Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Regulator of Calcineurin 1 (RCAN1)

  • Masakazu FujiwaraEmail author
  • Mohammad Ghazizadeh
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_389


Historical Background

Regulator of calcineurin 1 (RCAN1) was first isolated by Fuentes et al. in 1995 during a search for genes associated with clinical features of Down syndrome (e.g., mental retardation and congenital heart disease) (Fuentes et al. 1995). Coding sequences of RCAN1 were identified from the 21q22.1–q22.2 regions of human chromosome 21 by an Alu-splice PCR method. It was initially thought that RCAN1 was significantly associated with the Down syndrome phenotype (Fuentes et al. 1997b); thus RCAN1 was first designated Down syndrome critical region 1 (DSCR1). Future studies showed that the DSCR1 gene product is a calcineurin regulator, and the new name “regulator of calcineurin (RCAN)” was adopted to describe the gene function. Although RCAN1 is still referred to as DSCR1, ADAPT78, MCIP1, Calpressin1, RCN-1, Nebular,...

This is a preview of subscription content, log in to check access.


  1. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L, Heit JJ, Kim SK, et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature. 2006;441:595–600.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, et al. Down’s syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature. 2009;459:1126–30.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Cano E, Canellada A, Minami T, Iglesias T, Redondo JM. Depolarization of neural cells induces transcription of the Down syndrome critical region 1 isoform 4 via a calcineurin/nuclear factor of activated T cells-dependent pathway. J Biol Chem. 2005;280:29435–43.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Chan B, Greenan G, McKeon F, Ellenberger T. Identification of a peptide fragment of DSCR1 that competitively inhibits calcineurin activity in vitro and in vivo. Proc Natl Acad Sci U S A. 2005;102:13075–80.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Chang KT, Min KT. Drosophila melanogaster homolog of Down syndrome critical region 1 is critical for mitochondrial function. Nat Neurosci. 2005;8:1577–85.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Chang KT, Min KT. Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: implications for Down syndrome. Proc Natl Acad Sci U S A. 2009;106:17117–22.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Chang HY, Takei K, Sydor AM, Born T, Rusnak F, Jay DG. Asymmetric retraction of growth cone filopodia following focal inactivation of calcineurin. Nature. 1995;376:686–90.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Chang KT, Shi YJ, Min KT. The Drosophila homolog of Down’s syndrome critical region 1 gene regulates learning: implications for mental retardation. Proc Natl Acad Sci U S A. 2003;100:15794–9.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Crabtree GR, Olson EN. NFAT signaling: choreographing the social lives of cells. Cell. 2002;109(Suppl):S67–79.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Crawford DR, Leahy KP, Abramova N, Lan L, Wang Y, Davies KJ. Hamster adapt78 mRNA is a Down syndrome critical region homologue that is inducible by oxidative stress. Arch Biochem Biophys. 1997;342:6–12.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Davies KJ, Ermak G, Rothermel BA, Pritchard M, Heitman J, Ahnn J, Henrique-Silva F, Crawford D, Canaider S, Strippoli P, et al. Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. FASEB J. 2007;21:3023–8.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Ejima A, Tsuda M, Takeo S, Ishii K, Matsuo T, Aigaki T. Expression level of sarah, a homolog of DSCR1, is critical for ovulation and female courtship behavior in Drosophila melanogaster. Genetics. 2004;168:2077–87.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Ermak G, Morgan TE, Davies KJ. Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease. J Biol Chem. 2001;276:38787–94.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Ermak G, Harris CD, Davies KJ. The DSCR1 (Adapt78) isoform 1 protein calcipressin 1 inhibits calcineurin and protects against acute calcium-mediated stress damage, including transient oxidative stress. FASEB J. 2002;16:814–24.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Ermak G, Sojitra S, Yin F, Cadenas E, Cuervo AM, Davies KJA. Chronic expression of RCAN1-1L protein induced mitochondrial autophagy and metabolic shift from oxidative phosphorylation to glycolysis in neuronal cells. J Biol Chem. 2012;287:14088–98.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Fruman DA, Bierer BE, Benes JE, Burakoff SJ, Austen KF, Katz HR. The complex of FK506-binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation-induced cytokine transcripts, but not exocytosis, in mouse mast cells. J Immunol. 1995;154:1846–51.PubMedPubMedCentralGoogle Scholar
