Affinage

RCAN1

Calcipressin-1 · UniProt P53805

Length
252 aa
Mass
28.1 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RCAN1 is an endogenous regulator of the calcium/calmodulin-dependent phosphatase calcineurin, functioning as a central modulator of calcineurin-NFAT signaling across cardiovascular, immune, and neural systems. RCAN1 binds the linker region of the calcineurin A catalytic subunit via a minimal inhibitory peptide domain, blocking NFAT dephosphorylation and nuclear translocation; this inhibitory activity is enhanced by DYRK1A-mediated phosphorylation at Thr192 and by neddylation at K96/K104/K107, while TAK1 phosphorylation at Ser94/Ser136 converts RCAN1 from an inhibitor to a facilitator of calcineurin-NFAT signaling, and SCFβ-TrCP-mediated ubiquitination targets it for proteasomal degradation (PMID:10861295, PMID:21965663, PMID:23118980, PMID:19136967, PMID:18575781). Beyond calcineurin-NFAT regulation, RCAN1 maintains mitochondrial fusion by suppressing calcineurin-dependent DRP1 activation, controls axon outgrowth through cofilin-dependent actin dynamics, regulates TrkA endocytosis for neurotrophin signaling, modulates vesicle exocytosis kinetics, and regulates adult hippocampal neurogenesis through TET1 splicing (PMID:29362227, PMID:27185837, PMID:26658127, PMID:18180251, PMID:31304631). Cooperative overexpression of RCAN1 with DYRK1A—both encoded on chromosome 21—destabilizes NFAT signaling and underlies multiple Down syndrome-associated phenotypes including impaired neuronal differentiation, defective angiogenesis, and neurodegeneration (PMID:16554754, PMID:24352425, PMID:19458618).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Identification of RCAN1 as a direct physical inhibitor of calcineurin resolved how an endogenous protein modulates calcineurin-NFAT signaling, establishing the core molecular function of the gene.

    Evidence Co-immunoprecipitation, domain mapping to calcineurin A linker region, and NFAT nuclear translocation/transcription assays in mammalian cells

    PMID:10861295

    Open questions at the time
    • Structural basis of the RCAN1-calcineurin interface not resolved
    • Endogenous stoichiometry and tissue-specific regulation unknown
  2. 2002 Medium

    Demonstration that RCAN1 protects cells from oxidative and calcium stress established a cytoprotective role consistent with calcineurin inhibition, and that RCAN1 localizes preferentially to the nucleus suggested compartmentalized regulation.

    Evidence Tet-off regulated transgene and antisense knockdown with stress challenge in cell lines; GFP-fusion imaging with deletion mutagenesis

    PMID:12039863 PMID:12225619

    Open questions at the time
    • Nuclear versus cytoplasmic functional partitioning not mechanistically dissected
    • Phosphorylation sites controlling localization not identified
  3. 2004 High

    Discovery that RCAN1 is itself a VEGF/calcineurin target gene revealed a negative feedback loop in endothelial calcineurin-NFAT signaling, explaining how inflammatory gene expression (tissue factor, E-selectin, Cox-2) is self-limited.

    Evidence siRNA knockdown of RCAN1 in endothelial cells with NFAT reporter and genome-wide expression analysis

    PMID:15016650

    Open questions at the time
    • Identity of the calcineurin-responsive elements in the RCAN1 promoter only partially mapped
    • Contribution of individual RCAN1 isoforms to feedback not resolved
  4. 2005 High

    Mapping the minimal calcineurin-inhibitory peptide within RCAN1 demonstrated that a short competitive fragment suffices for full enzymatic inhibition, defining the pharmacologically relevant domain.

    Evidence In vitro and in vivo calcineurin phosphatase activity assays with synthetic peptide fragments

    PMID:16131541

    Open questions at the time
    • Atomic-resolution structure of peptide-calcineurin complex not determined
  5. 2006 High

    The demonstration that 1.5-fold increases in RCAN1 and DYRK1A synergistically suppress NFAT nuclear occupancy provided a molecular explanation for Down syndrome phenotypes caused by chromosome 21 trisomy.

    Evidence Mathematical modelling combined with genetic mouse models (calcineurin/Nfatc KO, Dscr1/Dyrk1a transgenic overexpression)

    PMID:16554754

    Open questions at the time
    • Quantitative contribution of each gene to individual DS phenotypes not separated
    • Whether other chromosome 21 genes modulate this circuit in vivo not tested
  6. 2008 High

    Multiple discoveries in 2008 expanded RCAN1's regulatory landscape: isoform-specific roles in angiogenesis (Ex4 inhibits, Ex1 promotes), ATF6-mediated ER stress induction linking unfolded protein response to calcineurin, SCFβ-TrCP-mediated ubiquitin-proteasomal degradation under oxidative stress, and regulation of vesicle exocytosis kinetics independent of acute calcineurin inhibition.

    Evidence RCAN1 KO mice with tumor xenograft and CsA rescue; ATF6 transgenic mice with calcineurin activity assay; in vitro ubiquitination assay with β-TrCP siRNA; carbon-fiber amperometry in chromaffin cells from KO and overexpressing mice

    PMID:18180251 PMID:18319259 PMID:18455125 PMID:18575781

    Open questions at the time
    • Mechanism by which RCAN1 regulates fusion pore kinetics independent of calcineurin not identified
    • Whether ATF6-RCAN1 axis operates beyond cardiomyocytes unknown
    • Phosphodegron recognized by β-TrCP not mapped
  7. 2009 High

    TAK1 phosphorylation of RCAN1 at Ser94/Ser136 was shown to convert RCAN1 from a calcineurin inhibitor to a facilitator, revealing a phosphorylation-dependent functional switch that promotes cardiomyocyte hypertrophy and mast cell activation, while simultaneous studies confirmed RCAN1 degradation by chaperone-mediated autophagy.

