Affinage

NR4A2

Nuclear receptor subfamily 4 group A member 2 · UniProt P43354

Length
598 aa
Mass
66.6 kDa
Annotated
2026-04-29
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR4A2 (Nurr1) is an orphan nuclear receptor transcription factor that functions as a master regulator of midbrain dopaminergic neuron identity and a signal-dependent modulator of inflammatory gene expression across multiple immune and neural cell types. It binds DNA as a monomer at NBRE elements or as a homodimer on NurRE inverted repeats to directly transactivate dopaminergic genes (TH, AADC, VMAT2, RET, Pitx3), cell-cycle regulators (CDK4, p21), and metabolic targets (osteocalcin, FAO genes, arginase 1, FGF23), while also repressing inflammatory gene transcription by docking to NF-κB p65 on target promoters and recruiting the CoREST/HDAC1/G9a/EZH2 corepressor complex (PMID:19345186, PMID:12915123, PMID:31723028, PMID:25953901). Although originally classified as a ligand-independent receptor due to a collapsed canonical ligand-binding pocket, its LBD is conformationally dynamic and accommodates endogenous ligands—prostaglandin A1 and the dopamine metabolite 5,6-dihydroxyindole—that form covalent adducts with Cys566, inducing activation-function helix repositioning and transcriptional activation (PMID:32451509, PMID:30853418, PMID:30416039). Beyond the nervous system, NR4A2 drives Foxp3 expression and regulatory T cell differentiation, promotes Th17 polarization via an IL-21 autocrine loop, and directs M2 macrophage polarization through arginase 1 induction, placing it at the interface of adaptive and innate immunity (PMID:21468021, PMID:23437182, PMID:25953901).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 Medium

    Establishing that NR4A2 coding variants found in psychiatric patients reduce transcriptional activity provided the first evidence that diminished Nurr1 function has pathological consequences beyond dopamine neuron specification.

    Evidence Direct sequencing of schizophrenia/manic-depression patients with in vitro reporter assays of mutant constructs

    PMID:11121187

    Open questions at the time
    • Single cohort; causality not established by family segregation or rescue
    • No structural basis for how exon 3 mutations reduce dimer activity
  2. 2003 High

    Demonstrating that Nurr1 directly induces AADC and VMAT2 in dopaminergic cells—and that these genes are deregulated in Nurr1 knockout embryos—established Nurr1 as an instructive transcription factor for the full dopamine biosynthesis and storage program, not just TH alone.

    Evidence Inducible Nurr1 cell line with DA content measurement; in situ hybridization in Nurr1 KO embryos

    PMID:12915123

    Open questions at the time
    • Genome-wide target repertoire not yet defined
    • Whether Nurr1 binds AADC/VMAT2 promoters directly was not shown by ChIP at this stage
  3. 2004 High

    Identifying that Nurr1 monomers bind an NBRE-like element in the osteocalcin promoter demonstrated that Nurr1 functions as a direct transcriptional activator outside the nervous system.

    Evidence EMSA, ChIP, and mutagenesis in primary osteoblasts

    PMID:15485875

    Open questions at the time
    • Physiological relevance of Nurr1 in bone homeostasis not fully delineated
  4. 2006 High

    Crystallographic analysis revealing a collapsed canonical ligand pocket with an alternative hydrophobic co-activator surface on the LBD explained how Nurr1 could be constitutively active yet still regulatable, resolving its classification as an 'orphan' receptor.

    Evidence Crystal structure analysis, site-directed mutagenesis, proteasome inhibitor experiments

    PMID:17032747

    Open questions at the time
    • Whether endogenous ligands exist was unresolved
    • Identity of co-activators recruited to the alternative surface unknown
  5. 2008 High

    Showing that NR4A2 augments IL-17 and IFN-γ promoter activity in pathogenic T cells and is required for encephalitogenic T cell function revealed a pro-inflammatory role for Nurr1 in adaptive immunity, distinct from its neurotrophic identity.

    Evidence Reporter assays plus EAE adoptive transfer model

    PMID:18550828

    Open questions at the time
    • Direct promoter binding not confirmed by ChIP
    • Mechanism distinguishing activating vs. repressive NR4A2 function in T cells vs. myeloid cells unclear
  6. 2009 High

    The discovery that Nurr1 docks onto NF-κB p65 at inflammatory gene promoters and recruits the CoREST corepressor complex to clear p65 provided the molecular mechanism for signal-dependent transrepression, explaining how Nurr1 protects dopaminergic neurons from neuroinflammation.

