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Gene Review

SIM2  -  single-minded family bHLH transcription...

Homo sapiens

Synonyms: BHLHE15, Class E basic helix-loop-helix protein 15, HMC13F06, HMC29C01, MGC119447, ...
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Disease relevance of SIM2


Psychiatry related information on SIM2

  • We previously postulated that the single-minded 2 (SIM2) gene identified on the human chromosome 21q22.2 is a good candidate gene for the pathogenesis of mental retardation in Down syndrome because its mouse homolog exhibits preferential expression in the mouse diencephalon during early embryogenesis [6].
  • Here, we studied SIM2 gene using a new approach to provide insights in understanding of its potential role in human development [7].
  • RESULTS: Patients assigned to SIM showed significant cognitive decline and progressed to dementia at a high rate, while a normal performance in RAVLT at baseline (NIM) predicted normal cognition after 3 years [8].

High impact information on SIM2

  • The production of virus and the synthesis of virus-specific RNA has been studied in Fv-1n/n (NIH/3T3, SIM) and Fv-1b/b (BALB/3T3, SIM-R) cell lines after infection with N- or B-tropic MuLV [9].
  • PER contains a motif of approximately 270 amino acids whose function is unknown (termed PAS) and which is also present in three transcription factors of the basic-helix-loop-helix (bHLH) type, in the D. melanogaster single-minded gene product (SIM), and in both subunits of the mammalian dioxin receptor complex [10].
  • Mining genome databases for therapeutic gold: SIM2 is a novel target for treatment of solid tumors [11].
  • Mouse pup testis cells were enriched for SSCs by selection with an anti-Thy-1 antibody and cultured on STO (SIM mouse embryo-derived thioguanine and ouabain resistant) feeders in a serum-free defined medium [12].
  • Intrigued by a possible association between a Down's syndrome gene and solid tumors, we monitored SIM2 expression in solid tumors [5].

Chemical compound and disease context of SIM2


Biological context of SIM2

  • This notion is supported by co-immunoprecipitation of EPO enhancer sequences with the SIM2 protein [2].
  • Our data suggest the existence of a hypoxic switch mechanism in cells that coexpress hypoxia-inducible factor and SIM proteins, where up-regulation and activation of hypoxia-inducible factor-1alpha is concomitant with attenuation of SIM activities [2].
  • However, SIM2 does map within the Down syndrome critical region and thus is a candidate gene that might contribute to the Down syndrome phenotype [3].
  • Further analysis with amino acid substitution of this small region of SIM2 protein revealed the critical role of five amino acid residues (Arg367, Lys373, Pro385, Tyr386, and Gln389) in NLS activity [14].
  • Transfection assay showed the presence of NLS activity in the small region of 23 and 21 amino acid residues at the central part of SIM2 and SIM1 proteins, respectively [14].

Anatomical context of SIM2

  • In cell lines engineered to stably express SIM1 and SIM2, we show that both are nuclear proteins that constitutively complex with the general bHLH/PAS partner factor, ARNT [2].
  • We used established somatic cell hybrid mapping panels to map SIM2 to chromosome 21 within subbands q22.2-q22 [3].
  • In adult mice mRNA for SIM1 was expressed in lung, skeletal muscle, and kidney, whereas the mRNA for SIM2 was found in the latter two [15].
  • Human Single-minded 1 (SIM1) and SIM2 genes were found as homologs of Drosophila sim gene which plays a key role in the midline cell lineage of the central nervous system [14].
  • In embryonic stages, SIM2 was identified predominantly in restricted regions of CNS, in ventral part of D1/D2 diencephalic neuroepithelium, along the neural tube and in a few cell subsets of dorsal root ganglia [7].

Associations of SIM2 with chemical compounds

  • We postulated that transcription factor SIM2 and E3 ubiquitin ligase Parkin may interact each other to play an important physiological role in the brain development which is controlled by ubiquitination [13].
  • In contrast, the carboxy-terminal half of the mouse SIM protein consists of a proline-rich region with no sequence homology to the Drosophila SIM protein [16].
  • GC-MS/SIM showed markedly high concentrations of hydroxyl radical-induced ring-opening products (e.g., 2,6-diamino-4-hydroxy-5-formamidopyrimidine) and 8-hydroxy adducts of adenine and guanine (e.g., 8-hydroxyguanine) in the DNA [17].
  • CONCLUSIONS: Neoral reduced the incidence of acute rejection compared with SIM, without significant increases in adverse events [18].
  • BACKGROUND: The microemulsion preconcentrate formulation of cyclosporine A (CsA) (Neoral) exhibits more uniform pharmacokinetics than the conventional formulation (Sandimmun; SIM) [18].

