RCAN1 explained

Down syndrome critical region gene 1, also known as DSCR1, is a protein that in humans is encoded by the RCAN1 gene.^[1]

Gene location and organization

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 promoter region with about 900 bp between exon 3 and 4 suggesting that the fourth isoform might be penetrated from another promoter.^[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]

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]

Clinical significance

This gene is located in the minimal candidate region for the Down syndrome phenotype, and is overexpressed in the brain of Down syndrome fetuses. Chronic overexpression of this gene may lead to neurofibrillary tangles such as those associated with Alzheimer's disease.^{[1] [6]} RCAN1 helps coordinate whole-body metabolism and can be an important target in treatment of obesity.^[7]

Associated diseases

Central nervous system

All Down syndrome (DS) patients develop neuropathological changes identical to the pathogenesis of Alzheimer's disease (AD) in middle age, such as neuritic plaques and neuronal loss. Therefore, DS patients are perfect models to study AD pathogenesis.^[8] Chronic DSCR1 overexpression is related with DS and AD,^[9] while its shortage is reported in Huntington's disease.^[10] DSCR1 expressed excessively in the Central Nervous System of embryos, and the protein is later overexpressed in 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, 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.^[11]

Cancer

It is suggested that the reason patients with Down syndrome are less predisposed to certain cancers is due to the impact of this gene of reducing blood supply to tumour cells.^[12] 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.^[12]

Interactions

DSCR1 has been shown to interact with Calcineurin.^[13]

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.^[14]

See also

• RCAN2
• RCAN3

References

Further reading

• Harris CD, Ermak G, Davies KJ . 7184948 . Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product calcipressin 1 (or RCAN1) in disease . Cellular and Molecular Life Sciences . 62 . 21 . 2477–86 . November 2005 . 16231093 . 10.1007/s00018-005-5085-4 . 11139107 .
• Keating DJ, Chen C, Pritchard MA . 12867672 . Alzheimer's disease and endocytic dysfunction: clues from the Down syndrome-related proteins, DSCR1 and ITSN1 . Ageing Research Reviews . 5 . 4 . 388–401 . November 2006 . 16442855 . 10.1016/j.arr.2005.11.001 .
• Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X . 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 . October 1995 . 8595418 . 10.1093/hmg/4.10.1935 .
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–13 . April 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . 6 . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–8 . April 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Fuentes JJ, Pritchard MA, Estivill X . Genomic organization, alternative splicing, and expression patterns of the DSCR1 (Down syndrome candidate region 1) gene . Genomics . 44 . 3 . 358–61 . September 1997 . 9325060 . 10.1006/geno.1997.4866 .
• Rothermel B, Vega RB, Yang J, Wu H, Bassel-Duby R, Williams RS . 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 . March 2000 . 10722714 . 10.1074/jbc.275.12.8719 . free .
• Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S . DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways . Human Molecular Genetics . 9 . 11 . 1681–90 . July 2000 . 10861295 . 10.1093/hmg/9.11.1681 . free .
• Ermak G, Morgan TE, Davies KJ . Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease . The Journal of Biological Chemistry . 276 . 42 . 38787–94 . October 2001 . 11483593 . 10.1074/jbc.M102829200 . free .
• Vega RB, Yang J, Rothermel BA, Bassel-Duby R, Williams RS . Multiple domains of MCIP1 contribute to inhibition of calcineurin activity . The Journal of Biological Chemistry . 277 . 33 . 30401–7 . August 2002 . 12063245 . 10.1074/jbc.M200123200 . free .
• Genescà L, Aubareda A, Fuentes JJ, Estivill X, De La Luna S, Pérez-Riba M . Phosphorylation of calcipressin 1 increases its ability to inhibit calcineurin and decreases calcipressin half-life . The Biochemical Journal . 374 . Pt 2 . 567–75 . September 2003 . 12809556 . 1223619 . 10.1042/BJ20030267 .
• Hesser BA, Liang XH, Camenisch G, Yang S, Lewin DA, Scheller R, Ferrara N, Gerber HP . 6 . 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 . July 2004 . 15016650 . 10.1182/blood-2004-01-0273 . free .
• Michtalik HJ, Narayan AV, Bhatt N, Lin HY, Mulligan MT, Zhang SL, Crawford DR . Multiple oxidative stress-response members of the Adapt78 family . Free Radical Biology & Medicine . 37 . 4 . 454–62 . August 2004 . 15256217 . 10.1016/j.freeradbiomed.2004.05.014 .
• Iizuka M, Abe M, Shiiba K, Sasaki I, Sato Y . 36918295 . 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 . 2004 . 15263820 . 10.1159/000079832 .
• Yao YG, Duh EJ . 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 . August 2004 . 15358155 . 10.1016/j.bbrc.2004.06.176 .
• Minami T, Horiuchi K, Miura M, Abid MR, Takabe W, Noguchi N, Kohro T, Ge X, Aburatani H, Hamakubo T, Kodama T, Aird WC . 6 . 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 . November 2004 . 15448146 . 10.1074/jbc.M406454200 . free .
• Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S . 6 . Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1 . Nature . 459 . 7250 . 1126–30 . June 2009 . 19458618 . 2724004 . 10.1038/nature08062 . 2009Natur.459.1126B .