    Evidence ChIP, Co-IP, reporter assays, siRNA, conditional knockout mice in microglia/astrocytes

    PMID:19345186

    Open questions at the time
    • Whether the CoREST-dependent mechanism operates in non-CNS inflammatory contexts was unknown
    • Post-translational modifications governing p65-docking were not identified
  7. 2009 High

    Genetic loss- and gain-of-function studies showing Nr4a2 is necessary and sufficient for GABAergic amacrine cell specification in the retina expanded its role beyond midbrain DA neurons to a general neuronal subtype selector.

    Evidence Conditional knockout and retroviral misexpression in mouse retina

    PMID:19692620

    Open questions at the time
    • Direct transcriptional targets in amacrine cells not identified
    • Whether Nr4a2 coordinates with the same co-regulators as in DA neurons unknown
  8. 2011 High

    Demonstrating that Nr4a2 directly binds the Foxp3 locus and mediates permissive histone modifications established it as a key inducer of regulatory T cell differentiation, bridging its immune roles from purely pro-inflammatory (Th17) to immunosuppressive (Treg).

    Evidence ChIP, conditional T cell–specific KO, in vitro suppression assays, colitis model

    PMID:21468021

    Open questions at the time
    • How the same factor drives both Th17 and Treg programs in different contexts was unresolved
    • Signals specifying the switch not identified
  9. 2011 High

    ChIP-based identification that PGE2-induced NR4A2 binds NBREs in fatty acid oxidation gene regulatory regions linked NR4A2 to metabolic reprogramming in colorectal cancer cells.

    Evidence ChIP, NBRE reporter assays, siRNA knockdown, metabolic assays

    PMID:21757690

    Open questions at the time
    • Whether NR4A2 regulation of FAO is a general metabolic function or cancer-specific unknown
  10. 2013 High

    Placing NR4A2 upstream of the IL-21 autocrine loop in Th17 differentiation—with rescue by exogenous IL-21—resolved the epistatic position of NR4A2 in the Th17 program.

    Evidence siRNA knockdown, cytokine rescue, in vivo EAE siRNA treatment

    PMID:23437182

    Open questions at the time
    • Whether NR4A2 directly binds IL-21 regulatory regions not confirmed by ChIP
  11. 2018 High

    NMR and HDX-MS revealed that the Nurr1 LBD pocket, though collapsed in crystals, is dynamically accessible on microsecond-to-millisecond timescales and can accommodate unsaturated fatty acids, overturning the view that the pocket is permanently occluded.

    Evidence Solution NMR, HDX-MS, molecular dynamics simulations

    PMID:30416039

    Open questions at the time
    • Identity of endogenous high-affinity ligands still unknown at this point
  12. 2019 High

    Crystal structures of DHI covalently bound to Cys566 in the Nurr1 LBD identified the first endogenous ligand for Nurr1—a dopamine metabolite—establishing a feedback mechanism linking dopamine catabolism to transcriptional maintenance of DA neuron identity.

    Evidence X-ray crystallography, biophysical binding assays, reporter assays, zebrafish model

    PMID:30853418

    Open questions at the time
    • Physiological concentrations of DHI in the brain and whether they reach activating levels not determined
    • Whether DHI activates Nurr1 in non-dopaminergic cells unknown
  13. 2019 High

    Crystal structures of the NR4A2 DBD dimer on NurRE DNA at 2.6–2.8 Å resolution defined the structural basis for homodimerization on inverted repeat elements, explaining how Nurr1 achieves diverse DNA-binding modes (monomer vs. dimer).

    Evidence X-ray crystallography with mutagenesis (V298K) and biochemical DNA-binding assays

    PMID:31723028

    Open questions at the time
    • Full-length structure including LBD-DBD communication not resolved
    • Heterodimer structure with RXR not determined
  14. 2020 High

    The crystal structure of PGA1 covalently adducted to Cys566 with a 21° shift of helix H12 provided the first high-resolution activation mechanism for Nurr1, showing that prostaglandin metabolites are bona fide endogenous agonists.