    Evidence Yeast two-hybrid identification of TAB2, Co-IP of TAK1-TAB1-RCAN1-calcineurin complex, in vitro kinase assay with mutagenesis; Rcan1 KO mast cells with calcineurin activity/NFAT/NF-κB reporters; CMA motif identification with lysosomal/macroautophagy inhibitors

    PMID:19124655 PMID:19136967 PMID:19509306

    Open questions at the time
    • Structural basis for how phosphorylation switches RCAN1 from inhibitor to facilitator unknown
    • Whether CMA and proteasomal degradation are independently regulated not established
  8. 2011 High

    DYRK1A was shown to phosphorylate RCAN1 at Ser112 (priming for GSK3β at Ser108) and Thr192 (enhancing calcineurin binding), while systems-level modelling revealed that RCAN1 functions as a concentration-dependent switch—inhibitor at low and facilitator at high levels—governed by PI3K-driven GSK3β nuclear export.

    Evidence In vitro kinase assay with site-directed mutagenesis and NFAT reporter; single-cell live imaging with mathematical modelling and PI3K pharmacological inhibition

    PMID:21172821 PMID:21965663

    Open questions at the time
    • In vivo validation of the dual-switch model in specific tissues not performed
    • Whether additional kinases contribute to the switch not explored
  9. 2012 Medium

    Neddylation of RCAN1 at K96/K104/K107 was found to stabilize the protein and potentiate calcineurin inhibition, while RCAN1 was linked to Aβ-induced tau hyperphosphorylation through calcineurin inhibition and GSK3β upregulation, and shown to interact with FMRP to regulate dendritic spine morphogenesis and local protein synthesis.

    Evidence NEDD8 conjugation assay with lysine mutagenesis and NFAT reporter; RCAN1 siRNA rescue of Aβ-induced tau phosphorylation in primary cortical neurons; Co-IP of RCAN1-FMRP with dendritic spine imaging and genetic epistasis

    PMID:21876249 PMID:22863780 PMID:23118980

    Open questions at the time
    • E3 ligase responsible for RCAN1 neddylation not identified
    • Whether FMRP interaction is calcineurin-dependent not tested
    • Direct versus indirect mechanism of GSK3β upregulation by RCAN1 unclear
  10. 2013 High

    RCAN1-DYRK1A cooperative suppression of NFAT was demonstrated to delay neuronal differentiation and alter cortical laminar fate in vivo, directly linking the dosage-sensitive calcineurin-NFAT circuit to Down syndrome neurodevelopmental defects.

    Evidence In utero electroporation in Ts1Cje Down syndrome mice with NFAT reporter assay and genetic epistasis

    PMID:24352425

    Open questions at the time
    • Whether postnatal correction of the RCAN1-DYRK1A imbalance rescues cortical deficits not tested
  11. 2015 High

    RCAN1 excess was shown to impair NGF-dependent TrkA endocytosis, compromising sympathetic neuron survival and innervation in a Down syndrome mouse model, establishing receptor trafficking as a calcineurin-dependent RCAN1 function.

    Evidence Live-cell TrkA trafficking assays in Ts65Dn Down syndrome mouse sympathetic neurons with genetic correction of RCAN1 dosage

    PMID:26658127

    Open questions at the time
    • Whether other receptor tyrosine kinases are similarly regulated by RCAN1-calcineurin not tested
  12. 2016 Medium

    RCAN1 was found to control axon outgrowth by modulating cofilin phosphorylation and actin dynamics in growth cones, and to mediate BDNF-induced local protein synthesis and growth cone turning, defining a non-transcriptional cytoskeletal role.

    Evidence Live imaging of growth cones, cofilin phosphorylation assays, RCAN1 KO and overexpression, growth cone turning assay

    PMID:27185837

    Open questions at the time
    • Whether cofilin regulation is calcineurin-dependent or through a separate pathway not fully resolved
    • Mechanism of RCAN1-dependent local translation not defined
  13. 2018 High

    RCAN1 was established as a maintainer of mitochondrial fusion in cardiomyocytes by inhibiting calcineurin-dependent DRP1 dephosphorylation and activation, with RCAN1 loss leading to mitochondrial fragmentation, impaired Ca2+ buffering, and increased ischemia/reperfusion injury.

    Evidence Cardiomyocyte RCAN1 KO and adenoviral overexpression with pharmacological DRP1/calcineurin inhibition, mitochondrial morphology imaging, and I/R injury model

    PMID:29362227

    Open questions at the time
    • Whether RCAN1-DRP1 axis operates in non-cardiac tissues with high mitochondrial demand not tested
    • Specific DRP1 phosphorylation site regulated by RCAN1-calcineurin not mapped
  14. 2019 Medium

    A calcineurin-independent function was uncovered: RCAN1 binds TET1 introns to regulate TET1 splicing, controlling TET1 protein levels and downstream miR-124 promoter demethylation, thereby regulating adult hippocampal neurogenesis.

