.1996.0001. PMID 8812055.
- Osoegawa K, Okano S, Kato Y et al. (1997). "A 19-kb CpG island associated with single-minded gene 2 in Down syndrome chromosomal region". DNA Res. 3 (3): 175–9. doi:10.1093/dnares/3.3.175. PMID 8905236.
- Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O (1997). "Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein". J. Biol. Chem. 272 (7): 4451–7. doi:10.1074/jbc.272.7.4451. PMID 9020169.
- Chrast R, Scott HS, Chen H et al. (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 Res. 7 (6): 615–24. doi:10.1101/gr.7.6.615. PMC 310662. PMID 9199934.
- Moffett P, Reece M, Pelletier J (1997). "The murine Sim-2 gene product inhibits transcription by active repression and functional interference". Mol. Cell. Biol. 17 (9): 4933–47. PMC 232345. PMID 9271372.
- Dahmane N, Ghezala GA, Gosset P et al. (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 et al. (1999). "Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome". Hum. Mol. Genet. 8 (8): 1409–15. doi:10.1093/hmg/8.8.1409. PMID 10400987.
- Hattori M, Fujiyama A, Taylor TD et al. (2000). "The DNA sequence of human chromosome 21". Nature 405 (6784): 311–9. doi:10.1038/35012518. PMID 10830953.
- Yamaki A, Tochigi J, Kudoh J et al. (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 (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". J. Biol. Chem. 277 (12): 10236–43. doi:10.1074/jbc.M110752200. PMID 11782478.
- Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Deyoung MP, Scheurle D, Damania H et al. (2003). "Down's syndrome-associated single minded gene as a novel tumor marker". Anticancer Res. 22 (6A): 3149–57. PMID 12530058.
- DeYoung MP, Tress M, Narayanan R (2003). "Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors". Proc. Natl. Acad. Sci. U.S.A. 100 (8): 4760–5. doi:10.1073/pnas.0831000100. PMC 153629. PMID 12676991.
- DeYoung MP, Tress M, Narayanan R (2003). "Down's syndrome-associated Single Minded 2 gene as a pancreatic cancer drug therapy target". Cancer Lett. 200 (1): 25–31. doi:10.1016/S0304-3835(03)00409-9. PMID 14550949.
- Yamaki A, Kudoh J, Shimizu N, Shimizu Y (2004). "A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2". Biochem. Biophys. Res. Commun. 313 (3): 482–8. doi:10.1016/j.bbrc.2003.11.168. PMID 14697214.
- Ooe N, Saito K, Mikami N et al. (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". Mol. Cell. Biol. 24 (2): 608–16. doi:10.1128/MCB.24.2.608-616.2004. PMC 343817. PMID 14701734.
|