DSCR1 in human is located at the centromeric border of the DSCR and encodes an inhibitor of calcineurin/ NFAT (nuclear factor activated T cells) signalling.[2]
DSCR1 genomic sequence of total 45 kb contain 7 exons and 6 introns , different cDNA analysis yield first four exons are alternative and code for two isoforms of 197 amino acids, and one isoform code for 171 amino acids which differ in their N terminal . While the rest of the 168 residues are common. There is also alternative promotor region with about 900 bp between exon 3 and 4 suggesting that the fourth isoform might be penetrated from another promotor.[3]
Function
The protein encoded by this gene interacts with calcineurin A and inhibits calcineurin-dependent signaling pathways of genetic transcription, possibly affecting central nervous system development. Three transcript variants encoding three different isoforms have been found for this gene.[1] In endothelial cells, VEGF stimulates RCAN1.4 expression which regulates gene expression, cell migration and tubular morphogenesis.[4]
Protein Structure
DSCR1 Consist of putative functional motifs and calcineurin binding domain. DSCR1 contains two proline-rich SH3 binding domain, usually named proline-rich domain (PRD), which defines the protein family. SH3 domains or PRD are very important to allow the binding of the protein to endocytosis-related proteins such as ITSN1 and amphiphysin 1 and 2.[5]
All Down syndrome (DS) patients progress neuropathological changes identical to the pathogenesis of Alzheimer disease (AD) after their middle age, such as neurotic plaques and neuronal loss in their brain, Therefor, DS patients are perfect models to study AD pathogenesis.[7]
Chronic DSCR1 overexpression is related with DS and, while its shortage is reported in Huntington’s disease. DSCR1 expressed excessively in the Central nervous system of embryos during their development, this protein is later overexpressed in differentiating neurons regions such as Brains of DS patients. However, neurotrophic peptide PACAP (or Pituitary adenylate cyclase-activating peptide) which is responsible for the development, differentiation, and survival, and various parts of memory and learning, Target RCNA1 in a Down syndrome related gene, induces the expression of regulator of calcineurin 1, through activation of the PKA-CREB pathway, and this is important to understand the mechanisms of neural differentiation and aim for proper expression of RCAN1.[8]
Cancer risk
It is suggested that the reason patients with Down's Syndrome are less predisposed to certain cancers is due to the impact of this gene of reducing blood supply to tumour cells.[9]
It is also proposed by epidemiological studies that DS patients are in greater risk of Leukaemia , on the other hand they are at lower risk of cancer and other angiogenesis related diseases such as Diabetic retinopathy and Atherosclerosis , indicating that one or more trisomic genes on chromosome 21 is responsible for protecting DS patients against cancer, and this cancer defence could be a result of angiogenesis suppression.[10]
Hydrogen peroxide (H2O2) increases the overexpression of protein RCAN1. However, anti-oxidants and inhibitors of mitogen-activated protein kinases (MAPK) treatment block the increased expression of RCAN1 by H2O2. Demonstrating that the increased expression is a result of generating reactive oxygen species and activation of MAPK. Furthermore, phosphorylation is important to regulator RCAN1 protein expression. Because phosphorylation of RCAN1 expression by H2O2 increases of the half-life of the protein.[12]
↑Arron, Joseph R.; Winslow, Monte M.; Polleri, Alberto; Chang, Ching-Pin; Wu, Hai; Gao, Xin; Neilson, Joel R.; Chen, Lei; Heit, Jeremy J. (June 2006). "NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21". Nature. 441 (7093): 595–600. doi:10.1038/nature04678. PMID16554754.
↑Martin KR, Corlett A, Dubach D, Mustafa T, Coleman HA, Parkington HC, Merson TD, Bourne JA, Porta S, Arbonés ML, Finkelstein DI, Pritchard MA (Jul 2012). "Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory". Human Molecular Genetics. 21 (13): 3025–3041. doi:10.1093/hmg/dds134. PMID22511596.
↑Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S (Jul 2000). "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Human Molecular Genetics. 9 (11): 1681–90. doi:10.1093/hmg/9.11.1681. PMID10861295.