    Evidence Co-IP and RNA splicing analysis in RCAN1 KO mice, TET1 level correction rescuing adult neurogenesis defects

    PMID:31304631

    Open questions at the time
    • Whether RCAN1-TET1 splicing regulation is direct RNA binding or mediated through a spliceosome component not determined
    • Generality of RCAN1 splicing regulation beyond TET1 unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic-resolution structure of the RCAN1-calcineurin complex, the full spectrum of calcineurin-independent RCAN1 functions, how isoform-specific and tissue-specific RCAN1 activities are coordinated, and whether therapeutic modulation of RCAN1 can ameliorate Down syndrome or neurodegeneration phenotypes.
  • No high-resolution structural model of the RCAN1-calcineurin complex exists
  • Calcineurin-independent functions (FMRP, TET1 splicing, vesicle exocytosis) lack mechanistic integration
  • Isoform-specific roles (Ex1 vs Ex4) in angiogenesis and neurodegeneration not fully dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
BTRCDYRK1AFMRPNEDD8PPP3CATAB2TAK1TET1
Complex memberships
TAK1-TAB1-TAB2-RCAN1-calcineurin signaling complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 RCAN1 (DSCR1) physically interacts with and inhibits calcineurin A (the catalytic subunit of PP2B/calcineurin). The RCAN1 binding region in calcineurin A is located in the linker region between the catalytic domain and the calcineurin B binding domain, outside other previously defined functional domains. Overexpression of RCAN1 inhibits calcineurin-dependent gene transcription through inhibition of NFAT nuclear translocation. Co-immunoprecipitation, functional transcription assays, domain mapping Human molecular genetics High 10861295
2006 DSCR1 (RCAN1) and DYRK1A act synergistically to prevent nuclear occupancy of NFATc transcription factors. Mathematical modelling and mouse genetic experiments (calcineurin- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice) show that 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes the NFAT regulatory circuit. Genetic mouse models (KO, transgenic overexpression), mathematical modelling, nuclear localization assays Nature High 16554754
2009 RCAN1 suppresses VEGF-mediated angiogenic signaling by inhibiting the calcineurin pathway in endothelial cells. A single extra transgenic copy of Dscr1 suppresses tumor growth through a deficit in tumor angiogenesis. Additionally, RCAN1 and DYRK1A together may markedly diminish angiogenesis. Transgenic mouse models, tumor xenograft assays, genetic KO experiments Nature High 19458618
2004 DSCR1 (RCAN1) is a VEGF target gene in endothelial cells. DSCR1 expression blocks dephosphorylation, nuclear translocation, and transcriptional activity of NFAT, forming a negative feedback loop with calcineurin signaling. Knockdown of endogenous DSCR1 increases NFAT activity and stimulates expression of inflammatory genes (tissue factor, E-selectin, Cox-2). siRNA knockdown, NFAT reporter assays, genome-wide gene expression analysis Blood High 15016650
2009 RCAN1 interacts with TAB2 (identified by yeast two-hybrid screen), recruiting TAK1, TAB1, and calcineurin into a macromolecular signalling complex. TAK1 phosphorylates RCAN1 at Ser94 and Ser136, converting RCAN1 from an inhibitor to a facilitator of calcineurin-NFAT signalling and enhancing NFATc1 nuclear translocation and cardiomyocyte hypertrophic growth. Calcineurin activation in turn dephosphorylates and inhibits TAK1 and TAB1. Yeast two-hybrid, Co-IP, in vitro phosphorylation assay, MEF KO cultures, cardiomyocyte hypertrophy assay Nature cell biology High 19136967
2011 Dyrk1A directly interacts with and phosphorylates RCAN1 at Ser112 and Thr192. Dyrk1A-mediated phosphorylation at Ser112 primes RCAN1 for GSK3β-mediated phosphorylation at Ser108. Phosphorylation at Thr192 enhances RCAN1 binding to calcineurin, potentiating its inhibitory activity, leading to reduced NFAT transcriptional activity and enhanced tau phosphorylation. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, NFAT reporter assay The Journal of biological chemistry High 21965663
2005 A small peptide fragment of DSCR1 competitively inhibits calcineurin phosphatase activity in vitro and in vivo, identifying the minimal calcineurin-inhibitory domain of RCAN1. In vitro calcineurin activity assay, in vivo inhibition assay Proceedings of the National Academy of Sciences of the United States of America High 16131541
2008 Targeted deletion of both DSCR1 isoforms leads to hyperactivated calcineurin and precocious endothelial apoptosis, inhibiting formation of an effective tumor vasculature. Pharmacological calcineurin inhibition (cyclosporin A) rescues the endothelial defect in DSCR1-/- mice, restoring tumor growth. The DSCR1.Ex4 isoform suppresses calcineurin-NFAT signaling blocking endothelial proliferation, while the DSCR1.Ex1 isoform may promote angiogenesis. Genetic KO mouse model, tumor xenograft, pharmacological rescue with cyclosporin A Cancer cell High 18455125
