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FLASH GENE
Symbol NR4A1 contributors: mct - updated : 02-05-2017
HGNC name nuclear receptor subfamily 4, group A, member 1
HGNC id 7980
Location 12q13.13      Physical location : 52.445.190 - 52.453.285
Synonym name
  • nerve growth factor-induced clone B
  • TR3 orphan receptor
  • steroid receptor TR3
  • early response protein NAK1
  • orphan nuclear receptor HMR
  • growth factor-inducible nuclear protein N10
  • testicular receptor 3
  • Synonym symbol(s) HMR, NP10, N10, TR3, GFRP1, NAK-1, NGFIB, NUR77, MGC9485, ST-59
    DNA
    TYPE functioning gene
    STRUCTURE 36.68 kb     8 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    text variants 1 and 2 encode the same protein
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 - 2699 64.5 598 - 2016 26440050
  • isoform 1
  • 7 - 2549 64.5 598 - 2016 26440050
  • isoform 1
  • 8 - 2603 - 611 - 2016 26440050
  • TR3 isoform 2
  • expression of TR3-iso2, in contrast to TR3-iso1, inhibits endothelial cell proliferation induced by VEGFA, histamine
  • differential function of TR3-iso2 correlates with the down-regulation of CCND1
  • 8 - 3530 - 652 - 2016 26440050
    EXPRESSION
    Rna function mRNA expression in endometrial stromal cells (hESCs) was significantly increased after decidualization stimulated by 8-Br-cAMP and medroxyprogesterone acetate (MPA)
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularvessel   highly Homo sapiens
    Endocrinethyroid    
    Nervousbrainhindbraincerebellum highly Mus musculus
    Respiratoryrespiratory tracttrachea  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  highly
    Epithelialsecretoryglandularendocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text fetal muscle
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal modulator domain, with AF-1 domain that plays a major role in transcriptional activation, cofactor recruitment, and intra- and intermolecular interactions
  • a central bipartite (class II) zinc finger DNA binding domain
  • a consensus MAP kinase site
  • C-terminal ligand binding domain (LBD) specifically interacted with highly conserved glycine-rich loop of PKC required for catalytic activity
  • HOMOLOGY
    interspecies homolog to murine Nr4a1 (91.8pc)
    homolog to rattus Nr4a1 (92.2pc)
    Homologene
    FAMILY
  • steroid/thyroid receptor superfamily
  • nuclear hormone receptor family
  • NR4A subfamily of the nuclear receptor superfamily
  • Nur77 gene family
  • CATEGORY signaling hormone , receptor nuclear
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    text
  • in the nucleus, NR4A1 can function in a context dependent manner either as an oncogenic survival factor, promoting cancer cell growth or as the opposite through the activation of apoptosis
  • following apoptotic stimuli NR4A1 translocates to mitochondria to initiate cell death processes
  • AR is colocalized with NR4A1 in the nucleus in an androgen-dependent manner
  • basic FUNCTION
  • hormone nuclear receptor (growth factor inducible nuclear protein N10), initiating apoptosis
  • likely functioning as a general coactivator of gene transcription
  • playing an important role in the LH-mediated steroidogenesis in Leydig cells
  • functioning as a PKC inhibitor
  • apoptotic effector protein that initiates apoptosis largely by translocating from the nucleus to the mitochondria, causing the release of cytochrome c
  • forms novel nuclear structures upon DNA damage that cause transcriptional arrest
  • mediator of cAMP action on STAR transcription in steroidogenic Leydig cells through interaction with CAMK1
  • important transcriptional factor in controlling NFKBIA expression in endothelial cells
  • negatively regulates the TNF-alpha- and interleukin-1beta-induced vascular endothelial cells activation by transcriptionally upregulation of NFKBIA expression
  • plays a key role in apoptosis in T cells, and its phosphorylation by the MEK-ERK-RSK cascade induces mitochondrial translocation and apoptosis in T cells
  • potentially playing an important role during the postmitotic differentiation of neuronal cells in the brain and retina