    Evidence 2.05 Å X-ray crystallography, mutagenesis, cell-based and in vivo MPTP model validation

    PMID:32451509

    Open questions at the time
    • Whether PGA1 or PGE1 reaches sufficient concentrations in the brain niche
    • Structural basis for inverse agonism or antagonism not established
  15. 2021 High

    NMR structural footprinting discriminating true LBD-binding ligands (amodiaquine, chloroquine) from non-binders among reported NR4A modulators clarified the pharmacological landscape and showed that many published 'Nurr1 agonists' act through Nurr1-independent mechanisms.

    Evidence Protein NMR footprinting, Nurr1-dependent and -independent reporter assays

    PMID:33289551

    Open questions at the time
    • Binding mode and co-crystal structure of chloroquine-class compounds not yet determined
    • In vivo selectivity profiles of validated LBD binders incomplete
  16. 2022 High

    Demonstrating that Nurr1 directly binds the HIV LTR and recruits the CoREST/HDAC1/G9a/EZH2 complex to silence HIV transcription in microglia extended the CoREST-dependent transrepression paradigm from inflammatory genes to viral latency maintenance.

    Evidence ChIP, DBD mutagenesis, transcriptomics in human microglial cells and iPSC-derived microglia

    PMID:35797416

    Open questions at the time
    • Whether Nurr1-mediated HIV silencing operates in other CNS reservoir cells (astrocytes, perivascular macrophages) unknown
    • Contribution relative to other latency-maintaining factors not quantified
  17. 2022 High

    Identification of the lncRNA LUCAT1 as a post-transcriptional regulator that controls NR4A2 mRNA splicing and stability via hnRNPs revealed a new layer of NR4A2 regulation that links lncRNA biology to inflammatory gene control.

    Evidence CHIRP-MS, RNA immunoprecipitation, RNA-seq in LUCAT1 KO cells

    PMID:36577072

    Open questions at the time
    • Whether LUCAT1-dependent splicing produces functionally distinct NR4A2 isoforms with altered activity
    • In vivo relevance of LUCAT1-NR4A2 axis in inflammation not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for how NR4A2 switches between transcriptional activation and CoREST-dependent transrepression in different cellular contexts; the full-length structure encompassing LBD-DBD allosteric communication; and the physiological ligand concentrations of DHI and prostaglandins in vivo.
  • No full-length NR4A2 structure available
  • Context-dependent switch between activation and repression mechanistically unresolved
  • In vivo ligand occupancy not measured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 13 GO:0003677 DNA binding 7 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3
Partners
FOXA2NCOR1NCOR2NFKB1 (P65/RELA)RCOR1TP53
Complex memberships
CoREST/HDAC1/G9a/EZH2 corepressor complex