2007 RCAN1 knockout mice exhibit deficits in spatial learning and memory, reduced associative cued memory, and impaired late-phase LTP, phenotypes similar to transgenic mice with increased calcineurin activity. RCAN1 KO mice display increased calcineurin activity, increased abundance of a cleaved calcineurin fragment, and decreased phosphorylation of the calcineurin substrate DARPP-32. RCAN1 knockout mouse behavioral testing, electrophysiology (L-LTP), calcineurin activity assay, western blotting The Journal of neuroscience High 18045910
2009 RCAN1 protein is degraded through two distinct pathways: the ubiquitin proteasome pathway and chaperone-mediated autophagy (CMA). Two CMA recognition motifs were identified in the RCAN1 protein. Inhibition of RCAN1 degradation reduces calcineurin-NFAT activity. Lysosomal inhibitor assays, macroautophagy inhibition, CMA disruption, promoter assay FASEB journal Medium 19509306
2008 RCAN1 is a novel ATF6-inducible gene. Activated ATF6 induces RCAN1 promoter activity, upregulates RCAN1 mRNA, inhibits calcineurin phosphatase activity, and exerts a growth-modulating effect in cardiac myocytes that is inhibited by RCAN1-targeted siRNA, linking ER stress signaling to calcineurin-NFAT pathway regulation. ATF6 transgenic mouse model, adenoviral overexpression, RCAN1 promoter-reporter assay, siRNA knockdown, calcineurin activity assay The Journal of biological chemistry High 18319259
2008 RCAN1/DSCR1 regulates vesicle exocytosis and fusion pore kinetics in chromaffin cells. Rcan1 controls the number of vesicles undergoing exocytosis and the speed at which the vesicle fusion pore opens and closes, independent of Ca2+ entry or readily releasable vesicle pool size. Acute calcineurin inhibition did not replicate the effect of RCAN1 overexpression. Carbon fibre amperometry in chromaffin cells from Rcan1 KO and RCAN1-overexpressing mice Human molecular genetics High 18180251
2011 RCAN1 overexpression in primary neurons activates caspase-9 and caspase-3, inducing neuronal apoptosis. This neurotoxicity is inhibited in caspase-3 knockout neurons. RCAN1-1 expression can be activated by dexamethasone through a functional glucocorticoid response element in the RCAN1-1 promoter. Primary neuron transfection, caspase activation assay, caspase-3 KO neurons, promoter reporter assay, ChIP The Journal of biological chemistry High 21216952
2012 RCAN1 (DSCR1) interacts with FMRP and regulates both dendritic spine morphogenesis and local protein synthesis. Decreasing FMRP levels restores the DSCR1-induced changes in dendritic spine morphology, placing DSCR1 as a novel regulator of FMRP. Co-immunoprecipitation, dendritic spine imaging, local protein synthesis assay, genetic epistasis The EMBO journal Medium 22863780
2011 RCAN1 increases the expression and activity of GSK-3β at a post-transcriptional level. RCAN1-1S isoform correlates with GSK-3β levels in human brain, suggesting RCAN1 modulates the calcineurin-GSK-3β equilibrium. Tet-off regulated RCAN1 transgene, Western blotting, microarray, isoform-specific analysis The FEBS journal Medium 16649988
2012 Amyloid-β upregulates RCAN1 expression through oxidative stress. RCAN1 proteins then inhibit calcineurin (a tau phosphatase) and induce expression of GSK-3β (a tau kinase), linking Aβ toxicity to tau hyperphosphorylation. Silencing RCAN1 prevents Aβ-induced tau hyperphosphorylation. Primary cortical neuron culture, siRNA knockdown, antioxidant treatment, tau phosphorylation western blot Journal of Alzheimer's disease Medium 21876249
2012 RCAN1-1L induces mitochondrial autophagy (mitophagy) through adenine nucleotide translocator-dependent mitochondrial permeability transition pore opening, and shifts cellular bioenergetics from aerobic respiration to glycolysis. Tet-regulated transgene induction, mitochondrial fractionation, mitophagy assays, metabolic assays The Journal of biological chemistry Medium 22389495
2015 Excess RCAN1 impairs neurotrophic support of sympathetic neurons by inhibiting calcineurin-dependent endocytosis of the NGF receptor TrkA. Genetically correcting RCAN1 levels in Down syndrome mice improves NGF-dependent receptor trafficking, neuronal survival, and innervation. Genetic mouse models (Down syndrome Ts65Dn), live-cell TrkA trafficking assays, genetic rescue of RCAN1 dosage Nature communications High 26658127
2013 Increased dosage of DSCR1 cooperates with DYRK1A to suppress NFATc transcription factor activity in neural progenitors, causing a delay in neuronal differentiation and alteration of laminar fate in the developing neocortex. Counteracting the dysregulated pathway ameliorates delayed neuronal differentiation in Ts1Cje Down syndrome mice. In utero electroporation, Ts1Cje mouse model, NFAT reporter assay, genetic epistasis Genes & development High 24352425
2016 RCAN1 controls axon outgrowth by modulating growth cone actin dynamics through regulation of cofilin phosphorylation (phospho/dephospho-cofilin). Additionally, DSCR1 mediates BDNF-induced local protein synthesis and growth cone turning. Live imaging, cofilin phosphorylation assays, DSCR1 KO and overexpression, growth cone turning assay The Journal of cell biology Medium 27185837
