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FLASH GENE
Symbol RCAN1 contributors: mct/pgu/shn - updated : 16-12-2012
HGNC name regulator of calcineurin 1
HGNC id 3040
Corresponding disease
TRI21 trisomy 21
Location 21q22.12      Physical location : 35.888.785 - 35.987.382
Synonym name
  • calcipressin-1
  • calcium and oxidant-inducible mRNA
  • down syndrome critical region protein 1
  • modulatory calcineurin-interacting protein 1
  • myocyte-enriched calcineurin-interacting protein 1
  • near DSCR proline-rich protein
  • Down syndrome candidate region 1
  • Down syndrome critical region gene 1
  • Synonym symbol(s) DSCR1, XE17-8, CSP1, DSC1, RCN1, MCIP1, ADAPT78, CSP1
    DNA
    TYPE functioning gene
    STRUCTURE 97.96 kb     7 Exon(s)
    regulatory sequence Binding site   enhancer   hormone   HRE
    text structure
  • exons 1-4 are alternative first exons (isoforms 1-4)
  • NFATC1 binds the regulatory sequence and trigger its enhancer activity
  • functional glucocorticoid response element was identified in the RCAN1 isoform 1 (RCAN1-1) promoter region, which is able to mediate the up-regulation of RCAN1 expression
  • MAPPING cloned Y linked N status provisional
    Map cen - D21S1254 - D21S1920 - RCAN1 - D21S1895 - D21S1921 - qter
    RNA
    TRANSCRIPTS type messenger
    text
  • contains two promoters and two translation initiation codons: one in the 5&
  • 8242;-UTR of exon 1 and the other in the 5&8242;-UTR of exon 4, which are responsible for transcriptional control of RCAN1-1 and RCAN1-4, respectively (PMID: 21216952)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    4 splicing 1414 - 197 fetal and adult liver, mostly expressed in heart muscle and fetal kidney, also highly expressed in areas of the brain in which calcineurin is highly expressed 2012 22389495
  • RCAN1-4
  • encoded by exon 4
  • 7 splicing 2457 - 252 fetal brain, highly expressed in the central nervous system 2012 22389495
  • DSCR1 Ia or RCAN1-1L
  • encoded by exon 1
  • has an N-terminal coding region longer than that previously described, and is able to interact with calcineurin A and to inhibit NF-AT-mediated transcriptional activation
  • up-regulated by VEGFA
  • can open the mitochondrial permeability transition pore, shift metabolism from oxidative phosphorylation to glycolysis, and induce mitophagy
  • 4 splicing 2302 - 117 fetal brain and adult heart 2012 22389495
  • encoded by exon 1
  • also called DSCR1 Ib, RCAN1-1S
  • an alternate 5' exon compared to variant 1. The resulting isoform (b) is shorter at the N-terminus compared to isoform a
  • positively modulates IL1R-mediated signaling pathways by regulating TOLLIP/IRAK1/TRAF6 complex formation (PMID: 19716405)
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly Homo sapiens
    Endocrinepancreas   moderately Homo sapiens
    Nervousbrain   highly Homo sapiens
    Reproductivefemale systemplacenta  moderately Homo sapiens
    Respiratoryrespiratory tractlarynx  highly
    Urinarybladder   highly
     kidney   moderately Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal highly Homo sapiens
    Muscularstriatumcardiac highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell Homo sapiens
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal, pregnancy
    Text highly in fetal brain, placenta, kidney
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal RNA recognition motif (RNA binding protein), an aggregation-prone domain
  • a short unique serine-proline motif (the FLISSPP signature of the family) including an ISPP XSPP box
  • a Cn-inhibitor RCAN (CIC) and the PxIxxT motifs
  • a putative DNA binding domain and a proline-rich domain with the characteristics of a SH3 domain ligand
  • a functional motif which binds calcineurin as well as two proline-rich SH3 binding domains
  • bind and inhibit calcineurin through the C-terminal region
  • HOMOLOGY
    interspecies homolog to drosophila Nebula
    ortholog to Rcan1, Mus musculus
    ortholog to Rcan1,Rattus norvegicus
    ortholog to RCAN1, Pan troglodytes
    intraspecies paralog to DSCR1L1,DSCR1L2
    Homologene
    FAMILY
  • RCAN family
  • CATEGORY regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text
  • localized in cytosol, mitochondria, and nucleus
  • basic FUNCTION
  • putatively involved in transcriptional regulation and/or signal transduction
  • inhibitor of calcineurin-mediated signaling pathway
  • may be involved in short-term protection against acute oxidative stress and other calcium-mediated stresses (when transiently expressed
  • endogenous inhibitor of calcineurin, an important intracellular phosphatase that mediates many cellular responses to calcium
  • playing a role during central nervous system development
  • regulating expression of inflammatory markers on activated endothelial cells
  • involved with DYRK1A in the cooperative destabilization of a regulatory circuit, leading to reduced NFATc activity
  • having a significant role in modulating signaling pathways underlying the balance between neuronal death and survival
  • calcineurin inhibitor that inactivates nuclear factor of activated T cells (NFATC) activity
  • regulates the number of vesicles undergoing exocytosis and the speed at which the vesicle fusion pore opens and closes
  • playing a role in the regulation of exocytosis and fusion pore dynamics
