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Showing NR4A2 — NURR1 is a alias.

NR4A2

Nuclear receptor subfamily 4 group A member 2 · UniProt P43354

Length
598 aa
Mass
66.6 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR4A2/Nurr1 is a ligand-regulated orphan nuclear receptor transcription factor that controls cell-type identity and inflammatory gene programs by binding NGFI-B response elements (NBRE) as a monomer and forming higher-order complexes on Nur-responsive elements (PMID:8737662, PMID:31723028, PMID:15485875). Structural work shows that two NR4A2 DNA-binding-domain molecules bind independently to everted repeats but form a dedicated dimer interface on inverted repeats, with Val298 essential for dimerization (PMID:31723028). In dopaminergic neurons it directly drives the machinery of dopamine synthesis and storage by upregulating AADC and VMAT2 (PMID:12915123). NR4A2 functions broadly as a transcriptional repressor of inflammation: it docks to NF-κB-p65 on inflammatory promoters and recruits the CoREST corepressor complex to clear p65 and silence transcription, a mechanism it redeploys to recruit CoREST/HDAC1/G9a/EZH2 to the HIV LTR and silence proviral transcription through direct DNA-binding-domain contacts (PMID:19345186, PMID:35797416). Although classified as an orphan receptor, its non-canonical ligand-binding domain is covalently activated by endogenous lipids and dopamine metabolites — PGA1 and the dopamine metabolite DHI each form a Michael adduct with Cys566 and stimulate transcriptional activity, and the AF-2 helix shifts conformation upon ligand binding (PMID:32451509, PMID:30853418). NR4A2 activity is further tuned by RXRα heterodimerization, where RXRα ligands paradoxically activate transcription by promoting heterodimer dissociation to release an active Nurr1 monomer (PMID:37102494). Across immune lineages it acts as a fate-determining factor, binding the Foxp3 locus to induce regulatory T cells, sustaining Th17 differentiation through autocrine IL-21, and promoting M2 macrophage polarization via arginase-1 (PMID:21468021, PMID:23437182, PMID:25953901). Its abundance and activity are regulated post-translationally by GSK-3-mediated phosphorylation that targets it for proteasomal degradation in an α-synuclein-driven loop relevant to Parkinson's disease (PMID:34609698).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 Medium

    Established NR4A2 as an inducible, sequence-specific DNA-binding factor, defining its identity as a transcription factor responsive to neuronal activity.

    Evidence EMSA demonstrating specific NBRE binding plus Northern blot induction after depolarization and seizure in PC12 cells and rat brain

    PMID:8737662

    Open questions at the time
    • Did not identify endogenous target genes
    • No structural basis for DNA recognition
  2. 2003 High

    Showed NR4A2 directly programs dopamine neuron physiology, linking the transcription factor to the biosynthetic and storage machinery of dopaminergic identity.

    Evidence Inducible Nurr1 cell line, retroviral overexpression, in situ hybridization in knockout embryos, and dopamine content assays

    PMID:12915123

    Open questions at the time
    • Direct promoter occupancy on AADC/VMAT2 not resolved here
    • Did not address co-regulator requirements
  3. 2009 High

    Defined the principal anti-inflammatory mechanism: NR4A2 represses NF-κB target genes by docking to p65 and recruiting the CoREST corepressor complex, explaining how a transcription factor can act as a context-dependent repressor.

    Evidence ChIP, co-IP, reporter assays, and loss-of-function in microglia and astrocytes with inflammatory/neurotoxicity readouts

    PMID:19345186

    Open questions at the time
    • Signal that triggers p65 docking incompletely defined
    • Generality across other inflammatory loci established later
  4. 2011 High

    Extended NR4A2 from neuronal identity to immune cell fate, showing it directly licenses the Treg program by binding the Foxp3 locus and depositing permissive chromatin marks.

    Evidence ChIP at Foxp3 locus, ectopic expression, conditional T-cell knockout, suppression assays, and colitis model

    PMID:21468021

    Open questions at the time
    • Co-regulators mediating permissive histone marks not identified
    • Relationship to its repressive CoREST mode unclear
  5. 2013 High

    Refined the immune role by placing NR4A2 in Th17 maturation through an autocrine IL-21 circuit, distinguishing its function from the master regulator RORγt.

    Evidence siRNA knockdown, in vitro Th17 differentiation, IL-21 cytokine rescue, and in vivo EAE model

    PMID:23437182

    Open questions at the time
    • Direct IL-21 promoter binding not shown
    • Interplay with the Treg-promoting role in the same cells unresolved
  6. 2019 High

    Resolved how an orphan receptor is endogenously controlled, showing the dopamine metabolite DHI covalently engages a non-canonical LBD pocket at Cys566 to activate transcription.