Evidence

Reading pass · 41 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, resulting in clearance of NF-κB-p65 and transcriptional repression, thereby protecting dopaminergic neurons from inflammation-induced death. ChIP, co-immunoprecipitation, reporter assays, siRNA knockdown, primary cell culture, conditional knockout mice 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), activating Nurr1 transcriptional function in a Nurr1-dependent manner. X-ray crystallography (2.05 Å), biophysical binding assays, mutagenesis, cell-based reporter 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 underlying dopamine homeostasis. X-ray crystallography, biophysical binding assays, cell-based reporter assays, zebrafish model Cell chemical biology High 30853418
2018 The canonical ligand-binding pocket of Nurr1 LBD, although collapsed in crystal structures, is dynamic and exchanges between conformations on the microsecond-to-millisecond timescale, with high solvent accessibility that permits binding of unsaturated fatty acids. Solution NMR spectroscopy, hydrogen/deuterium exchange mass spectrometry, molecular dynamics simulations Structure High 30416039
2006 The Nurr1 LBD lacks a canonical co-activator-binding site but possesses an alternative hydrophobic surface on the opposite side from the classical site; site-directed mutagenesis of this region abolished or altered transcriptional activity, and Nurr1 LBD activity correlates with proteasome-dependent degradation. Crystal structure analysis, site-directed mutagenesis, transcriptional reporter assays, proteasome inhibitor experiments Journal of molecular endocrinology High 17032747
2019 Structural and biochemical analyses of NR4A2 DNA-binding domain (DBD) bound to Nur-responsive elements (NurREs) at 2.6-2.8 Å resolution revealed that two NR4A2-DBD molecules form a novel dimer interface on an inverted repeat element, and mutation of the interfacial residue V298K or DNA bases involved in the interaction abolished dimerization. X-ray crystallography, mutagenesis, biochemical DNA-binding assays, bioinformatics The Journal of biological chemistry High 31723028
2011 Nr4a2 directly binds regulatory regions of the Foxp3 locus and mediates permissive histone modifications, inducing Foxp3 expression and Treg differentiation; Nr4a2 deletion in T cells attenuates Treg induction and causes aberrant Th1 induction. ChIP, ectopic expression, siRNA knockdown, conditional T cell-specific knockout mice, in vitro suppression assays, colitis model Nature communications High 21468021
2008 NR4A2 augments promoter activities of IL-17 and IFN-γ genes in pathogenic T cells, and siRNA-mediated knockdown of NR4A2 significantly reduces IL-17 and IFN-γ production and attenuates the ability of encephalitogenic T cells to transfer EAE. Promoter-luciferase reporter assays, forced expression, siRNA knockdown, EAE adoptive transfer model PNAS High 18550828
2013 NR4A2 controls full Th17 differentiation via autocrine IL-21 signaling; NR4A2 knockdown prevents IL-17 and IL-21 production and reduces IL-23R expression, and the differentiation defect is rescued by exogenous IL-21. siRNA knockdown, in vitro Th17 differentiation assays, cytokine rescue experiments, in vivo siRNA treatment in EAE model PLoS ONE High 23437182
2003 Nurr1 directly regulates dopamine synthesis and storage in MN9D dopamine cells by increasing expression of aromatic L-amino acid decarboxylase (AADC) and vesicular monoamine transporter-2 (VMAT2); VMAT2 upregulation requires continuous Nurr1 expression, and AADC and VMAT2 are deregulated in midbrain DA cells of Nurr1 knockout embryos. Inducible Nurr1 cell line, DA content measurement, in situ hybridization in knockout embryos Experimental cell research High 12915123
2004 Nurr1 directly transactivates the osteocalcin (Ocn) gene in osteoblasts by binding as a monomer to an NBRE-like site in the proximal Ocn promoter; endogenous Nurr1 binds this site in chromatin immunoprecipitation assays, and mutation of the NBRE-like site abolishes Nurr1-dependent promoter activation. EMSA, ChIP, luciferase reporter assays with deletion/mutation analysis, adenoviral Nurr1 overexpression in primary osteoblasts The Journal of biological chemistry High 15485875
2012 Nurr1 directly regulates Pitx3 expression in dopaminergic neurons by binding to a non-canonical NBRE consensus sequence 5' of the Pitx3 gene; deletion of this sequence abolishes Nurr1-driven reporter expression, and direct Nurr1-Pitx3 promoter interaction was confirmed in dopaminergic cell cultures and embryonic midbrain tissue by ChIP. Reporter assays with deletion/mutation analysis, ChIP in cell cultures and embryonic tissue, dose-dependent overexpression PLoS ONE High 22363463