Physical interactions of SIM2

  • A series of deletion constructs revealed that Parkin actually binds to SIM2 with the IBR (294-377)-RING2 (378-465) domains and that the sites for poly-ubiquitination of SIM2 reside within the PAS1-PAS2 region (aa 141-289) [13].

Regulatory relationships of SIM2

  • These results suggested that binding of a protein transcription factor(s) such as c-myb or that alike regulates transcription of the SIM2 gene by binding to a small upstream region [6].

Other interactions of SIM2

  • 3. Analysis of the HPE patient-derived somatic cell hybrids showed that SIM2 is not deleted in two of three patients and thus is not a likely candidate for HPE1, the HPE gene on chromosome 21 [3].
  • BACH1 was significantly overexpressed in fetal DS (p < 0.008) as compared to controls whereas RUNX1 and ERG proteins were comparable between groups, and SIM2 l was not detectable in any specimen [19].
  • PAS (PER, ARNT, SIM) proteins play important roles in adaptation to low atmospheric and cellular oxygen levels, exposure to certain environmental pollutants, and diurnal oscillations in light and temperature [20].
  • Transcription factor single-minded 2 (SIM2) is ubiquitinated by the RING-IBR-RING-type E3 ubiquitin ligases [13].
  • Human SIM2 is the ortholog of Drosophila single-minded (sim), a master regulator of neurogenesis and transcriptional factor controlling midline cell fate determination [7].

Analytical, diagnostic and therapeutic context of SIM2

  • Northern blot analysis revealed one mRNA SIM1 species of approximately 9.5 kb and four different mRNA SIM2 species of 2.7, 3, 4.4, and 6 kb in human fetal kidney [1].
  • Whole-mount embryo in situ hybridization experiments revealed that the SIM mRNA is expressed prominently in the diencephalon of mouse embryos at 8-9.5 days postcoitum [16].
  • Sequence analysis revealed that the cluster was a long CpG island extending 19, 128 nucleotides which includes in the first and second exons of hSIM2 [21].
  • Primarily through percent identity plots (PIPs) of SIM comparative sequence alignments, the sequence of coding regions, putative alternative exons, conserved noncoding regions, and correlation in repetitive element insertions were easily determined [22].
  • Here we quantified multiple oxidized bases in nuclear and mitochondrial DNA of frontal, parietal, and temporal lobes and cerebellum from short postmortem interval AD brain and age-matched control subjects using gas chromatography/mass spectrometry with selective ion monitoring (GC/MS-SIM) and stable labeled internal standards [23].