    Evidence X-ray crystallography, biophysical binding assays, cellular transcription assays, and zebrafish model

    PMID:30853418

    Open questions at the time
    • Physiological concentrations of DHI in target cells not established
    • Reversibility of the covalent adduct unaddressed
  7. 2019 High

    Provided the structural logic of NR4A2 DNA recognition, distinguishing independent binding on everted repeats from a novel dimer interface on inverted repeats.

    Evidence X-ray crystal structures of the DBD on inverted and everted elements with Val298Lys mutagenesis and EMSA

    PMID:31723028

    Open questions at the time
    • Functional consequence of homodimer vs monomer binding on target genes not mapped
    • Full-length receptor context not captured
  8. 2020 High

    Identified an endogenous lipid ligand mechanism, with PGA1 forming a Cys566 Michael adduct and driving a 21-degree AF-2 helix shift that activates transcription, and validated relevance in vivo.

    Evidence 2.05 Å crystal structure of Nurr1-LBD/PGA1, biophysical binding, mutagenesis, cellular assays, and MPTP mouse model

    PMID:32451509

    Open questions at the time
    • Whether multiple endogenous Cys566 ligands compete in vivo unknown
    • Selectivity over other Cys residues not fully defined
  9. 2021 High

    Connected NR4A2 abundance to Parkinson's pathology by mapping a GSK-3 phosphodegron that drives α-synuclein-dependent ubiquitination and proteasomal loss of the receptor.

    Evidence Deletion and point mutants spanning aa123-134, GSK-3 activity assays, proteasome inhibitor rescue, and ubiquitination IP

    PMID:34609698

    Open questions at the time
    • E3 ligase mediating ubiquitination not identified
    • Direct vs indirect role of GSK-3 not fully separated
  10. 2022 High

    Generalized the CoREST repression mechanism to viral silencing, showing NR4A2 recruits CoREST/HDAC1/G9a/EZH2 to the HIV LTR via direct DBD-dependent binding.

    Evidence ChIP, DBD mutant, overexpression/knockdown, and transcriptomics in human microglial models

    PMID:35797416

    Open questions at the time
    • Whether latency reversal can override this silencing unknown
    • Endogenous signal recruiting the complex to LTR not defined
  11. 2023 High

    Revealed a non-classical activation logic in which RXRα ligands activate Nurr1-RXRα transcription by promoting heterodimer dissociation rather than by direct agonism.

    Evidence NMR structural footprinting, protein-protein interaction assays, and cellular transcription assays

    PMID:37102494

    Open questions at the time
    • Cellular ratio of monomer vs heterodimer states not quantified
    • Target genes selectively affected by dissociation unmapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NR4A2 toggles between transcriptional activation and CoREST-mediated repression at distinct loci, and how endogenous ligand occupancy, RXRα dimerization, and GSK-3 degradation are integrated to set context-specific output, remains unresolved.
  • No unified model linking ligand state to activator/repressor switching
  • Cell-type determinants of partner choice unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 1
Partners
CORESTFOXA2GSK3RELARXRASNCATP53
Complex memberships
CoREST/HDAC1/G9a/EZH2 corepressor complexNurr1-RXRα heterodimer