  • targeting APOA5, inducing the promoter activity by direct binding to a NR4A1 response element
  • novel regulator of APOA5 gene expression
  • important factor in the development of thymocytes
  • crucial for nuclear translocation of DAP3 in the apoptosis induced by TCR stimulation
  • essential mediator of neuroprotection after exposure to neuropathological stress
  • key downstream mediator of CREB1-induced neuroprotection
  • immediate-early response gene whose expression is rapidly induced by various extracellular stimuli
  • acts to promote the growth and survival of colon cancer cells and serves as an important mediator of the Wnt/ābeta-catenin and AP-1 signaling pathways
  • plays an active role in decidual prolactin expression in human endometrial stromal cells
  • NR4A1, NR4A2 modulate mesenchymal stromal cell migration
  • induction of NR4A1, NR4A2, NR4A3 in activated mast cells and NR4A family nuclear receptors are implicated in the regulation of mast cell function
  • NR4A2, NR4A1 functions directly at DNA repair sites by a process that requires phosphorylation by PRKDC, and represent an entirely novel component of DNA damage response in the process of DSB repair
  • association of FHL2 with NR4A1 plays a pivotal role in vascular disease
  • NR4A1 and NR4A2 differentially contribute to object location versus object recognition memory
  • NR4A1, NR4A2, NR4A3 have key roles in determining CD4(+) T cell fates in the thymus and thus contribute to immune homeostasis
  • plays important roles in regulating cell proliferation, differentiation and apoptosis (pMID: 23660295)
  • NR4A1, NR4A2, NR4A3 are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in glucose metabolism and energy status
  • key role for NR4A1 as regulator of the immune response to apoptotic cells (ACs) and of the maintenance of tolerance to "dying self
  • functions as a master transcription factor for the development of the thymus-specific macrophage subset
  • protects pancreatic beta-cells against ER stress-mediated apoptosis by up-regulating BIRC5 expression and down-regulating DDIT3 expression, which we termed as "positive and negative regulation
  • is a key regulator of catecholamine production by macrophages
  • NR1D1 and NR4A1 serve similar or complementary functions in the APOA4-mediated regulation of gluconeogenesis
  • modulate the inflammatory response of macrophages
  • plays likely a role in controlling correct cerebellar development
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    text inducing T cell receptor induced apoptosis of thymocytes
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA binding
    RNA
    small molecule
    protein
  • molecular target for ERK2 signals
  • key regulators of CYP11B2 expression and of adrenal aldosterone production
  • cross-talk between GRIN3B and NR4A1 receptors is a mechanism modulating the transcriptional activities of these orphan nuclear receptors
  • functionally associated with DAP3 on TCR-mediated apoptosis
  • interacting with EP300 and HDAC1 (acetylation of NR4A1 is modulated by EP300 and HDAC1, suggesting that acetylation is an important post-translational modification for the rapid turnover of NR4A1 protein)
  • directly regulate GDNF transcription (FSH-induced NR4A1 regulates the expression of GDNF in Sertoli cells to stimulate the proliferation of A spermatogonia)
  • NR4A1, NR4A2 interact with PRKDC and, upon exposure to DNA damage, translocate to DSB foci by a mechanism requiring the activity of PARP1
  • is a novel PIN1 substrate, and the mitogenic function of NR4A1 depends on PIN1-induced isomerization
  • FHL2 represses NR4A1 transcriptional activity in a dose-dependent manner
  • AR physically interacts and colocalizes with NR4A1 in the nucleus in the presence of androgen
  • AR protein, translocated into the nucleus in the presence of androgen, modulates likely NR4A1 transactivation
  • PIN1 is a novel binding partner of NR4A1, NR4A2, NR4A3