↑Kim, Seon Sook; Seo, Su Ryeon (2013-01-29). "Hydrogen peroxide-induced MAPK activation causes the increase of RCAN1 (DSCR1) protein expression". Genes & Genomics. 35 (1): 111–116. doi:10.1007/s13258-013-0080-x. ISSN1976-9571.
Further reading
Harris CD, Ermak G, Davies KJ (Nov 2005). "Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product calcipressin 1 (or RCAN1) in disease". Cellular and Molecular Life Sciences : CMLS. 62 (21): 2477–86. doi:10.1007/s00018-005-5085-4. PMID16231093. Check date values in: |year= / |date= mismatch (help)
Keating DJ, Chen C, Pritchard MA (Nov 2006). "Alzheimer's disease and endocytic dysfunction: clues from the Down syndrome-related proteins, DSCR1 and ITSN1". Ageing Research Reviews. 5 (4): 388–401. doi:10.1016/j.arr.2005.11.001. PMID16442855.
Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X (Oct 1995). "A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart". Human Molecular Genetics. 4 (10): 1935–44. doi:10.1093/hmg/4.10.1935. PMID8595418. Check date values in: |year= / |date= mismatch (help)
Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (Apr 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID8619474.
Fuentes JJ, Pritchard MA, Estivill X (Sep 1997). "Genomic organization, alternative splicing, and expression patterns of the DSCR1 (Down syndrome candidate region 1) gene". Genomics. 44 (3): 358–61. doi:10.1006/geno.1997.4866. PMID9325060.
Rothermel B, Vega RB, Yang J, Wu H, Bassel-Duby R, Williams RS (Mar 2000). "A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling". The Journal of Biological Chemistry. 275 (12): 8719–25. doi:10.1074/jbc.275.12.8719. PMID10722714.
Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S (Jul 2000). "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Human Molecular Genetics. 9 (11): 1681–90. doi:10.1093/hmg/9.11.1681. PMID10861295.
Ermak G, Morgan TE, Davies KJ (Oct 2001). "Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease". The Journal of Biological Chemistry. 276 (42): 38787–94. doi:10.1074/jbc.M102829200. PMID11483593.
Vega RB, Yang J, Rothermel BA, Bassel-Duby R, Williams RS (Aug 2002). "Multiple domains of MCIP1 contribute to inhibition of calcineurin activity". The Journal of Biological Chemistry. 277 (33): 30401–7. doi:10.1074/jbc.M200123200. PMID12063245.
Hesser BA, Liang XH, Camenisch G, Yang S, Lewin DA, Scheller R, Ferrara N, Gerber HP (Jul 2004). "Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells". Blood. 104 (1): 149–58. doi:10.1182/blood-2004-01-0273. PMID15016650.
Michtalik HJ, Narayan AV, Bhatt N, Lin HY, Mulligan MT, Zhang SL, Crawford DR (Aug 2004). "Multiple oxidative stress-response members of the Adapt78 family". Free Radical Biology & Medicine. 37 (4): 454–62. doi:10.1016/j.freeradbiomed.2004.05.014. PMID15256217. Check date values in: |year= / |date= mismatch (help)
Iizuka M, Abe M, Shiiba K, Sasaki I, Sato Y (2004). "Down syndrome candidate region 1,a downstream target of VEGF, participates in endothelial cell migration and angiogenesis". Journal of Vascular Research. 41 (4): 334–44. doi:10.1159/000079832. PMID15263820.
Yao YG, Duh EJ (Aug 2004). "VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis?". Biochemical and Biophysical Research Communications. 321 (3): 648–56. doi:10.1016/j.bbrc.2004.06.176. PMID15358155.
Minami T, Horiuchi K, Miura M, Abid MR, Takabe W, Noguchi N, Kohro T, Ge X, Aburatani H, Hamakubo T, Kodama T, Aird WC (Nov 2004). "Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis". The Journal of Biological Chemistry. 279 (48): 50537–54. doi:10.1074/jbc.M406454200. PMID15448146. Check date values in: |year= / |date= mismatch (help)