  17. 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. Hum Mol Genet. 1995;4:1935–44.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Fuentes JJ, Pritchard MA, Estivill X. Genomic organization, alternative splicing, and expression patterns of the DSCR1 (Down syndrome candidate region 1) gene. Genomics. 1997a;44:358–61.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Fuentes JJ, Pucharcos C, Pritchard M, Estivill X. Alu-splice PCR: a simple method to isolate exon-containing fragments from cloned human genomic DNA. Hum Genet. 1997b;101:346–50.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Fuentes JJ, Genesca L, Kingsbury TJ, Cunningham KW, Perez-Riba M, Estivill X, de la Luna S. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet. 2000;9:1681–90.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Fujiwara M, Hasebe T, Kajita M, Ishizuya-Oka A, Ghazizadeh M, Kawanami O. RCAN1 regulates vascular branching during Xenopus laevis angiogenesis. J Vasc Res. 2011;48:104–18.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Genesca L, Aubareda A, Fuentes JJ, Estivill X, De La Luna S, Perez-Riba M. Phosphorylation of calcipressin 1 increases its ability to inhibit calcineurin and decreases calcipressin half-life. Biochem J. 2003;374:567–75.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Gorlach J, Fox DS, Cutler NS, Cox GM, Perfect JR, Heitman J. Identification and characterization of a highly conserved calcineurin binding protein, CBP1/calcipressin, in Cryptococcus neoformans. EMBO J. 2000;19:3618–29.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Harris CD, Ermak G, Davies KJ. RCAN1-1L is overexpressed in neurons of Alzheimer’s disease patients. FEBS J. 2007;274:1715–24.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Hasle H. Pattern of malignant disorders in individuals with Down’s syndrome. Lancet Oncol. 2001;2:429–36.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Hilioti Z, Gallagher DA, Low-Nam ST, Ramaswamy P, Gajer P, Kingsbury TJ, Birchwood CJ, Levchenko A, Cunningham KW. GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs. Genes Dev. 2004;18:35–47.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Iizuka M, Abe M, Shiiba K, Sasaki I, Sato Y. Down syndrome candidate region 1,a downstream target of VEGF, participates in endothelial cell migration and angiogenesis. J Vasc Res. 2004;41:334–44.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Javadov S, Karmazyn M. Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection. Cell Physiol Biochem. 2007;20:1–22.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Keating DJ, Dubach D, Zanin MP, Yu Y, Martin K, Zhao YF, Chen C, Porta S, Arbones ML, Mittaz L, et al. DSCR1/RCAN1 regulates vesicle exocytosis and fusion pore kinetics: implications for Down syndrome and Alzheimer’s disease. Hum Mol Genet. 2008;17:1020–30.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Kingsbury TJ, Cunningham KW. A conserved family of calcineurin regulators. Genes Dev. 2000;14:1595–604.PubMedPubMedCentralGoogle Scholar
