DSCR1

DSCR1
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1WEY
Identifikatori
Aliasi	RCAN1
Vanjski ID-jevi	OMIM: 602917 MGI: 1890564 HomoloGene: 3251 GeneCards: RCAN1
Lokacija gena (čovjek)
Hrom.	Hromosom 21 (čovjek)
Kraj	34,615,113 bp
Lokacija gena (miš)
Hrom.	Hromosom 16 (miš)
Kraj	92,267,755 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity; • vezivanje sa DNK; • GO:0001948, GO:0016582 vezivanje za proteine; • calcium-dependent protein serine/threonine phosphatase regulator activity; • vezivanje identičnih proteina; • nucleic acid binding;
Ćelijska komponenta	• citoplazma; • jedro;
Biološki proces	• regulation of calcineurin-NFAT signaling cascade; • central nervous system development; • calcineurin-NFAT signaling cascade; • Krvotok; • GO:0072468 Transdukcija signala; • calcium-mediated signaling; • GO:0009373 regulation of transcription, DNA-templated; • regulation of phosphoprotein phosphatase activity; • negative regulation of calcineurin-NFAT signaling cascade;
	Izvori:Amigo / QuickGO
Ortolozi
	1827
	54720
	ENSG00000159200
	ENSMUSG00000022951
	P53805
	Q9JHG6
NM_001285389; NM_001285391; NM_001285392; NM_001285393; NM_004414;
	NM_203417; NM_203418; NM_001331016
	NM_001081549; NM_019466
NP_001272318; NP_001272320; NP_001272321; NP_001272322; NP_001317945;
	NP_004405; NP_981962; NP_981963
	NP_001075018; NP_062339
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Gen 1 kritične regije Downovog sindroma, znan i kao DSCR1, jest protein koji je kod ljudi kodiran genom DSCR1 sa hromosoma 21.^[5]

RCAN1 je gen koji kod ljudi kodira protein DSCR1.

Lokacija i organizacija gena

DSCR1 kod ljudi nalazi se na centromernoj granici DSCR i kodira inhibitor signalizacije kalcineurina/NFAT (jedarnim faktorom aktiviranih T-ćelija).^[6]

Genomska sekvenca DSCR1 od ukupno 45 kb sadrži sedam egzona i šeast introna , a različite analize cDNK daju da su prva četiri egzona alternativna i kodiraju dvije izoforme od po 197 aminokiselina i jedan kod izoforme za 171 aminokiselina, koje se razlikuju po N terminalu. Dok je ostatak od 168 ostataka uobičajen, postoji i alternativni promotorski region sa oko 900 bp između egzona 3 i 4, što sugerira da bi četvrta izoforma mogla poticati iz drugog promotora.^[7]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 252 aminokiseline, a molekulska težina 28.079 Da.^[5]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MEDGVAGPQL	GAAAEAAEAA	EARARPGVTL	RPFAPLSGAA	EADEGGGDWS
FIDCEMEEVD	LQDLPSATIA	CHLDPRVFVD	GLCRAKFESL	FRTYDKDITF
QYFKSFKRVR	INFSNPFSAA	DARLQLHKTE	FLGKEMKLYF	AQTLHIGSSH
LAPPNPDKQF	LISPPASPPV	GWKQVEDATP	VINYDLLYAI	SKLGPGEKYE
LHAATDTTPS	VVVHVCESDQ	EKEEEEEMER	MRRPKPKIIQ	TRRPEYTPIH
LS

Struktura

DSCR1 sastoji se od pretpostavljenih funkcionalnih motiva i domena za vezivanje kalcineurina. DSCR1 sadrži dva SH3 vezujuća domena bogata prolinom, koja se obično i označavaju kao domen bogat prolinom (PRD), koji definira porodicu proteina. SH3 domeni ili PRD su veoma važni kako bi se omogućilo vezivanje proteina za proteine povezane s endocitozom kao što su ITSN1 i amfifizin 1 i 2.^[8]

Funkcija

Protein kodiran ovim genom stupa u interakciju sa kalcineurinom A i inhibira kalcineurin zavisne signalne puteve genetičke transkripcije, što može uticati na razvoj centralnog nervnog sistema. Za ovaj gen pronađene su tri varijante transkripta koje kodiraju tri različite izoforme.^[5] U endotelnim ćelijama, VEGF stimulira ekspresiju RCAN1.4, koja reguliše ekspresiju gena, migraciju ćelija i tubulsku morfogenezu.^[9]

Klinički značaj

Ovaj gen se nalazi u regiji minimalnog kandidata za fenotip Dovnovog sindroma i prekomjerno je eksprimiran u mozgu fetusa s Downovim sindromom. Hronična prekomerna ekspresija ovog gena može dovesti do neurofibrilskih zapleta poput onih povezanih sa Alzheimerovom bolešću.^[5]^[10] RCAN1 pomaže u koordinaciji metabolizma cijelog tijela i može biti važna meta u liječenju gojaznosti.^[11]