2018 RCAN1 maintains a more fused mitochondrial network by inhibiting calcineurin-dependent activation of the fission protein DRP1. In RCAN1-depleted cardiomyocytes, increased CN activity promotes DRP1-mediated fragmentation, reduces mitochondrial membrane potential and Ca2+ buffering capacity, and increases susceptibility to ischemia/reperfusion injury. Cardiomyocyte RCAN1 KO and adenoviral overexpression, mitochondrial morphology imaging, O2 consumption assay, I/R injury model, pharmacological DRP1 and calcineurin inhibition Circulation research High 29362227
2012 NEDD8 is conjugated to RCAN1 (RCAN1-1S) at lysine residues K96, K104, and K107. Neddylation enhances RCAN1 protein stability by inhibiting proteasomal degradation, increases RCAN1 binding to calcineurin, and potentiates RCAN1 inhibitory activity toward downstream NFAT signaling. NEDD8 conjugation assay, mutagenesis of lysine residues, co-immunoprecipitation, NFAT reporter assay PloS one Medium 23118980
2008 Oxidative stress (H2O2) induces SCFβ-TrCP ubiquitin ligase-mediated ubiquitination of RCAN1, leading to its proteasomal degradation. β-TrCP interacts with RCAN1 in response to H2O2, and siRNA knockdown of β-TrCP abolishes H2O2-induced RCAN1 decrease. In vitro ubiquitination assay, co-immunoprecipitation, siRNA knockdown, western blotting International journal of molecular medicine Medium 18575781
2008 CREB activates proteasomal degradation of RCAN1/DSCR1 through the ubiquitin-proteasome pathway. CREB enhances ubiquitination and increases the turnover rate of RCAN1, and this requires CREB's transcriptional activation domain. Proteasome inhibitor experiments, ubiquitination assay, CREB overexpression and dominant-negative constructs, pulse-chase analysis FEBS letters Medium 18485898
2005 Raf-1 is a binding partner of DSCR1. Two Raf-1 binding regions exist in DSCR1: one in the N-terminus and one in the C-terminus. Calpain cleavage of DSCR1 generates fragments with differential binding affinity to Raf-1 versus calcineurin. GST pulldown, co-immunoprecipitation, calpain cleavage assay Archives of biochemistry and biophysics Low 15935327
2002 DSCR1 protein (calcipressin 1) protects cells against acute oxidative stress and calcium stress. Resistance to these stresses increased as a function of DSCR1/calcipressin 1 expression and decreased when gene/protein expression diminished, consistent with calcineurin inhibition being the protective mechanism. Stable transfection, tet-off regulated transgene expression, antisense oligonucleotides, cell viability assays after H2O2 and calcium ionophore A23187 challenge FASEB journal Medium 12039863
2003 Oxidative stress causes rapid hyperphosphorylation of DSCR1 protein. Phosphorylation of serines in the calcineurin-interacting conserved region of DSCR1 attenuates its inhibition of calcineurin, suggesting phosphorylation modulates calcineurin inhibitory activity. H2O2 treatment of cells, kinase inhibitor studies, in vitro calcineurin inhibition assay with phosphorylated peptides Free radical biology & medicine Medium 12927602
2002 DSCR1 subcellular localization is preferentially nuclear, independent of isoform or cell line. A segment in the C-terminus is important for nuclear localization, and serine/threonine residues in this region regulate nuclear targeting, suggesting phosphorylation-dependent regulation of DSCR1 localization. GFP fusion constructs in multiple cell lines, deletion mutagenesis, site-directed mutagenesis BMC cell biology Medium 12225619
2011 RCAN1 functions as an inhibitor of calcineurin when its levels are low and as a facilitator when levels are high. Nuclear export of GSK3β, promoted by PI3K signaling, switches on the facilitative role of RCAN1 through sequential phosphorylation, forming a hidden incoherent regulatory switch. Single-cell live imaging, mathematical modelling, pharmacological PI3K inhibition, NFAT localization assays Journal of cell science Medium 21172821
2019 DSCR1 binds to TET1 introns to regulate splicing of TET1, modulating TET1 protein level. TET1 in turn controls demethylation of the miR-124 promoter to modulate miR-124 expression, thereby regulating adult hippocampal neurogenesis. Correcting TET1 levels in DSCR1 KO mice prevents defective adult neurogenesis. Co-IP, RNA splicing analysis, DSCR1 KO mice, TET1 level correction, adult neurogenesis assays The EMBO journal Medium 31304631
2010 RCAN1.4 expression is induced by VEGFR-2 activation in a Ca2+ and PKC-delta dependent manner. siRNA silencing of RCAN1.4 results in increased NFAT-regulated gene expression, decreased cellular migration, and disrupted tubular morphogenesis. PKC inhibitors, siRNA knockdown of PKC-delta, RCAN1.4 siRNA, endothelial cell migration and tube formation assays, NFAT reporter PloS one Medium 20625401