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Nurr1 inhibits pro-inflammatory gene expression in microglia and astrocytes by docking to NF-κB-p65 on target inflammatory gene promoters in a signal-dependent manner, then recruiting the CoREST corepressor complex, which results in clearance of NF-κB-p65 and transcriptional repression. Chromatin immunoprecipitation, co-immunoprecipitation, reporter assays, loss-of-function (siRNA/knockout) with defined inflammatory phenotype readout Cell High 19345186
2020 Prostaglandin E1 (PGE1) and its metabolite PGA1 directly bind the ligand-binding domain (LBD) of Nurr1; PGA1 forms a covalent Michael adduct with Cys566 and induces a 21° conformational shift of the activation function-2 helix (H12), stimulating Nurr1 transcriptional activity. X-ray crystallography (2.05 Å structure of Nurr1-LBD/PGA1), biophysical binding assays, site-directed mutagenesis, cellular transcription assays, in vivo MPTP mouse model Nature chemical biology High 32451509
2019 The dopamine metabolite 5,6-dihydroxyindole (DHI) binds directly to the Nurr1 LBD within a non-canonical pocket, forming a covalent adduct with Cys566, and stimulates Nurr1 transcriptional activity including target genes governing dopamine homeostasis. X-ray crystallography, biophysical binding assays, cellular transcription assays, zebrafish functional model Cell chemical biology High 30853418
2023 RXRα ligands activate Nurr1-RXRα transcription by weakening Nurr1-RXRα LBD heterodimer affinity and promoting heterodimer dissociation (PPI inhibition), releasing a transcriptionally active Nurr1 monomer from a repressive heterodimeric complex — a mechanism distinct from classical agonism. NMR spectroscopy structural footprinting, protein-protein interaction assays, cellular transcription assays eLife High 37102494
2019 X-ray crystal structures of the NR4A2 DNA-binding domain bound to inverted and everted Nur-responsive elements reveal that two NR4A2-DBD molecules bind independently to the everted repeat but form a novel dimer interface on the inverted repeat; substitution of interface residue Val298 to Lys abolishes dimerization. X-ray crystallography (2.6–2.8 Å), site-directed mutagenesis, EMSA/biochemical binding assays The Journal of biological chemistry High 31723028
2003 Nurr1 directly regulates dopamine synthesis and storage in MN9D dopamine cells by increasing expression of AADC and VMAT2; VMAT2 upregulation requires continuous Nurr1 expression, and both AADC and VMAT2 are deregulated in Nurr1 knockout embryo midbrain. Inducible Nurr1 cell line, retroviral overexpression, in situ hybridization in knockout embryos, dopamine content assay Experimental cell research High 12915123
2011 Nr4a2 directly binds regulatory regions of the Foxp3 gene locus, mediates permissive histone modifications, and is required for induction and maintenance of Foxp3-expressing regulatory T cells; Nr4a2 deletion attenuates Treg induction and causes aberrant Th1 responses. ChIP at Foxp3 locus, ectopic expression, conditional knockout in T cells, in vitro and in vivo Treg suppression assays, colitis model Nature communications High 21468021
2021 α-Synuclein activates GSK-3, which phosphorylates NURR1 at a domain comprising amino acids 123-PSSPPTPSTPS-134, leading to ubiquitination and proteasomal degradation of NURR1 and loss of dopaminergic markers. Sequential deletion mutants and single-point mutants of NURR1, GSK-3 activity assays, proteasome inhibitor rescue, immunoprecipitation of ubiquitinated NURR1 Molecular neurobiology High 34609698
2005 Multiple Nurr1 splice variants (nurr1a, nurr1b, nurr1c, TINUR, nurr2, nurr2c) are produced in rat and human dopamine neurons via alternative splicing in exons 3 and 7; these variants have significantly reduced transcriptional activity compared with full-length Nurr1, and nurr2/nurr2c act as dominant negatives. RT-PCR identification of splice variants, transfection reporter assays in dopaminergic SK-N-AS cells, dominant-negative functional assays Journal of neurochemistry Medium 16313515
2004 Nurr1 directly transactivates the osteocalcin (Ocn) gene in osteoblasts by binding as a monomer to an NBRE-like element in the proximal Ocn promoter; chromatin immunoprecipitation confirmed endogenous Nurr1 occupancy at this site, and mutation of the NBRE-like site markedly blunted transcriptional response. EMSA, chromatin immunoprecipitation, promoter-luciferase reporter assays, adenoviral Nurr1 overexpression in primary osteoblasts The Journal of biological chemistry High 15485875