  31. Kishi T, Ikeda A, Nagao R, Koyama N. The SCFCdc4 ubiquitin ligase regulates calcineurin signaling through degradation of phosphorylated Rcn1, an inhibitor of calcineurin. Proc Natl Acad Sci U S A. 2007;104:17418–23.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Lee JI, Dhakal BK, Lee J, Bandyopadhyay J, Jeong SY, Eom SH, Kim DH, Ahnn J. The Caenorhabditis elegans homologue of Down syndrome critical region 1, RCN-1, inhibits multiple functions of the phosphatase calcineurin. J Mol Biol. 2003;328:147–56.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Lee JE, Jang H, Cho EJ, Youn HD. Down syndrome critical region 1 enhances the proteolytic cleavage of calcineurin. Exp Mol Med. 2009;41:471–7.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Liu FC, Graybiel AM. Spatiotemporal dynamics of CREB phosphorylation: transient versus sustained phosphorylation in the developing striatum. Neuron. 1996;17:1133–44.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Liu X, Zhao D, Qin L, Li J, Zeng H. Transcription enhancer factor 3 (TEF3) mediates the expression of Down syndrome candidate region 1 isoform 1 (DSCR1-1L) in endothelial cells. J Biol Chem. 2008;283:34159–67.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Liu Q, Busby JC, Molkentin JD. Interaction between TAK1-TAB1-TAB2 and RCAN1-calcineurin defines a signalling nodal control point. Nat Cell Biol. 2009;11:154–61.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Ma H, Xiong H, Liu T, Zhang L, Godzik A, Zhang Z. Aggregate formation and synaptic abnormality induced by DSCR1. J Neurochem. 2004;88:1485–96.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Mair W, Morantte I, Rodrigues AP, Manning G, Montminy M, Shaw RJ, Dillin A. Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature. 2011;470:404–8.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Mao Z, Wiedmann M. Calcineurin enhances MEF2 DNA binding activity in calcium-dependent survival of cerebellar granule neurons. J Biol Chem. 1999;274:31102–7.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Mehta S, Li H, Hogan PG, Cunningham KW. Domain architecture of the regulators of calcineurin (RCANs) and identification of a divergent RCAN in yeast. Mol Cell Biol. 2009;29:2777–93.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Minami T, Horiuchi K, Miura M, Abid MR, Takabe W, Noguchi N, Kohro T, Ge X, Aburatani H, Hamakubo T, et al. Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J Biol Chem. 2004;279:50537–54.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Mulero MC, Aubareda A, Orzaez M, Messeguer J, Serrano-Candelas E, Martinez-Hoyer S, Messeguer A, Perez-Paya E, Perez-Riba M. Inhibiting the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway with a regulator of calcineurin-derived peptide without affecting general calcineurin phosphatase activity. J Biol Chem. 2009;284:9394–401.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Olson EN, Williams RS. Calcineurin signaling and muscle remodeling. Cell. 2000;101:689–92.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Qin L, Zhao D, Liu X, Nagy JA, Hoang MV, Brown LF, Dvorak HF, Zeng H. Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway. Mol Cancer Res. 2006;4:811–20.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Ryeom S, Greenwald RJ, Sharpe AH, McKeon F. The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin. Nat Immunol. 2003;4:874–81.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Ryeom S, Baek KH, Rioth MJ, Lynch RC, Zaslavsky A, Birsner A, Yoon SS, McKeon F. Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. Cancer Cell. 2008;13:420–31.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Vega RB, Yang J, Rothermel BA, Bassel-Duby R, Williams RS. Multiple domains of MCIP1 contribute to inhibition of calcineurin activity. J Biol Chem. 2002;277:30401–7.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Vega RB, Rothermel BA, Weinheimer CJ, Kovacs A, Naseem RH, Bassel-Duby R, Williams RS, Olson EN. Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy. Proc Natl Acad Sci U S A. 2003;100:669–74.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Yang J, Rothermel B, Vega RB, Frey N, McKinsey TA, Olson EN, Bassel-Duby R, Williams RS. Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res. 2000;87:E61–8.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Yao YG, Duh EJ. VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis? Biochem Biophys Res Commun. 2004;321:648–56.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Zhao P, Xiao X, Kim AS, Leite MF, Xu J, Zhu X, Ren J, Li J. c-Jun inhibits thapsigargin-induced ER stress through up-regulation of DSCR1/Adapt78. Exp Biol Med (Maywood). 2008;233:1289–300.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Molecular Pathophysiology, Institute for Advanced Medical SciencesGraduate School of Medicine, Nippon Medical SchoolKawasakiJapan