2017 RCAN1.4 regulates agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA silencing of RCAN1 inhibits VEGF-mediated cytoskeletal reorganisation and directed cell migration. Morpholino silencing of zebrafish RCAN1.4 orthologue disrupts vascular development. siRNA knockdown, VEGFR-2 internalization assay, cell polarity assay, migration/sprouting assays, zebrafish morpholino knockdown Angiogenesis Medium 28271280
2011 RCAN1 activates CREB phosphorylation and cAMP response element-mediated gene transcription. This CREB activation is dependent on RCAN1's ability to inhibit calcineurin activity. RCAN1 overexpression, CREB phosphorylation western blot, CRE-luciferase reporter assay, calcineurin inhibition The Journal of biological chemistry Low 21890628
2009 RCAN1 (Rcan1) negatively regulates FcεRI-mediated mast cell activation by inhibiting calcineurin activity, thereby suppressing NFAT and NF-κB activation and reducing cytokine production and degranulation. Rcan1 expression in mast cells is controlled by the transcription factor Egr1 through a functional Egr1 binding site in the Rcan1 promoter. Rcan1 KO mice, mast cell calcineurin activity assay, NFAT/NF-κB reporter assays, Egr1 promoter binding (EMSA/ChIP), passive cutaneous anaphylaxis The Journal of experimental medicine High 19124655
2015 RCAN1 contributes to circadian rhythmicity in cardiac protection from ischemia/reperfusion. RCAN1 KO mice lose the time-of-day difference in infarct size, while calcineurin inhibition by FK506 restores protection in PM-operated animals, placing RCAN1-calcineurin signaling as a mediator of circadian cardiac protection. RCAN1 KO and transgenic mice, timed I/R surgery, FK506 pharmacological rescue, echocardiography Journal of molecular and cellular cardiology Medium 24838101
2013 RCAN1 regulates CD36 expression in macrophages and its genetic inactivation reduces atherosclerosis in Apoe-/- mice. This is mechanistically linked to diminished oxLDL uptake, resistance to oxLDL-mediated inhibition of macrophage migration, and increased anti-inflammatory marker expression. Haematopoietic Rcan1 is the key contributor, demonstrated by bone marrow transplantation. Rcan1/Apoe double KO mice, bone marrow transplantation, macrophage oxLDL uptake, CD36 expression analysis EMBO molecular medicine Medium 24127415
2015 RCAN1 overexpression in mice promotes age-dependent tau pathology and dysregulation of DRP1 activity associated with mitochondrial dysfunction and oxidative stress, identifying RCAN1 as an upstream regulator of DRP1-mediated mitochondrial fission. Brain-specific RCAN1.1S transgenic mice, tau phosphorylation assay, DRP1 activity assay, memory tests, mitochondrial function assays Acta neuropathologica Medium 26497675
2017 LRRK2 phosphorylates RCAN1-1S, and during IL-1β treatment this promotes formation of protein complexes including Tollip-RCAN1, decreases Tollip-IRAK1 binding, increases IRAK1-TRAF6 complex formation, and enhances TAK1 activity and NF-κB transcriptional activity. In vitro kinase assay, co-immunoprecipitation, LRRK2 overexpression, NF-κB reporter assay Frontiers in cellular neuroscience Low 28553204
2015 RCAN1 interacts with IκBα and affects phosphorylation of IκBα at tyrosine 42, thereby inhibiting NF-κB signaling. The N-terminal 1-103aa of RCAN1 is sufficient for NF-κB inhibition. Co-immunoprecipitation, IκBα tyrosine phosphorylation assay, RCAN1 domain mapping, NF-κB reporter, lymphoma xenograft Cell death & disease Low 26492364
2010 C/EBPβ cooperates with NFAT to regulate RCAN1-4 expression. C/EBPβ binds multiple conserved sites in the RCAN1-4 proximal promoter, directly interacts with NFAT, and is required for maximal calcineurin-induced RCAN1-4 expression. C/EBPβ can also activate RCAN1-4 expression independently of calcineurin. EMSA, ChIP, co-immunoprecipitation of C/EBPβ and NFAT, luciferase reporter assay, C/EBPβ siRNA depletion The Journal of biological chemistry High 20371871
2011 In Drosophila, sarah (sra, the RCAN1 ortholog) is required for normal sleep. sra sleep defects are suppressed by calcineurin (CN) mutations, placing sra and CN in a common pathway regulating sleep. Pan-neural expression of sra rescues the behavioral phenotype, indicating neuronal sra function is required. Drosophila sra mutant sleep analysis, CN subunit KO, genetic epistasis (sra;CN double mutants), pan-neural rescue The Journal of neuroscience Medium 21900555
2019 RCAN1.4 expression is suppressed by DNA methylation mediated by DNMT1 and DNMT3b in liver fibrosis. RCAN1.4 overexpression alleviates liver fibrosis through inhibition of CaN/NFAT3 signaling, while RCAN1.4 knockdown exacerbates TGF-β1-induced fibrosis. Bisulfite sequencing, ChIP assay for DNMT1/DNMT3b, rAAV8-RCAN1.4 overexpression in mouse liver, NFAT3 reporter Theranostics Medium 31285763
2004 DSCR1 expression stimulates SOD1 (Cu,Zn superoxide dismutase) gene expression and increases SOD1 enzyme activity in PC12 cells, identified through microarray analysis of DSCR1-regulated mRNAs. Tet-off regulated DSCR1 transgene in PC12 cells, microarray, SOD1 enzyme activity assay FASEB journal Low 14718387