2010 Nurr1 regulates RET expression in adult rat midbrain dopaminergic neurons; adeno-associated vector-delivered anti-Nurr1 ribozyme knockdown reduces RET mRNA by ~77% and RET protein by ~47% in the substantia nigra; Nurr1 induces RET promoter transcription in a cell-type and concentration-dependent manner independent of NBRE elements. AAV-delivered ribozyme knockdown in vivo, qRT-PCR, microdialysis, reporter assays in cell lines Journal of neurochemistry Medium 20533997
2009 Nurr1 interacts with p53 and represses its transcriptional assembly and activity in an interaction-dependent, dose-dependent manner; Nurr1 overexpression decreases Bax expression and protects cells from doxorubicin-induced apoptosis. Co-immunoprecipitation, reporter assays, siRNA knockdown, overexpression, apoptosis assays Molecular cancer research Medium 19671681
2015 NR4A2 (Nurr1) transcriptionally activates arginase 1 expression by directly binding to its promoter in macrophages, and NR4A2 expression induced by TLR ligands (via PI3K-Akt signaling) promotes alternative (M2) macrophage polarization. ChIP, luciferase reporter assays, forced expression, siRNA knockdown, flow cytometry, adoptive transfer sepsis model The Journal of biological chemistry High 25953901
2014 PTH increases Nurr1 mRNA/protein levels prior to FGF23 induction; Nurr1 is essential for PTH-mediated FGF23 transcription and binds directly to functional Nurr1 binding sites in the FGF23 promoter as confirmed by ChIP in osteoblast-like cells. ChIP, luciferase reporter assays, siRNA knockdown, in vivo CKD rat model, immunohistochemistry Kidney international High 24940803
2011 NR4A2 directly transactivates the proximal MMP-13 promoter via its DNA binding domain; NR4A2 overexpression in synoviocytes promotes proliferation, survival, anchorage-independent growth, migration, and invasion; a DNA-binding domain point mutation abolishes MMP-13 transcriptional activation. Stable overexpression, lentiviral shRNA knockdown, luciferase reporter assays with mutation analysis, proliferation and invasion assays Arthritis and rheumatism High 22275273
2011 PGE2-induced NR4A2 increases fatty acid oxidation in colorectal cancer cells by inducing multiple FAO pathway genes via direct binding to Nur77-binding response elements (NBREs) in their regulatory regions, with concomitant recruitment of transcriptional coactivators. ChIP, NBRE reporter assays, siRNA knockdown, metabolic assays (fatty acid oxidation) The Journal of biological chemistry High 21757690
2008 Nurr1 transcriptionally regulates alpha-synuclein expression; decreased Nurr1 expression increases alpha-synuclein transcription, establishing Nurr1 as a transcriptional repressor of alpha-synuclein. Nurr1 overexpression and knockdown with mRNA level measurement, transcriptional assays Neuroreport Medium 18463503
2005 Multiple splice variants of Nurr1 (nurr1a, nurr1b, nurr1c, TINUR, nurr2, nurr2c) are produced by alternative RNA splicing in dopamine neurons; variants nurr1a, nurr1b, nurr1c, and TINUR have significantly reduced transcriptional activity compared with full-length Nurr1, while nurr2 and nurr2c act as dominant negatives. RT-PCR, sequencing, transfection-based transcriptional reporter assays in dopaminergic SK-N-AS cells Journal of neurochemistry Medium 16313515
2016 Nurr1 directly inhibits p21 (Waf1/Cip1) gene transcription by binding to the p21 promoter in a p53-independent manner, thereby promoting G1-S progression and intestinal epithelial cell proliferation after ischemia/reperfusion injury. ChIP, luciferase reporter assays with deletion/mutation analysis, siRNA knockdown, overexpression, cell cycle analysis Journal of molecular medicine High 27553040
2009 Nr4a2 is downstream of Brn3a in the developing habenula and mediates expression of a subset of Brn3a-regulated transcripts; Nr4a2 is expressed in a subset of habenular neurons and is required for their proper differentiation as shown by microarray analysis in Brn3a null embryos. Microarray analysis of Brn3a null embryos, in situ hybridization, genetic epistasis analysis The Journal of neuroscience Medium 19906978
2009 Nr4a2 is necessary and sufficient for specification of GABAergic amacrine cell subtype identity in the retina; its targeted inactivation eliminates dopaminergic and p57Kip2+ amacrine cells with a concomitant increase in calbindin+ amacrine cells, and misexpressed Nr4a2 promotes GABAergic AC differentiation. Conditional knockout mice, retroviral misexpression, dominant-negative construct, immunostaining The Journal of neuroscience High 19692620