  • play a protective role against cell stress
  • functions mainly, if not exclusively, as a regulator of calcineurin, a phosphatase that mediates many cellular responses to calcium
  • having a vascular role, and a potential new target for treating vascular- and calcineurin-related disorders
  • suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway
  • NFAT-dependent, injury-inducible, early gene that may serve to negatively regulate vascular smooth muscle cells phenotypic switching
  • functions as a mediator of stress- and APP-induced neuronal death contributing to Alzheimer disease pathogenesis in Down syndrome
  • acts as an important regulatory component in the control of CREB1 signaling
  • increased the phosphorylation of CREB1 and cAMP response element-mediated gene transcription in response to the activation of the intracellular cAMP pathway
  • regulator of mitochondrial autophagy (mitophagy) and induction of RCAN1-1L can cause dramatic degradation of mitochondria
  • important player in autophagy and such elusive phenomena as the mitochondrial permeability transition pore
  • plays an important role in normal brain development and function and its up-regulation likely contributes to the neural deficits associated with trisomy 21
  • role of RCAN1 as a tumor suppressor in oncogenic KRAS-mediated pancreatic tumorigenesis
  • its upregulation is neuroprotective in the presence of APP upregulation (delays neurodegeneration and protects against APP-induced axonal transport defects by restoring calcineurin and GSK3B signaling)
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    text putative
    PATHWAY
    metabolism
    signaling signal transduction
    a component important component of the CREB1 regulatory circuit acting by placing a constraint on calcineurin activity
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • calcineurin A
  • calcineurin
  • ubiquitously expressed transcript, UXT
  • Raf-1
  • beta-TrCP in response to H2O2 stimulation
  • TEAD4
  • Tollip
  • Dyrk1A
  • signal transducer and activator of transcription 2, STAT2
  • NEDD8 is conjugated to RCAN1 (RCAN1-1S) via three lysine residues, K96, K104, and K107 (neddylation enhances RCAN1 protein stability without affecting its cellular location)
  • cell & other
    REGULATION
    activated by the stress hormone dexamethasone
    induced by VEGF, but also by other compounds activating calcineurin signaling, suggesting a more general role for RCAN1 in activated endothelial cells
    transiently by stresses to temporarily protect cells against further potentially lethal challenges
    Phosphorylated by Dyrk1A
    MAPK and glycogen synthase kinase-3
    PRKACA, able to phosphorylate RCAN1 (PRKACA acts as an important regulatory component in the control of RCAN1 function through phosphorylation)
    Other decreased protein level by CREB1, mediated by the ubiquitin-proteasome pathway
    ASSOCIATED DISORDERS
    corresponding disease(s) TRI21
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    chronic overexpression associated with Alzheimer disease or Down syndrome progression, and contributes to neuronal dysfunction in these neurological disorders
    constitutional     --over  
    increases neuronal susceptibility to oxidative stress
    constitutional     --over  
    in brains of Down syndrome fetuses, and in the cerebral cortex and hippocampus of sporadic AD patients
    constitutional     --over  
    promoted endothelial cell proliferation and angiogenesis
    constitutional     --over  
    increased expression of in individuals with trisomy 21 is probably a significant contributor to the decreased cancer incidence in this population
    constitutional     --over  
    in primary neurons activates caspase-9 and caspase-3 and subsequently induces neuronal apoptosis
    constitutional     --over  
    may contribute to AD pathogenesis by mediating neuronal death in the brains of DS and AD patients
    constitutional     --over  
    overexpression of RCAN1, as observed in DS and AD, may enhance CREB1 signaling by blocking calcineurin activity
    constitutional       loss of function
    can contribute to Huntington disease
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerative 
    therapeutic targets in the context of neurodegenerative processes
    cancerangiogenesis 
    signaling pathway that regulates RCAN1 expression are excellent targets for cancer anti-angiogenic therapy
    cancer  
    calcineurin signalling pathway, and its regulators RCAN1 and DYRK1A, are potential therapeutic targets in cancers arising in all individuals
    neurology  
    potential new target for treating calcineurin-related brain disorders
    ANIMAL & CELL MODELS
  • overexpressed in the brain of Down syndrome fetuses
  • lack of MCIP1 exacerbated the hypertrophic response to activated calcineurin expressed from a muscle-specific transgene
  • RCAN1 knockout mice exhibited an attenuated mesenteric vasoconstriction to phenylephrine as compared with wild-type
  • H2O2 induces decrease in RCAN1 in hippocampal and cortical neurons
  • modestly increased Rcan1 expression afforded by a single extra copy is sufficient to suppress pancreatic tumorigenesis mediated by oncogenic KrasG12D in mice through attenuation of calcineurin–NFAT signaling