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 530 16554754
2000 DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Human molecular genetics 395 10861295
2009 Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 286 19458618
2001 Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease. The Journal of biological chemistry 177 11483593
1997 Genomic organization, alternative splicing, and expression patterns of the DSCR1 (Down syndrome candidate region 1) gene. Genomics 165 9325060
2006 Phosphorylation inhibits turnover of the tau protein by the proteasome: influence of RCAN1 and oxidative stress. The Biochemical journal 148 16939415
2004 Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells. Blood 139 15016650
2009 Interaction between TAK1-TAB1-TAB2 and RCAN1-calcineurin defines a signalling nodal control point. Nature cell biology 112 19136967
2002 The DSCR1 (Adapt78) isoform 1 protein calcipressin 1 inhibits calcineurin and protects against acute calcium-mediated stress damage, including transient oxidative stress. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 111 12039863
2008 Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. Cancer cell 110 18455125
2016 Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway. Molecular psychiatry 109 27872486
2011 Amyloid-β toxicity and tau hyperphosphorylation are linked via RCAN1 in Alzheimer's disease. Journal of Alzheimer's disease : JAD 109 21876249
2009 Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 101 19509306
2005 Identification of a peptide fragment of DSCR1 that competitively inhibits calcineurin activity in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America 97 16131541
2011 Regulator of calcineurin 1 (RCAN1) facilitates neuronal apoptosis through caspase-3 activation. The Journal of biological chemistry 95 21216952
2020 Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4. Cancer letters 90 32004570
2007 The Down syndrome critical region protein RCAN1 regulates long-term potentiation and memory via inhibition of phosphatase signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 90 18045910
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 : CMLS 90 16231093
2008 Coordination of growth and endoplasmic reticulum stress signaling by regulator of calcineurin 1 (RCAN1), a novel ATF6-inducible gene. The Journal of biological chemistry 87 18319259
2007 RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration. Human molecular genetics 74 17341486
2012 Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory. Human molecular genetics 69 22511596
2008 DSCR1/RCAN1 regulates vesicle exocytosis and fusion pore kinetics: implications for Down syndrome and Alzheimer's disease. Human molecular genetics 69 18180251
2011 Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation. The Journal of biological chemistry 67 21965663
2000 A new gene family including DSCR1 (Down Syndrome Candidate Region 1) and ZAKI-4: characterization from yeast to human and identification of DSCR1-like 2, a novel human member (DSCR1L2). Genomics 67 10756093
2009 Two key genes closely implicated with the neuropathological characteristics in Down syndrome: DYRK1A and RCAN1. BMB reports 66 19192387
2007 RCAN1-1L is overexpressed in neurons of Alzheimer's disease patients. The FEBS journal 65 17331188
2012 Regulation of RCAN1 translation and its role in oxidative stress-induced apoptosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 63 23038757
2003 Oxidative and calcium stress regulate DSCR1 (Adapt78/MCIP1) protein. Free radical biology & medicine 63 12927602
2015 RCAN1 overexpression promotes age-dependent mitochondrial dysregulation related to neurodegeneration in Alzheimer's disease. Acta neuropathologica 59 26497675
2012 Chronic expression of RCAN1-1L protein induces mitochondrial autophagy and metabolic shift from oxidative phosphorylation to glycolysis in neuronal cells. The Journal of biological chemistry 59 22389495
2017 RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells. Angiogenesis 57 28271280
2001 Dscr1, a novel endogenous inhibitor of calcineurin signaling, is expressed in the primitive ventricle of the heart and during neurogenesis. Mechanisms of development 57 11231093
2020 Disruption of super-enhancer-driven tumor suppressor gene RCAN1.4 expression promotes the malignancy of breast carcinoma. Molecular cancer 56 32771023
2006 Alzheimer's disease and endocytic dysfunction: clues from the Down syndrome-related proteins, DSCR1 and ITSN1. Ageing research reviews 56 16442855
2008 Calcium/calcineurin signaling in primary cortical astrocyte cultures: Rcan1-4 and cyclooxygenase-2 as NFAT target genes. Glia 55 18293408
2006 RCAN1 (DSCR1 or Adapt78) stimulates expression of GSK-3beta. The FEBS journal 53 16649988
2012 Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury. Journal of neuroinflammation 51 22397398
2018 Down Syndrome Critical Region 1 Gene, Rcan1, Helps Maintain a More Fused Mitochondrial Network. Circulation research 50 29362227
2012 Kaposi's sarcoma herpesvirus K15 protein contributes to virus-induced angiogenesis by recruiting PLCγ1 and activating NFAT1-dependent RCAN1 expression. PLoS pathogens 50 23028325
2017 RCAN1-4 is a thyroid cancer growth and metastasis suppressor. JCI insight 49 28289712
2019 Methylation of RCAN1.4 mediated by DNMT1 and DNMT3b enhances hepatic stellate cell activation and liver fibrogenesis through Calcineurin/NFAT3 signaling. Theranostics 47 31285763
2012 DSCR1 interacts with FMRP and is required for spine morphogenesis and local protein synthesis. The EMBO journal 45 22863780
2011 Calcineurin and its regulator sra/DSCR1 are essential for sleep in Drosophila. The Journal of neuroscience : the official journal of the Society for Neuroscience 44 21900555
2015 RCAN1 links impaired neurotrophin trafficking to aberrant development of the sympathetic nervous system in Down syndrome. Nature communications 43 26658127
2016 A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes. PLoS genetics 42 27195491
2013 Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells. Genes & development 42 24352425
2014 RCAN1 overexpression exacerbates calcium overloading-induced neuronal apoptosis. PloS one 41 24751678
2011 A hidden incoherent switch regulates RCAN1 in the calcineurin-NFAT signaling network. Journal of cell science 41 21172821
2010 VEGF stimulates RCAN1.4 expression in endothelial cells via a pathway requiring Ca2+/calcineurin and protein kinase C-delta. PloS one 40 20625401
2004 Aggregate formation and synaptic abnormality induced by DSCR1. Journal of neurochemistry 40 15009650
2014 Calcineurin and its regulator, RCAN1, confer time-of-day changes in susceptibility of the heart to ischemia/reperfusion. Journal of molecular and cellular cardiology 39 24838101
2012 Increased expression of the glucose-responsive gene, RCAN1, causes hypoinsulinemia, β-cell dysfunction, and diabetes. Endocrinology 39 23011918
2011 Do RCAN1 proteins link chronic stress with neurodegeneration? FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 21680892