2009 Nr4a2 is expressed downstream of Brn3a in habenular neurons and mediates expression of a subset of Brn3a-regulated transcripts, establishing Nr4a2 as a component of a gene regulatory pathway for habenula development. Microarray in Brn3a null embryos, in situ hybridization, genetic epistasis The Journal of neuroscience Medium 19906978
2009 Nr4a2 is required for specification of a GABAergic amacrine cell subtype in the retina; targeted inactivation results in loss of dopaminergic and p57Kip2+ amacrine cells with a concomitant increase in calbindin+ ACs, and misexpressed Nr4a2 promotes GABAergic AC differentiation while its dominant-negative form suppresses it. Conditional knockout, retroviral misexpression, dominant-negative overexpression, immunofluorescence phenotyping The Journal of neuroscience High 19692620
2005 PGE2 rapidly induces NR4A2 expression in colorectal carcinoma cells via a cAMP/PKA-dependent mechanism; NR4A2 binds cognate NBRE response elements and enhances transcription, and PGE2-mediated protection from apoptosis is completely blocked by a dominant-negative NR4A2 construct. Reporter assays with NBRE construct, dominant-negative NR4A2, PKA pathway inhibitors, apoptosis assays The Journal of biological chemistry Medium 16293616
2011 PGE2-induced NR4A2 increases fatty acid oxidation in colon cancer cells by directly binding Nur77-binding response elements (NBREs) in the promoters of fatty acid oxidation genes and recruiting transcriptional coactivators. ChIP demonstrating NR4A2 binding to NBRE elements in FAO gene promoters, coactivator recruitment assays, fatty acid oxidation measurements, gene expression analysis The Journal of biological chemistry Medium 21757690
2013 NR4A2 is required for full Th17 differentiation by controlling autocrine IL-21 signaling; siRNA knockdown of NR4A2 prevents IL-17 and IL-21 production despite normal RORγt expression, and exogenous IL-21 restores Th17 differentiation in NR4A2-deficient cells. siRNA knockdown, in vitro Th17 differentiation assays, cytokine rescue with exogenous IL-21, in vivo siRNA treatment in EAE model PloS one High 23437182
2009 Nurr1 interacts directly with p53 and represses p53 transcriptional activity in an interaction-dependent and dose-dependent manner, decreasing Bax expression and protecting cells from doxorubicin-induced apoptosis. Co-immunoprecipitation of Nurr1-p53 complex, reporter assays for p53 transcriptional activity, siRNA knockdown of Nurr1, apoptosis assays Molecular cancer research Medium 19671681
2015 Nurr1 and Foxa2 physically interact and synergistically protect midbrain dopamine neurons; AAV-mediated co-delivery of both factors in a PD mouse model markedly protects neurons and motor behaviors through both cell-autonomous actions in DA neurons and paracrine actions in neighboring glia. Co-immunoprecipitation of Nurr1-Foxa2 interaction, AAV gene delivery in PD mouse model, behavioral and histological assessment EMBO molecular medicine Medium 25759364
2015 Nr4a2 promotes alternative (M2) macrophage polarization; exogenous Nr4a2 expression transcriptionally activates arginase 1 by directly binding its promoter, and Nr4a2-expressing macrophages confer protection in endotoxin-induced sepsis. Chromatin immunoprecipitation/reporter assay for arginase 1 promoter, overexpression and knockdown in macrophages, adoptive transfer sepsis model The Journal of biological chemistry Medium 25953901
2008 Nurr1 transcriptionally regulates alpha-synuclein expression; decreased Nurr1 expression (as seen in PD patients with Nurr1 mutations) increases alpha-synuclein transcription. Nurr1 overexpression/knockdown with measurement of alpha-synuclein mRNA and reporter assays Neuroreport Medium 18463503
2020 α-Synuclein (WT or A53T) reduces Nurr1 transcription by downregulating NF-κB expression, thereby inhibiting NF-κB binding to the Nurr1 promoter region (−605 to −418 bp); α-SYN does not affect Nurr1 mRNA stability or directly bind the Nurr1 promoter. Promoter deletion/reporter assays, ChIP for NF-κB at Nurr1 promoter, mRNA stability assays, overexpression of WT and A53T α-SYN Frontiers in molecular neuroscience Medium 32477062