  • PIN1 enhances protein stability of NR4A1 in an isomerase-dependent manner by acting on phosphorylated NR4A1 involving protein kinase CK2-mediated phosphorylation of the Ser(152)-Pro(153) motif in NR4A1
  • in melanoma cells both CRH and UCN1 regulate TYRP1 gene expression via NR4A2/NR4A1 production, independent of pro-opiomelanocortin or alpha-melanocyte-stimulating hormone stimulation
  • interaction between NR4A1 and SSR3 (ligand-binding domain of NR4A1 was required for SSR3 binding, and the C terminus of SSR3 was responsible for its interaction with NR4A1)
  • NKX6-1 induces expression of NR4A1 and NR4A3 orphan nuclear receptors, and these factors are both necessary and sufficient for NKX6-1-mediated beta-cell proliferation
  • is a novel negative regulator of EDN1 expression in vascular ECs through an inhibitory interaction with the JUN pathway
  • novel role for NR4A1 in regulating the development and frequency of CD8(+) T cells through direct transcriptional control of RUNX3
  • NR4A1 functionally interacts with NFATC3 and GATA4 and inhibits their transcriptional activities, which are critical for the development of cardiac hypertrophy
  • critical role for NR4A1 in regulating the expansion, differentiation, and function of CD8(+) T cells through direct transcriptional repression of IRF4
  • NR1D1, is a cofactor in APOA4-mediated downregulation of gluconeogenesis, and APOA4-induced increase in NR4A1 expression in hepatocytes mediates further repression of gluconeogenesis
  • IGFBP3 may trigger osteoarthritis by inducing the chondrocytes apoptotic through nucleus-mitochondria translocation of NR4A1
  • NR4A1 binds directly to the CXCL12 promoter, resulting in inhibition of CXCL12 expression
  • NR4A1 protects pancreatic beta-cells against H2O2 mediated apoptosis by up-regulating WT1 expression
  • NR4A1 nuclear export requires RXRA as a carrier
  • DLL4 and JAG1 mediated NR4A1-induced angiogenic responses and signaling molecules, but not the expression of integrins
  • cell & other
    REGULATION
    activated by various kinds of stimulation for apoptosis induction, and TCR stimulation is known to be a potent activator of NR4A1 transcription
    induced by MEF2 after increase of intracellular calcium concentration and dissociation of MEF2 from CABIN1
    LH
    the cAMP axis in response to glucagon
    CREB1 in neurons exposed to stressful insults and function as mediator of CREB1-induced neuronal survival
    hormones known to activate STAR expression
    inhibited by phosphorylated and inhibited by AKT1
    (NUR77) mediated transcription inhibited by PML
    AR (inhibits NR4A1 transactivation by blocking the recruitment of NR4A1 coactivators)
    Other regulated by HDAC1 (HDAC1 decreased the acetylation level, protein level, and transcriptional activity of NR4A1 (
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in a majority of human colon tumors compared to their nontumorous tissues (
    tumoral     --low  
    of NR4A1 and NR4A3 was a common feature in leukemic blasts from human acute myeloid leukemia patients
    Susceptibility to tardive dyskinesia (TD)
    Variant & Polymorphism SNP
  • single nucleotide polymorphism (SNP) marker rs2603751 and rs2701124 showed a nominal association with the risk of TD
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cardiovascularatheroma 
    down-regulation of Nur77 by atorvastatin suggests a novel therapy strategy for atherogenesis based on suppression of vascular smooth muscle cells proliferation
    cancer  
    identification of pro-apoptotic agents inducing NR4A expression or acting as agonists suggests that these members could serve as potential targets for cancer therapy
    immunologyinflammatory 
    interesting target to treat chronic inflammatory disease
    miscelleaneoushypertension 
    Activation of Nur77 may represent a useful therapeutic strategy for preventing certain cardiovascular diseases, such as atherosclerosis and pulmonary artery hypertension
    ANIMAL & CELL MODELS
  • expression increased in diabetic mice that exhibit elevated gluconeogenesis
  • Nr4a1-deficient mice show increases in CD8 T cell effector responses with improved clearance of Listeria monocytogenes