DSCR1 in human is located at thecentromeric border of the DSCR and encodes an inhibitor of calcineurin/NFAT (nuclear factor activated T cells) signalling.[6]
DSCR1 genomic sequence of total 45 kb contain 7exons and 6introns, differentcDNA 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 theirN terminal . While the rest of the 168 residues are common. There is also alternativepromoter region with about 900 bp between exon 3 and 4 suggesting that the fourth isoform might be penetrated from another promoter.[7]
Theprotein encoded by this gene interacts withcalcineurin A and inhibits calcineurin-dependentsignaling pathways of genetic transcription, possibly affectingcentral nervous system development. Threetranscript variants encoding three differentisoforms have been found for this gene.[5] Inendothelial cells,VEGF stimulates RCAN1.4 expression which regulates gene expression, cell migration and tubular morphogenesis.[8]
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 asITSN1 andamphiphysin 1 and 2.[9]
This gene is located in the minimal candidate region for theDown syndromephenotype, and is overexpressed in the brain of Down syndrome fetuses. Chronicoverexpression of this gene may lead toneurofibrillary tangles such as those associated withAlzheimer's disease.[5][10] RCAN1 helps coordinate whole-body metabolism and can be an important target in treatment of obesity.[11]
All Down syndrome (DS) patients develop neuropathological changes identical to the pathogenesis ofAlzheimer's disease (AD) in middle age, such asneuritic plaques and neuronal loss. Therefore, DS patients are perfect models to study AD pathogenesis.[12] Chronic DSCR1 overexpression is related with DS and AD,[13] while its shortage is reported inHuntington's disease.[14] DSCR1 expressed excessively in the Central Nervous System of embryos, and the protein is later overexpressed in brains of DS patients. However, neurotrophic peptidePACAP (or Pituitary adenylate cyclase-activating peptide) which is responsible for the development, differentiation, and survival, and various parts of memory and learning, targets RCAN1, 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.[15]
It is suggested that the reason patients withDown syndrome are less predisposed to certain cancers is due to the impact of this gene of reducing blood supply to tumour cells.[16]It is also proposed by epidemiological studies that DS patients are in greater risk ofleukaemia, on the other hand they are at lower risk of cancer and otherangiogenesis related diseases such asdiabetic retinopathy andatherosclerosis, 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.[16]
Hydrogen peroxide (H2O2) increases the overexpression of protein RCAN1. However, anti-oxidants and inhibitors ofmitogen-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.[18]
^Keating DJ, Chen C, Pritchard MA (November 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.S2CID12867672.
^Kim SS, Seo SR (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.S2CID15858776.
Keating DJ, Chen C, Pritchard MA (November 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.S2CID12867672.
Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X (October 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.
Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (April 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 (September 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.
Michtalik HJ, Narayan AV, Bhatt N, Lin HY, Mulligan MT, Zhang SL, Crawford DR (August 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.
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.S2CID36918295.
Yao YG, Duh EJ (August 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.Bibcode:2004BBRC..321..648Y.doi:10.1016/j.bbrc.2004.06.176.PMID15358155.