2012 NR4A2 directly transactivates the MMP-13 promoter through its DNA-binding domain in synoviocytes; a point mutation in the NR4A2 DNA-binding domain abolishes transcriptional activation of MMP-13, and endogenous NR4A2 knockdown reduces synoviocyte proliferation, migration, and MMP-13 expression. MMP-13 promoter reporter assays, DNA-binding domain point mutant, lentiviral shRNA knockdown, proliferation/migration/invasion assays Arthritis and rheumatism High 22275273
2019 NURR1 activates skeletal muscle glucose uptake and glycogen storage; transgenic overexpression of NURR1 in skeletal muscle enhances physical performance and prevents hyperglycemia and hepatic steatosis in mice. Transgenic mouse overexpression, metabolic phenotyping (glucose tolerance, glycogen assays), exercise-response enhancer analysis Proceedings of the National Academy of Sciences of the United States of America Medium 31110021
2022 Nurr1 recruits the CoREST/HDAC1/G9a/EZH2 transcription repressor complex to the HIV LTR by directly binding consensus Nurr1 binding sites in the U3 region, silencing HIV transcription in microglial cells; mutation of the Nurr1 DNA-binding domain blocks HIV suppression. ChIP assay, Nurr1 DBD mutant, Nurr1 overexpression/knockdown, transcriptomic analysis PLoS pathogens High 35797416
2020 Nurr1 performs anti-inflammatory function partly by directly binding the RasGRP1 intron to regulate RasGRP1 expression, which in turn modulates the Ras-Raf-MEK-ERK signaling cascade during LPS-induced inflammation in microglia. ChIP-seq in LPS-stimulated BV2 cells, RasGRP1 expression analysis, ERK pathway activation assays Scientific reports Medium 32612143
2020 Nurr1 suppresses NF-κB/NLRP3 inflammasome signaling in Müller cells; high glucose decreases Nurr1 expression and nuclear translocation, leading to p65 activation and NLRP3 upregulation via p65 binding to the NLRP3 promoter. Nurr1 overexpression/knockdown, nuclear fractionation, ChIP for p65 at NLRP3 promoter, in vivo Nurr1 agonist treatment in STZ mouse model Neuropeptides Medium 32461025
2021 NR4A2 function in the medial habenula is required for reinstatement of cocaine-associated behaviors; HDAC3 disengages from the Nr4a2 locus in the MHb during cocaine-primed reinstatement, and loss of NR4A2 function via a dominant-negative splice variant (NURR2C) in the MHb blocks reinstatement. ChIP for HDAC3 at Nr4a2 locus in MHb, stereotaxic viral delivery of dominant-negative NURR2C, behavioral cocaine reinstatement assay Neuropharmacology Medium 30998946
2009 Nurr1 protein is expressed in microglia and located in both cytoplasm and nucleus; LPS stimulation increases Nurr1 expression and promotes its translocation from cytoplasm to nucleus via ERK, JNK, and PI3K/Akt pathways (ERK partially mediates nuclear translocation). Western blot, immunofluorescence, subcellular fractionation, pathway inhibitors (ERK, JNK, P38 MAPK, PI3K/Akt) in primary microglia Neuroimmunomodulation Medium 19246938
2013 Nurr1 expression in hippocampal neurons is regulated in an activity-dependent manner via voltage-dependent calcium channels (VDCCs) and calcineurin, but not CaMK; blocking VDCCs or calcineurin prevents activity-induced Nurr1 upregulation. High KCl/bicuculline stimulation, tetrodotoxin blockade, pharmacological VDCC inhibitors, calcineurin and CaMK inhibitors, Western blot in primary hippocampal neurons Neuroscience letters Medium 24291696
2016 The p53 pathway induces miR-34 expression, which directly suppresses NR4A2 via a miRNA recognition element in the NR4A2 3' UTR; conversely, NR4A2 overexpression blocks induction of p53 target genes including mir-34a and rescues cells from p53-induced proliferation inhibition, forming a feedback network. 3' UTR reporter screen, miR-34 overexpression, p53 pathway activation, mutagenesis of miRNA recognition element, proliferation rescue assays Scientific reports Medium 27121375
2020 Chloroquine directly binds the Nurr1 ligand-binding domain and promotes its transcriptional activity; it also upregulates Nurr1 expression via the CREB signaling pathway. Chloroquine activates TREG cell differentiation and Foxp3 expression in a Nurr1-dependent manner in vitro and in an IBD animal model. Ligand binding assay (direct binding to Nurr1 LBD), T cell differentiation assays, Nurr1 knockout/knockdown functional rescue, IBD mouse model Scientific reports Medium 31664129
