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FLASH GENE

Symbol

RCAN1

contributors: mct/pgu/shn - updated : 13-09-2023

HGNC name	regulator of calcineurin 1
HGNC id	3040

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_203418 4 splicing 1414 NP_981963 - 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 NM_004414 7 splicing 2457 NP_004405 - 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 NM_203417 4 splicing 2302 NP_981962 - 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) NM_001285392 4 - 2327 NP_001272321 - 117 - 2022 36429004 NM_001285389 4 - 2210 NP_001272318 - 171 - 2022 36429004 NM_001285391 4 - 2533 NP_001272320 - 277 - 2022 36429004 NM_001331016 3 - 922 NP_001317945 - 205 - 2022 36429004 NM_001285393 4 - 2264 NP_001272322 - 117 - 2022 36429004

EXPRESSION

Type	ubiquitous

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Homo sapiens Endocrine pancreas       moderately Homo sapiens Nervous brain       highly Homo sapiens Reproductive female system placenta     moderately Homo sapiens Respiratory respiratory tract larynx     highly Urinary bladder       highly   kidney       moderately Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal   highly Homo sapiens Muscular striatum cardiac   highly

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Homo sapiens Nervous neuron 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)
	involved in the development of small cell lung cancer, and it might be a cancer-inhibiting gene for the formation of bone metastases in small cell lung cancer
	RCAN1 is a "switch" for bidirectional synaptic plasticity
	has a protective effect on myocardial ischemia/reperfusion injury, myocardial hypertrophy and intramural hematoma/aortic rupture mainly mediated by maintaining mitochondrial function and inhibiting calcineurin and Rho kinase activity
	molecular antitumor functions of RCAN1 are largely dependent on calcineurin
	role of RCAN1 in enamel, suggesting that increased RCAN1 levels in the ameloblasts of individuals with DS may impact enamel formation by altering both the redox environment and mitochondrial function, as well as decreasing the expression of enamel-specific genes

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)
	RCAN1 acts upstream from FLNA in regulating radial migration, suggesting that impairment of RCAN1-FLNA pathway may underlie Periventricular heterotopia (PH) pathogenesis
	PRKACA regulates calcineurin function through the phosphorylation of RCAN1
	RCAN1 can inhibit the nuclear translocation of NFKB1 protein then affect the activity of NFKB1 signaling pathway in glioma cells
	RCAN1 inhibits BACE2 turnover by attenuating proteasome-mediated BACE2 degradation

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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 tumoral     --over   markedly reduced glioma cells viability

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurology neurodegenerative   therapeutic targets in the context of neurodegenerative processes cancer angiogenesis   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 neurology neurodegenerative alzheimer potential of targeting RCAN1 as a new therapeutic approach

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
	RCAN1-TG mice display T cell developmental defects in the thymus and peripheral immune tissues
	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