  1. 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. Chrast, R., Scott, H.S., Chen, H., Kudoh, J., Rossier, C., Minoshima, S., Wang, Y., Shimizu, N., Antonarakis, S.E. Genome Res. (1997) [Pubmed]
  2. 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. Woods, S.L., Whitelaw, M.L. J. Biol. Chem. (2002) [Pubmed]
  3. 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. Muenke, M., Bone, L.J., Mitchell, H.F., Hart, I., Walton, K., Hall-Johnson, K., Ippel, E.F., Dietz-Band, J., Kvaløy, K., Fan, C.M. Am. J. Hum. Genet. (1995) [Pubmed]
  4. Down's syndrome-associated Single Minded 2 gene as a pancreatic cancer drug therapy target. DeYoung, M.P., Tress, M., Narayanan, R. Cancer Lett. (2003) [Pubmed]
  5. Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors. DeYoung, M.P., Tress, M., Narayanan, R. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  6. Molecular mechanisms of human single-minded 2 (SIM2) gene expression: identification of a promoter site in the SIM2 genomic sequence. Yamaki, A., Tochigi, J., Kudoh, J., Minoshima, S., Shimizu, N., Shimizu, Y. Gene (2001) [Pubmed]
  7. Spatial and temporal localization during embryonic and fetal human development of the transcription factor SIM2 in brain regions altered in Down syndrome. Rachidi, M., Lopes, C., Charron, G., Delezoide, A.L., Paly, E., Bloch, B., Delabar, J.M. Int. J. Dev. Neurosci. (2005) [Pubmed]
  8. Identifying patients at high and low risk of cognitive decline using Rey Auditory Verbal Learning Test among middle-aged memory clinic outpatients. Andersson, C., Lindau, M., Almkvist, O., Engfeldt, P., Johansson, S.E., Eriksdotter Jonhagen, M. Dementia and geriatric cognitive disorders. (2006) [Pubmed]
  9. Effect of Fv-1 gene product on synthesis of N-tropic and B-tropic murine leukemia viral RNA. Jolicoeur, P., Baltimore, D. Cell (1976) [Pubmed]
  10. PAS is a dimerization domain common to Drosophila period and several transcription factors. Huang, Z.J., Edery, I., Rosbash, M. Nature (1993) [Pubmed]
  11. Mining genome databases for therapeutic gold: SIM2 is a novel target for treatment of solid tumors. Ratan, R.R. Trends Pharmacol. Sci. (2003) [Pubmed]
  12. Growth factors essential for self-renewal and expansion of mouse spermatogonial stem cells. Kubota, H., Avarbock, M.R., Brinster, R.L. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  13. Transcription factor single-minded 2 (SIM2) is ubiquitinated by the RING-IBR-RING-type E3 ubiquitin ligases. Okui, M., Yamaki, A., Takayanagi, A., Kudoh, J., Shimizu, N., Shimizu, Y. Exp. Cell Res. (2005) [Pubmed]
  14. A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2. Yamaki, A., Kudoh, J., Shimizu, N., Shimizu, Y. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  15. Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein. Probst, M.R., Fan, C.M., Tessier-Lavigne, M., Hankinson, O. J. Biol. Chem. (1997) [Pubmed]
  16. The mammalian single-minded (SIM) gene: mouse cDNA structure and diencephalic expression indicate a candidate gene for Down syndrome. Yamaki, A., Noda, S., Kudoh, J., Shindoh, N., Maeda, H., Minoshima, S., Kawasaki, K., Shimizu, Y., Shimizu, N. Genomics (1996) [Pubmed]
  17. Fourier-transform infrared spectroscopy and gas chromatography-mass spectrometry reveal a remarkable degree of structural damage in the DNA of wild fish exposed to toxic chemicals. Malins, D.C., Gunselman, S.J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  18. Comparison of microemulsion and conventional formulations of cyclosporine A in preventing acute rejection in de novo kidney transplant patients. The U.K. Neoral Renal Study Group. Pollard, S.G., Lear, P.A., Ready, A.R., Moore, R.H., Johnson, R.W. Transplantation (1999) [Pubmed]
  19. Overexpression of transcription factor BACH1 in fetal Down syndrome brain. Ferrando-Miguel, R., Cheon, M.S., Yang, J.W., Lubec, G. J. Neural Transm. Suppl. (2003) [Pubmed]
  20. The basic helix-loop-helix-PAS protein MOP9 is a brain-specific heterodimeric partner of circadian and hypoxia factors. Hogenesch, J.B., Gu, Y.Z., Moran, S.M., Shimomura, K., Radcliffe, L.A., Takahashi, J.S., Bradfield, C.A. J. Neurosci. (2000) [Pubmed]
  21. A 19-kb CpG island associated with single-minded gene 2 in Down syndrome chromosomal region. Osoegawa, K., Okano, S., Kato, Y., Nishimura, Y., Soeda, E. DNA Res. (1996) [Pubmed]
  22. Comparative sequence analysis of a gene-rich cluster at human chromosome 12p13 and its syntenic region in mouse chromosome 6. Ansari-Lari, M.A., Oeltjen, J.C., Schwartz, S., Zhang, Z., Muzny, D.M., Lu, J., Gorrell, J.H., Chinault, A.C., Belmont, J.W., Miller, W., Gibbs, R.A. Genome Res. (1998) [Pubmed]
  23. Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease. Wang, J., Xiong, S., Xie, C., Markesbery, W.R., Lovell, M.A. J. Neurochem. (2005) [Pubmed]
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