2021 Amodiaquine, chloroquine, and cytosporone B directly bind the Nurr1 LBD as detected by NMR structural footprinting, whereas other reported NR4A modulators (C-DIM12, celastrol, camptothecin, IP7e, isoalantolactone, TMPA, and three HTS derivatives) do not bind the Nurr1 LBD. Protein NMR structural footprinting, transcription assays (Nurr1-dependent and Nurr1-independent) Journal of medicinal chemistry High 33289551
2022 LUCAT1 lncRNA controls splicing and stability of NR4A2 mRNA by interacting with RNA-binding proteins hnRNP C, M, and A2B1; loss of LUCAT1 leads to altered splicing and reduced/delayed NR4A2 expression upon LPS stimulation, while NR4A2-deficient cells show elevated inflammatory gene expression. RNA-binding protein mass spectrometry (CHIRP-MS), RNA immunoprecipitation, splicing analysis, NR4A2 knockdown with inflammatory gene expression readout Proceedings of the National Academy of Sciences of the United States of America Medium 36577072
2015 NR4A2 directly transactivates the distal prolactin (PRL) promoter in synoviocytes, requiring a functional DNA-binding domain; deletional analysis maps the NR4A2-responsive region to −270 to −32 bp, and shRNA depletion of endogenous NR4A receptors reduces basal and PGE2-induced PRL levels by 95%. Reporter assays with deletional and DBD mutant constructs, shRNA knockdown, ELISA for secreted PRL Journal of inflammation (London, England) Medium 25717285
2020 NR4A2 directly suppresses CCR5 transcription by binding its promoter and induces M2 macrophage polarization; NR4A2 overexpression in a diabetic cardiomyopathy rat model reduces M1 macrophage proportion and alleviates myocardial injury in a CCR5-dependent manner. Bioinformatic prediction of NR4A2 binding, ChIP/reporter validation of CCR5 promoter binding, NR4A2 overexpression in rats, M1/M2 macrophage flow cytometry Microvascular research Low 34774582
2020 NR4A2 is a downstream target of Notch1 signaling in hepatocellular carcinoma; overexpression of active Notch1 (ICN1) increases NR4A2 expression, while Notch1 knockdown decreases NR4A2, and both genes co-operatively suppress p21 and p63 to promote HCC cell growth. Notch1 ICN1 overexpression and knockdown, qPCR/western blot of NR4A2, cell proliferation and FACS assays Oncotarget Low 28423575
2021 NURR1 regulates autophagy-mediated gemcitabine resistance in pancreatic cancer cells via a NURR1-ATG7/ATG12 axis; NURR1 is required for gemcitabine-induced cytoprotective autophagy, and its knockdown (siRNA or CRISPR/Cas9) or antagonism by C-DIM12 restores gemcitabine sensitivity. RNA sequencing in NURR1-expressing and CRISPR-KO cells, KEGG pathway analysis, NURR1 KD/KO and antagonist treatment, autophagy and viability assays Cancer research communications Medium 35582016
2022 An age-dependent shift in NURR1 dimerization occurs in human RPE cells, from NURR1-RXRα heterodimers toward NURR1-NURR1 homodimers; NURR1 overexpression and activation attenuates TNF-α-induced epithelial-to-mesenchymal transition in human RPE cells independently of age. Co-immunoprecipitation of NURR1 dimerization states from primary human RPE cells, overexpression and pharmacological activation, EMT marker analysis, in vivo AMD mouse models Proceedings of the National Academy of Sciences of the United States of America Medium 35867766
1996 HZF-3 (an alias of NURR1/NR4A2) is an immediate-early gene induced by membrane depolarization in PC12 cells and by seizures in rat brain; it encodes a protein that specifically binds the NGFI-B response element (NBRE) by EMSA. EMSA demonstrating specific NBRE binding, Northern blot induction kinetics following depolarization and seizure Brain research. Molecular brain research Medium 8737662
2020 NR4A2 promotes ESCC growth; METTL3-mediated m6A methylation of NR4A2 mRNA, stabilized by IGF2BP2, increases NR4A2 expression in response to methionine/SAM, and NR4A2 knockdown reduces ESCC cell proliferation. RNA m6A methylation analysis, IGF2BP2 RIP, NR4A2 siRNA knockdown, proliferation assays, integrative omics Cell death and differentiation Medium 38570607
2020 Nurr1 directly targets the CDK4 promoter in gastric cancer cells to enhance CDK4 expression and facilitate cell proliferation; Nurr1 is induced by H. pylori via the PI3K/AKT-Sp1 pathway, with Sp1 binding the Nurr1 promoter. ChIP for Nurr1 at CDK4 promoter, reporter assays, Nurr1 knockdown/overexpression, in vitro and xenograft proliferation assays EBioMedicine Medium 32114387