Povezane bolesti

Centralni nervni sistem

Svi pacijenti sa Downovim sindromom (DS) razvijaju neuropatološke promjene identične patogenezi Alzheimerove bolesti (AD) u srednjim godinama, kao što su neuritski plakovi i gubitak neurona. Stoga su pacijenti sa DS savršeni modeli za proučavanje patogeneze AD.^[12] Chronic DSCR1 overexpression is related with DS and AD,^[13] dok je njegov nedostatak zabilježen u pacijenata sa Hungtintonovom bolešću.^[14] DSCR1 se prekomjerno eksprimira u centralnom nervnom sistemu embriona, a protein je kasnije pretjerano eksprimiran u mozgu pacijenata sa DS. Međutim, neurotrofni peptid PACAP (ili peptid koji aktivira hipofiznu adenilat-ciklazu) koji je odgovoran za razvoj, diferencijaciju i preživljavanje, te različite dijelove pamćenja i učenja, cilja na RCAN1, gen vezan za Downov sindrom, inducirajući ekspresiju regulatora kalcineurina 1, aktivacijom PKA-CREB puta, što je važno za razumijevanje mehanizama nervne diferencijacije i za cilj pravilnog eksprimiranja RCAN1.^[15]

Kancer

Pretpostavlja se da je razlog zašto su pacijenti sa Downovim sindromom manje predisponirani na određene tipove raka posljedica uticaja ovog gena na smanjenje opskrbe tumorskih ćelija krvlju.^[16] Epidemiološke studije također sugeriraju da su pacijenti sa DS-om u većem riziku od leukemija, a s druge strane imaju manji rizik od raka i drugih bolesti povezanih s angiogenezom, kao što su dijabeteska retinopatija i ateroskleroza, što ukazuje da je jedan ili više trisomijskih gena na hromosomu 21 odgovorni za zaštitu pacijenata sa DS od raka, a ova odbrana može biti rezultat supresije angiogeneze.^[16]

Interakcije

Pokazalo se da DSCR1 reaguje sa kalcineurinom.^[17]

Vodik-peroksid (H₂O₂) povećava prekomjernu ekspresiju proteina RCAN1. Međutim, antioksidansi i inhibitori tretmana mitogen-aktiviranih protein kinaza (MAPK) blokiraju povećanu ekspresiju RCAN1 pomoću H₂O₂. Pokazujući da je povećana ekspresija rezultat stvaranja reaktivnih vrsta kisika i aktivacije MAPK. Nadalje, ekspresije proteina važna je za regulaciju RCAN1 fosforilacija. Zato što fosforilacija eksprimira RCAN1 pomoću H₂O₂ produžava poluživot proteina.^[18]

Također pogledajte

RCAN2
RCAN3

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000159200 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000022951 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b ^c ^d "Entrez Gene: DSCR1 Down syndrome critical region gene 1".
^ Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, et al. (June 2006). "NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21". Nature. 441 (7093): 595–600. Bibcode:2006Natur.441..595A. doi:10.1038/nature04678. PMID 16554754. S2CID 4428187.
^ Pfister SC, Machado-Santelli GM, Han SW, Henrique-Silva F (September 2002). "Mutational analyses of the signals involved in the subcellular location of DSCR1". BMC Cell Biology. 3: 24. doi:10.1186/1471-2121-3-24. PMC 128833. PMID 12225619.
^ 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. PMID 16442855. S2CID 12867672.
^ Holmes K, Chapman E, See V, Cross MJ (July 2010). "VEGF stimulates RCAN1.4 expression in endothelial cells via a pathway requiring Ca2+/calcineurin and protein kinase C-delta". PLOS ONE. 5 (7): e11435. Bibcode:2010PLoSO...511435H. doi:10.1371/journal.pone.0011435. PMC 2897886. PMID 20625401.
^ Martin KR, Corlett A, Dubach D, Mustafa T, Coleman HA, Parkington HC, et al. (July 2012). "Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory". Human Molecular Genetics. 21 (13): 3025–41. doi:10.1093/hmg/dds134. PMID 22511596.
^ 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. doi:10.15252/embr.201744706. ISSN 1469-3178. PMC 6280800. PMID 30389725.
^ Sun X, Wu Y, Herculano B, Song W (2014-04-21). "RCAN1 overexpression exacerbates calcium overloading-induced neuronal apoptosis". PLOS ONE. 9 (4): e95471. Bibcode:2014PLoSO...995471S. doi:10.1371/journal.pone.0095471. PMC 3994074. PMID 24751678.
^ Ermak G, Morgan TE, Davies KJ (October 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. PMID 11483593. S2CID 38420676.
^ Ermak G, Hench KJ, Chang KT, Sachdev S, Davies KJ (May 2009). "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. doi:10.1074/jbc.M900639200. PMC 2673253. PMID 19270310.
^ Lee EH, Kim SS, Lee S, Baek KH, Seo SR (August 2015). "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. doi:10.1074/jbc.M115.639476. PMC 4543660. PMID 26157140.
^ ^a ^b Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, et al. (June 2009). "Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1". Nature. 459 (7250): 1126–30. Bibcode:2009Natur.459.1126B. doi:10.1038/nature08062. PMC 2724004. PMID 19458618.
^ Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S (July 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. PMID 10861295.
^ Kim SS, Seo SR (2013-01-29). "Hydrogen peroxide-induced MAPK activation causes the increase of RCAN1 (DSCR1) protein expression". Genes & Genomics (jezik: engleski). 35 (1): 111–116. doi:10.1007/s13258-013-0080-x. ISSN 1976-9571. S2CID 15858776.