2013 A major role for RCAN1 in atherosclerosis progression. EMBO molecular medicine 38 24127415
2018 RCAN1 is a marker of oxidative stress, induced in acute pancreatitis. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 36 30139658
2014 Calcineurin-NFAT activation and DSCR-1 auto-inhibitory loop: how is homoeostasis regulated? Journal of biochemistry 36 24505143
2009 Regulator of calcineurin (RCAN1-1L) is deficient in Huntington disease and protective against mutant huntingtin toxicity in vitro. The Journal of biological chemistry 36 19270310
2020 Genome-wide mRNA profiling identifies RCAN1 and GADD45A as regulators of the transitional switch from survival to apoptosis during ER stress. The FEBS journal 35 31880863
2013 Chronic high levels of the RCAN1-1 protein may promote neurodegeneration and Alzheimer disease. Free radical biology & medicine 35 23369757
2011 Behavioral characterization of a mouse model overexpressing DSCR1/ RCAN1. PloS one 34 21364922
2014 Aberrant expression of RCAN1 in Alzheimer's pathogenesis: a new molecular mechanism and a novel drug target. Molecular neurobiology 32 24752590
2014 Overexpression of Rcan1-1L inhibits hypoxia-induced cell apoptosis through induction of mitophagy. Molecules and cells 32 25377251
2010 The CCAAT/enhancer binding protein beta (C/EBPbeta) cooperates with NFAT to control expression of the calcineurin regulatory protein RCAN1-4. The Journal of biological chemistry 32 20371871
2013 Nebula/DSCR1 upregulation delays neurodegeneration and protects against APP-induced axonal transport defects by restoring calcineurin and GSK-3β signaling. PLoS genetics 31 24086147
2004 DSCR1(Adapt78) modulates expression of SOD1. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 14718387
2017 The neuronal and endocrine roles of RCAN1 in health and disease. Clinical and experimental pharmacology & physiology 29 29094385
2015 The RCAN1 inhibits NF-κB and suppresses lymphoma growth in mice. Cell death & disease 29 26492364
2009 Integrative genomics identifies DSCR1 (RCAN1) as a novel NFAT-dependent mediator of phenotypic modulation in vascular smooth muscle cells. Human molecular genetics 29 19926569
2018 Epigenetic regulation of RCAN1 expression in kidney disease and its role in podocyte injury. Kidney international 28 30366682
2008 Upregulation of DSCR1 (RCAN1 or Adapt78) in the peri-infarct cortex after experimental stroke. Experimental neurology 28 18485347
2008 c-Jun inhibits thapsigargin-induced ER stress through up-regulation of DSCR1/Adapt78. Experimental biology and medicine (Maywood, N.J.) 27 18641051
2016 DSCR1 is required for both axonal growth cone extension and steering. The Journal of cell biology 26 27185837
2005 Raf-1 is a binding partner of DSCR1. Archives of biochemistry and biophysics 26 15935327
2020 Inhibition of miR-103a-3p suppresses the proliferation in oral squamous cell carcinoma cells via targeting RCAN1. Neoplasma 25 32122140
2014 RCAN1 regulates mitochondrial function and increases susceptibility to oxidative stress in mammalian cells. Oxidative medicine and cellular longevity 25 25009690
2009 Rcan1 negatively regulates Fc epsilonRI-mediated signaling and mast cell function. The Journal of experimental medicine 24 19124655
2000 The murine DSCR1-like (Down syndrome candidate region 1) gene family: conserved synteny with the human orthologous genes. Gene 24 11080588
2013 A single extra copy of Dscr1 improves survival of mice developing spontaneous lung tumors through suppression of tumor angiogenesis. Cancer letters 22 24051307
2007 Brain expression of the calcineurin inhibitor RCAN1 (Adapt78). Archives of biochemistry and biophysics 22 17910944
2009 Glucocorticoid evoked upregulation of RCAN1-1 in human leukemic CEM cells susceptible to apoptosis. Journal of molecular signaling 21 19725972
2002 Mutational analyses of the signals involved in the subcellular location of DSCR1. BMC cell biology 21 12225619
2011 The regulator of calcineurin 1 (RCAN1/DSCR1) activates the cAMP response element-binding protein (CREB) pathway. The Journal of biological chemistry 20 21890628
2008 CREB activates proteasomal degradation of DSCR1/RCAN1. FEBS letters 20 18485898
2007 Overexpression of DSCR1 blocks zinc-induced neuronal cell death through the formation of nuclear aggregates. Molecular and cellular neurosciences 20 17596961
2018 RCAN1.4 acts as a suppressor of cancer progression and sunitinib resistance in clear cell renal cell carcinoma. Experimental cell research 19 30267660
2017 Leucine-Rich Repeat Kinase 2 (LRRK2) Stimulates IL-1β-Mediated Inflammatory Signaling through Phosphorylation of RCAN1. Frontiers in cellular neuroscience 19 28553204
2017 Pyrrolidine dithiocarbamate (PDTC) inhibits inflammatory signaling via expression of regulator of calcineurin activity 1 (RCAN1): Anti-inflammatory mechanism of PDTC through RCAN1 induction. Biochemical pharmacology 19 28712932
2011 Regulator of Calcineurin 1 Isoform 4 (RCAN1.4) Is Overexpressed in the Glomeruli of Diabetic Mice. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 19 22128263
2022 RCAN1 deficiency aggravates sepsis-induced cardiac remodeling and dysfunction by accelerating mitochondrial pathological fission. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 18 36305917
2019 DSCR1-mediated TET1 splicing regulates miR-124 expression to control adult hippocampal neurogenesis. The EMBO journal 18 31304631
2012 Covalent NEDD8 conjugation increases RCAN1 protein stability and potentiates its inhibitory action on calcineurin. PloS one 18 23118980
2007 Down syndrome candidate region 1-like 1 (DSCR1-L1) mimics the inhibitory effects of DSCR1 on calcineurin signaling in endothelial cells and inhibits angiogenesis. The Journal of surgical research 18 17610901
2003 DSCR1(Adapt78)--a Janus gene providing stress protection but causing Alzheimer's disease? IUBMB life 18 12716059
2024 Suppression of RCAN1 alleviated lipid accumulation and mitochondrial fission in diabetic cardiomyopathy. Metabolism: clinical and experimental 17 39053690
2013 Calcineurin-Rcan1 interaction contributes to stem cell factor-mediated mast cell activation. Journal of immunology (Baltimore, Md. : 1950) 17 24218457
2005 Restoration of DSCR1 to disomy in the trisomy 16 mouse model of Down syndrome does not correct cardiac or craniofacial development anomalies. Developmental dynamics : an official publication of the American Association of Anatomists 17 15906378
2017 The regulator of calcineurin 1 (RCAN1) inhibits nuclear factor kappaB signaling pathway and suppresses human malignant glioma cells growth. Oncotarget 16 28061453
2013 CREB-mediated Bcl-2 expression contributes to RCAN1 protection from hydrogen peroxide-induced neuronal death. Journal of cellular biochemistry 16 23150431
2008 Oxidative stress-induced ubiquitination of RCAN1 mediated by SCFbeta-TrCP ubiquitin ligase. International journal of molecular medicine 16 18575781
2008 Transcription enhancer factor 3 (TEF3) mediates the expression of Down syndrome candidate region 1 isoform 1 (DSCR1-1L) in endothelial cells. The Journal of biological chemistry 16 18840614