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 775 19345186
2002 Mutations in NR4A2 associated with familial Parkinson disease. Nature genetics 380 12496759
2005 The role of Nurr1 in the development of dopaminergic neurons and Parkinson's disease. Progress in neurobiology 270 16243425
2013 NURR1 in Parkinson disease--from pathogenesis to therapeutic potential. Nature reviews. Neurology 200 24126627
2011 The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells. Nature communications 178 21468021
2003 Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells. Experimental cell research 140 12915123
2000 NURR1 mutations in cases of schizophrenia and manic-depressive disorder. American journal of medical genetics 123 11121187
2004 Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells. Cell and tissue research 122 15340833
2004 Nuclear hormone receptor NR4A2 is involved in cell transformation and apoptosis. Cancer research 110 15548686
2016 Nurr1-Based Therapies for Parkinson's Disease. CNS neuroscience & therapeutics 103 27012974
2009 Brn3a and Nurr1 mediate a gene regulatory pathway for habenula development. The Journal of neuroscience : the official journal of the Society for Neuroscience 101 19906978
2005 Prostaglandin E2 regulates the nuclear receptor NR4A2 in colorectal cancer. The Journal of biological chemistry 99 16293616
2012 Differential roles for Nr4a1 and Nr4a2 in object location vs. object recognition long-term memory. Learning & memory (Cold Spring Harbor, N.Y.) 97 23161447
2019 Molecular Insights into NR4A2(Nurr1): an Emerging Target for Neuroprotective Therapy Against Neuroinflammation and Neuronal Cell Death. Molecular neurobiology 93 30684217
2018 Nurr1 (NR4A2) regulates Alzheimer's disease-related pathogenesis and cognitive function in the 5XFAD mouse model. Aging cell 85 30515963
2015 Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease. EMBO molecular medicine 79 25759364
2006 Translated mutation in the Nurr1 gene as a cause for Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 77 16532445
2020 PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function. Nature chemical biology 76 32451509
2015 Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis. The Journal of biological chemistry 75 25953901
2007 Expression and function of nr4a2, lmx1b, and pitx3 in zebrafish dopaminergic and noradrenergic neuronal development. BMC developmental biology 74 18053265
2017 Nurr1:RXRα heterodimer activation as monotherapy for Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 72 28348207
2000 Hippocampal expression of the orphan nuclear receptor gene hzf-3/nurr1 during spatial discrimination learning. Neurobiology of learning and memory 69 10933901
2013 Nuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signalling. PloS one 67 23437182
2019 Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite. Cell chemical biology 58 30853418
2012 Role of nuclear receptor NR4A2 in gastrointestinal inflammation and cancers. World journal of gastroenterology 57 23322982
2012 Structure-dependent activation of NR4A2 (Nurr1) by 1,1-bis(3'-indolyl)-1-(aromatic)methane analogs in pancreatic cancer cells. Biochemical pharmacology 56 22405837
2020 Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1. Journal of medicinal chemistry 55 33289551
2020 The orphan nuclear receptor Nurr1 is responsive to non-steroidal anti-inflammatory drugs. Communications chemistry 54 36703399
2011 The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss. International journal of obesity (2005) 54 22143616
2001 Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in schizophrenic patients. American journal of medical genetics 54 11803525
2011 Nuclear receptors Nur77 and Nurr1 modulate mesenchymal stromal cell migration. Stem cells and development 53 21480782
2017 NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival. Blood 49 28637666
2011 Nuclear orphan receptor NR4A2 modulates fatty acid oxidation pathways in colorectal cancer. The Journal of biological chemistry 47 21757690
1998 Nurr1 mRNA expression in neonatal and adult rat brain following kainic acid-induced seizure activity. Brain research. Molecular brain research 47 9729370
2022 Parkinson's disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1) in cortical neurons. NPJ Parkinson's disease 45 36151217
2019 NURR1 activation in skeletal muscle controls systemic energy homeostasis. Proceedings of the National Academy of Sciences of the United States of America 45 31110021
2009 NGFI-B nuclear orphan receptor Nurr1 interacts with p53 and suppresses its transcriptional activity. Molecular cancer research : MCR 44 19671681
2023 Protective effect of Nr4a2 (Nurr1) against LPS-induced depressive-like behaviors via regulating activity of microglia and CamkII neurons in anterior cingulate cortex. Pharmacological research 43 36948326
2020 The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer's Disease-related Pathogenesis. Aging and disease 43 32489714
2009 A Nurr1 pathway for neuroprotection. Cell 43 19345183
2004 Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts. The Journal of biological chemistry 43 15485875
2018 Compensatory Expression of Nur77 and Nurr1 Regulates NF-κB-Dependent Inflammatory Signaling in Astrocytes. Molecular pharmacology 42 30111648
2023 An optimized Nurr1 agonist provides disease-modifying effects in Parkinson's disease models. Nature communications 41 37463889
2012 Orphan nuclear receptor NR4A2 induces synoviocyte proliferation, invasion, and matrix metalloproteinase 13 transcription. Arthritis and rheumatism 40 22275273
2008 Nurr1 transcriptionally regulates the expression of alpha-synuclein. Neuroreport 40 18463503
2022 The lncRNA LUCAT1 is elevated in inflammatory disease and restrains inflammation by regulating the splicing and stability of NR4A2. Proceedings of the National Academy of Sciences of the United States of America 39 36577072
2022 The role of NURR1 in metabolic abnormalities of Parkinson's disease. Molecular neurodegeneration 37 35761385
2020 Dysfunctional Nurr1 promotes high glucose-induced Müller cell activation by up-regulating the NF-κB/NLRP3 inflammasome axis. Neuropeptides 36 32461025
2022 Nurr1 Modulation Mediates Neuroprotective Effects of Statins. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 35 35488520
2020 α-Synuclein Negatively Regulates Nurr1 Expression Through NF-κB-Related Mechanism. Frontiers in molecular neuroscience 35 32477062
2019 Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases. Scientific reports 35 31664129
2016 Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease. Oncotarget 35 26862735
2009 Characterisation of a novel NR4A2 mutation in Parkinson's disease brain. Neuroscience letters 35 19429166
1999 Organization of the human orphan nuclear receptor Nurr1 gene. Gene 35 10216261
2009 Nurr1 expression and its modulation in microglia. Neuroimmunomodulation 34 19246938