Dopunska literatura

Harris CD, Ermak G, Davies KJ (November 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. 62 (21): 2477–86. doi:10.1007/s00018-005-5085-4. PMID 16231093. S2CID 7184948.
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. PMID 16442855. S2CID 12867672.
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. PMID 8595418.
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. PMID 8619474.
Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, et al. (April 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
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. PMID 9325060.
Rothermel B, Vega RB, Yang J, Wu H, Bassel-Duby R, Williams RS (March 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. PMID 10722714.
Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S (July 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. PMID 10861295.
Ermak G, Morgan TE, Davies KJ (October 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. PMID 11483593.
Vega RB, Yang J, Rothermel BA, Bassel-Duby R, Williams RS (August 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. PMID 12063245.
Genescà L, Aubareda A, Fuentes JJ, Estivill X, De La Luna S, Pérez-Riba M (September 2003). "Phosphorylation of calcipressin 1 increases its ability to inhibit calcineurin and decreases calcipressin half-life". The Biochemical Journal. 374 (Pt 2): 567–75. doi:10.1042/BJ20030267. PMC 1223619. PMID 12809556.
Hesser BA, Liang XH, Camenisch G, Yang S, Lewin DA, Scheller R, et al. (July 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. PMID 15016650.
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. PMID 15256217.
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. PMID 15263820. S2CID 36918295.
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. doi:10.1016/j.bbrc.2004.06.176. PMID 15358155.
Minami T, Horiuchi K, Miura M, Abid MR, Takabe W, Noguchi N, et al. (November 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. PMID 15448146.
Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, et al. (June 2009). "Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1". Nature. 459 (7250): 1126–30. Bibcode:2009Natur.459.1126B. doi:10.1038/nature08062. PMC 2724004. PMID 19458618.

Vanjski linkovi

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000159200 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000022951 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: DSCR1 Down syndrome critical region gene 1".

[6] Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, et al. (June 2006). "NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21". Nature. 441 (7093): 595–600. Bibcode:2006Natur.441..595A. doi:10.1038/nature04678. PMID 16554754. S2CID 4428187.

[7] Pfister SC, Machado-Santelli GM, Han SW, Henrique-Silva F (September 2002). "Mutational analyses of the signals involved in the subcellular location of DSCR1". BMC Cell Biology. 3: 24. doi:10.1186/1471-2121-3-24. PMC 128833. PMID 12225619.

[8] 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. PMID 16442855. S2CID 12867672.

[pmid20625401-9] Holmes K, Chapman E, See V, Cross MJ (July 2010). "VEGF stimulates RCAN1.4 expression in endothelial cells via a pathway requiring Ca2+/calcineurin and protein kinase C-delta". PLOS ONE. 5 (7): e11435. Bibcode:2010PLoSO...511435H. doi:10.1371/journal.pone.0011435. PMC 2897886. PMID 20625401.

[doi.10.1093/hmg/dds134-10] Martin KR, Corlett A, Dubach D, Mustafa T, Coleman HA, Parkington HC, et al. (July 2012). "Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory". Human Molecular Genetics. 21 (13): 3025–41. doi:10.1093/hmg/dds134. PMID 22511596.

[11] 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. doi:10.15252/embr.201744706. ISSN 1469-3178. PMC 6280800. PMID 30389725.

[12] Sun X, Wu Y, Herculano B, Song W (2014-04-21). "RCAN1 overexpression exacerbates calcium overloading-induced neuronal apoptosis". PLOS ONE. 9 (4): e95471. Bibcode:2014PLoSO...995471S. doi:10.1371/journal.pone.0095471. PMC 3994074. PMID 24751678.

[13] Ermak G, Morgan TE, Davies KJ (October 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. PMID 11483593. S2CID 38420676.

[14] Ermak G, Hench KJ, Chang KT, Sachdev S, Davies KJ (May 2009). "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. doi:10.1074/jbc.M900639200. PMC 2673253. PMID 19270310.

[15] Lee EH, Kim SS, Lee S, Baek KH, Seo SR (August 2015). "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. doi:10.1074/jbc.M115.639476. PMC 4543660. PMID 26157140.

[pmid19458618-16] Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, et al. (June 2009). "Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1". Nature. 459 (7250): 1126–30. Bibcode:2009Natur.459.1126B. doi:10.1038/nature08062. PMC 2724004. PMID 19458618.

[pmid10861295-17] Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S (July 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. PMID 10861295.

[18] Kim SS, Seo SR (2013-01-29). "Hydrogen peroxide-induced MAPK activation causes the increase of RCAN1 (DSCR1) protein expression". Genes & Genomics (jezik: engleski). 35 (1): 111–116. doi:10.1007/s13258-013-0080-x. ISSN 1976-9571. S2CID 15858776.

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