Notes and References

1. Web site: RCAN1 regulator of calcineurin 1 [Homo sapiens (human) ]]. 2022-12-28.
2. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L, Heit JJ, Kim SK, Yamasaki N, Miyakawa T, Francke U, Graef IA, Crabtree GR . 4428187 . 6 . NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21 . Nature . 441 . 7093 . 595–600 . June 2006 . 16554754 . 10.1038/nature04678 . 2006Natur.441..595A .
3. Pfister SC, Machado-Santelli GM, Han SW, Henrique-Silva F . Mutational analyses of the signals involved in the subcellular location of DSCR1 . BMC Cell Biology . 3 . 24 . September 2002 . 12225619 . 128833 . 10.1186/1471-2121-3-24 . free .
4. Holmes K, Chapman E, See V, Cross MJ . VEGF stimulates RCAN1.4 expression in endothelial cells via a pathway requiring Ca2+/calcineurin and protein kinase C-delta . PLOS ONE . 5 . 7 . e11435 . July 2010 . 20625401 . 2897886 . 10.1371/journal.pone.0011435 . 2010PLoSO...511435H . free .
5. Keating DJ, Chen C, Pritchard MA . 12867672 . Alzheimer's disease and endocytic dysfunction: clues from the Down syndrome-related proteins, DSCR1 and ITSN1 . Ageing Research Reviews . 5 . 4 . 388–401 . November 2006 . 16442855 . 10.1016/j.arr.2005.11.001 .
6. Martin KR, Corlett A, Dubach D, Mustafa T, Coleman HA, Parkington HC, Merson TD, Bourne JA, Porta S, Arbonés ML, Finkelstein DI, Pritchard MA . 6 . Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory . Human Molecular Genetics . 21 . 13 . 3025–41 . July 2012 . 22511596 . 10.1093/hmg/dds134 . free .
7. Rotter. David. Peiris. Heshan. Grinsfelder. D. Bennett. Martin. Alyce M.. Burchfield. Jana. Parra. Valentina. Hull. Christi. Morales. Cyndi R.. Jessup. Claire F.. Matusica. Dusan. Parks. Brian W.. December 2018. Regulator of Calcineurin 1 helps coordinate whole-body metabolism and thermogenesis. EMBO Reports. 19. 12. e44706. 10.15252/embr.201744706. 1469-3178. 6280800. 30389725.
8. Sun X, Wu Y, Herculano B, Song W . RCAN1 overexpression exacerbates calcium overloading-induced neuronal apoptosis . PLOS ONE . 9 . 4 . e95471 . 2014-04-21 . 24751678 . 3994074 . 10.1371/journal.pone.0095471 . 2014PLoSO...995471S . free .
9. Ermak G, Morgan TE, Davies KJ . 38420676 . Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease . The Journal of Biological Chemistry . 276 . 42 . 38787–94 . October 2001 . 11483593 . 10.1074/jbc.M102829200 . free .
10. Ermak G, Hench KJ, Chang KT, Sachdev S, Davies KJ . Regulator of calcineurin (RCAN1-1L) is deficient in Huntington disease and protective against mutant huntingtin toxicity in vitro . The Journal of Biological Chemistry . 284 . 18 . 11845–53 . May 2009 . 19270310 . 10.1074/jbc.M900639200 . 2673253 . free .
11. Lee EH, Kim SS, Lee S, Baek KH, Seo SR . Pituitary Adenylate Cyclase-activating Polypeptide (PACAP) Targets Down Syndrome Candidate Region 1 (DSCR1/RCAN1) to control Neuronal Differentiation . The Journal of Biological Chemistry . 290 . 34 . 21019–31 . August 2015 . 26157140 . 4543660 . 10.1074/jbc.M115.639476 . free .
12. Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S . 6 . Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1 . Nature . 459 . 7250 . 1126–30 . June 2009 . 19458618 . 2724004 . 10.1038/nature08062 . 2009Natur.459.1126B .
13. Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S . DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways . Human Molecular Genetics . 9 . 11 . 1681–90 . July 2000 . 10861295 . 10.1093/hmg/9.11.1681 . free .
14. Kim. Seon Sook. Seo. Su Ryeon . 15858776. vanc . 2013-01-29. Hydrogen peroxide-induced MAPK activation causes the increase of RCAN1 (DSCR1) protein expression. Genes & Genomics. en. 35. 1. 111–116. 10.1007/s13258-013-0080-x. 1976-9571.