2009 Subtype specification of GABAergic amacrine cells by the orphan nuclear receptor Nr4a2/Nurr1. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 19692620
2007 Increased expression of the orphan nuclear receptor NURR1 in psoriasis and modulation following TNF-alpha inhibition. The Journal of investigative dermatology 33 17671512
2023 Development of a Potent Nurr1 Agonist Tool for In Vivo Applications. Journal of medicinal chemistry 32 37127285
2020 Nurr1 performs its anti-inflammatory function by regulating RasGRP1 expression in neuro-inflammation. Scientific reports 32 32612143
2016 The orphan nuclear receptor NR4A2 is part of a p53-microRNA-34 network. Scientific reports 32 27121375
2022 Medicinal Chemistry and Chemical Biology of Nurr1 Modulators: An Emerging Strategy in Neurodegeneration. Journal of medicinal chemistry 30 35797147
2021 Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review. Frontiers in molecular neuroscience 30 34880728
2022 CB2 receptor activation inhibits the phagocytic function of microglia through activating ERK/AKT-Nurr1 signal pathways. Acta pharmacologica Sinica 29 35132190
2020 Loss-of-Function Mutations in NR4A2 Cause Dopa-Responsive Dystonia Parkinsonism. Movement disorders : official journal of the Movement Disorder Society 29 31922365
2012 The function and mechanisms of Nurr1 action in midbrain dopaminergic neurons, from development and maintenance to survival. International review of neurobiology 29 22748824
2019 NURR1 deficiency is associated to ADHD-like phenotypes in mice. Translational psychiatry 28 31455763
2019 Nuclear receptor 4A2 (NR4A2) is a druggable target for glioblastomas. Journal of neuro-oncology 28 31754919
2005 Identification and characterization of human NR4A2 polymorphisms in attention deficit hyperactivity disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 28 15635701
2023 Sodium Butyrate Ameliorates Deoxynivalenol-Induced Oxidative Stress and Inflammation in the Porcine Liver via NR4A2-Mediated Histone Acetylation. Journal of agricultural and food chemistry 27 37384814
2020 HPV-induced Nurr1 promotes cancer aggressiveness, self-renewal, and radioresistance via ERK and AKT signaling in cervical cancer. Cancer letters 27 33010383
2016 Adenovirus-mediated expression of orphan nuclear receptor NR4A2 targeting hepatic stellate cell attenuates liver fibrosis in rats. Scientific reports 27 27646469
2022 Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson's Disease. International journal of molecular sciences 26 36555826
2020 De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy. Genetics in medicine : official journal of the American College of Medical Genetics 26 32366965
2021 Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1. Experimental & molecular medicine 25 33479411
2005 Dopamine neurons express multiple isoforms of the nuclear receptor nurr1 with diminished transcriptional activity. Journal of neurochemistry 25 16313515
2022 Recruitment of the CoREST transcription repressor complexes by Nerve Growth factor IB-like receptor (Nurr1/NR4A2) mediates silencing of HIV in microglial cells. PLoS pathogens 24 35797416
2021 Fragment-like Chloroquinolineamines Activate the Orphan Nuclear Receptor Nurr1 and Elucidate Activation Mechanisms. Journal of medicinal chemistry 24 33629841
2019 Structural basis of binding of homodimers of the nuclear receptor NR4A2 to selective Nur-responsive DNA elements. The Journal of biological chemistry 24 31723028
2024 Unveiling the methionine cycle: a key metabolic signature and NR4A2 as a methionine-responsive oncogene in esophageal squamous cell carcinoma. Cell death and differentiation 23 38570607
2022 NURR1 expression regulates retinal pigment epithelial-mesenchymal transition and age-related macular degeneration phenotypes. Proceedings of the National Academy of Sciences of the United States of America 23 35867766
2019 NURR1 Impairment in Multiple Sclerosis. International journal of molecular sciences 23 31574937
2019 NURR1 and ERR1 Modulate the Expression of Genes of a DRD2 Coexpression Network Enriched for Schizophrenia Risk. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 31811028
2015 Orphan nuclear receptor NR4A2 induces transcription of the immunomodulatory peptide hormone prolactin. Journal of inflammation (London, England) 22 25717285
2019 Transplantation of Nurr1-overexpressing neural stem cells and microglia for treating parkinsonian rats. CNS neuroscience & therapeutics 21 31087449
2017 NURR1 Downregulation Favors Osteoblastic Differentiation of MSCs. Stem cells international 21 28769982
2016 Nurr1 expression is modified by inflammation in microglia. Neuroreport 21 27532877
2011 Identification of Endothelin-1 and NR4A2 as CD133-regulated genes in colon cancer cells. The Journal of pathology 21 21826669
1996 HZF-3, an immediate-early orphan receptor homologous to NURR1/NOT: induction upon membrane depolarization and seizures. Brain research. Molecular brain research 21 8737662
2013 Nurr1 expression is regulated by voltage-dependent calcium channels and calcineurin in cultured hippocampal neurons. Neuroscience letters 20 24291696
2021 Transcriptional Profiling of Monocytes Deficient in Nuclear Orphan Receptors NR4A2 and NR4A3 Reveals Distinct Signalling Roles Related to Antigen Presentation and Viral Response. Frontiers in immunology 19 34248958
2021 α-Synuclein Induces the GSK-3-Mediated Phosphorylation and Degradation of NURR1 and Loss of Dopaminergic Hallmarks. Molecular neurobiology 19 34609698
2021 Nuclear Receptor 4A2 (NR4A2/NURR1) Regulates Autophagy and Chemoresistance in Pancreatic Ductal Adenocarcinoma. Cancer research communications 19 35582016
2017 Activated Notch signaling augments cell growth in hepatocellular carcinoma via up-regulating the nuclear receptor NR4A2. Oncotarget 19 28423575
2021 Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1. ACS chemical biology 18 34165961
2019 Epigenetic regulation of immediate-early gene Nr4a2/Nurr1 in the medial habenula during reinstatement of cocaine-associated behavior. Neuropharmacology 18 30998946
2023 Molecular basis of ligand-dependent Nurr1-RXRα activation. eLife 17 37102494
2020 Orphan nuclear receptor Nurr1 promotes Helicobacter pylori-associated gastric carcinogenesis by directly enhancing CDK4 expression. EBioMedicine 17 32114387
2016 Nuclear receptor expression atlas in BMDCs: Nr4a2 restricts immunogenicity of BMDCs and impedes EAE. European journal of immunology 17 27184189
2023 Downregulation of microRNA-145a-5p promotes steatosis-to-NASH progression through upregulation of Nr4a2. Journal of hepatology 16 37463623
2021 NR4A2 alleviates cardiomyocyte loss and myocardial injury in rats by transcriptionally suppressing CCR5 and inducing M2 polarization of macrophages. Microvascular research 16 34774582

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