2000 Three missense mutations in exon 3 of NURR1 identified in schizophrenic and manic-depressive patients each cause a ~30-40% reduction in in vitro transcriptional activity of NURR1 dimers. Direct sequencing, in vitro transcriptional activity assays with mutant constructs American journal of medical genetics Medium 11121187
2022 The lncRNA LUCAT1 controls splicing and stability of NR4A2 mRNA by interacting with heterogeneous nuclear ribonucleoproteins (hnRNP C, M, A2B1); cells lacking LUCAT1 show altered NR4A2 splicing, reduced and delayed NR4A2 expression, and elevated inflammatory gene expression. CHIRP-MS (comprehensive identification of RNA-binding proteins by mass spectrometry), RNA immunoprecipitation, RNA-seq, LPS stimulation with LUCAT1 KO PNAS High 36577072
2022 Nurr1 binds directly to consensus binding sites in the U3 region of the HIV LTR and recruits the CoREST/HDAC1/G9a/EZH2 repressor complex, suppressing HIV transcription in microglial cells; mutation of the Nurr1 DNA-binding domain blocks HIV suppression. ChIP, Nurr1 overexpression and knockdown, DNA-binding domain mutagenesis, transcriptomics in human microglial cells and iPSC-derived microglia PLoS pathogens High 35797416
2015 Nurr1 and Foxa2 physically interact and synergistically protect midbrain dopaminergic neurons against toxic insults both cell-autonomously (in mDA neurons) and in a paracrine mode (via forced expression in neighboring glia); combined AAV-mediated delivery of both factors markedly protected mDA neurons for at least 1 year in a PD mouse model. Co-immunoprecipitation, AAV-mediated gene delivery in PD mouse model, primary cell culture protection assays EMBO molecular medicine Medium 25759364
2020 Nurr1 directly binds to the RasGRP1 intron and regulates RasGRP1 expression; RasGRP1 in turn regulates the Ras-Raf-MEK-ERK signaling cascade in LPS-induced inflammation in microglia, providing a novel mechanism of Nurr1's anti-inflammatory function. ChIP-seq in LPS-stimulated BV2 cells, ChIP validation, siRNA knockdown, ERK pathway analysis Scientific reports High 32612143
2013 Nurr1 expression is regulated by neural activity through voltage-dependent calcium channels (VDCCs) and calcineurin in hippocampal and cortical neurons; calcineurin but not CaMK is critical for activity-dependent Nurr1 induction. Pharmacological inhibitors of VDCCs and calcineurin/CaMK, KCl/bicuculline/tetrodotoxin manipulations, Western blot/mRNA measurement Neuroscience letters Medium 24291696
2021 Amodiaquine, chloroquine, and cytosporone B bind directly to the Nurr1 LBD as confirmed by protein NMR structural footprinting; many other reported NR4A-active ligands do not bind Nurr1 LBD and show Nurr1-independent transcriptional effects. Protein NMR structural footprinting, transcriptional reporter assays with Nurr1-dependent and Nurr1-independent readouts Journal of medicinal chemistry High 33289551
2021 Nurr1 agonists (chloroquinolineamine analogs) activate Nurr1 transcriptional activity as monomer, homodimer, and heterodimer, and induce robust recruitment of NCoR1 and NCoR2 co-regulators to the Nurr1 LBD while promoting Nurr1 dimerization. TR-FRET co-regulator recruitment assays, dimerization assays, cellular reporter assays with response elements, gene expression in human astrocytes Journal of medicinal chemistry Medium 33629841
2019 Chloroquine activates Nurr1 function by two distinct mechanisms: direct binding to Nurr1's LBD to promote transcriptional activity, and upregulation of Nurr1 expression through the CREB signaling pathway; CQ activates TREG differentiation and Foxp3 expression in a Nurr1-dependent manner. Ligand-binding assays (LBD), reporter assays, siRNA and conditional knockout, in vivo IBD model Scientific reports Medium 31664129
2016 NR4A2 (Nurr1) NF-κB transrepression in astrocytes involves nuclear-specific inhibition of p65 binding at inflammatory gene promoters without preventing p65 nuclear translocation; combined RNAi knockdown of Nur77 and Nurr1 abolishes the anti-inflammatory effect of C-DIM5. ChIP-seq, quantitative PCR arrays, nuclear/cytoplasmic fractionation, siRNA combined knockdown, MPTP mouse astrocyte model Molecular pharmacology High 30111648
2021 NR4A2 suppresses CCR5 gene transcription by binding directly to its promoter in macrophages, and NR4A2 overexpression induces M2 macrophage polarization, protecting cardiomyocytes from high glucose-induced damage; this protective effect is blocked by CCR5 re-expression. Bioinformatic prediction, luciferase reporter assays, NR4A2 overexpression in vivo and in vitro, co-culture, flow cytometry Microvascular research Medium 34774582
2020 α-Synuclein overexpression (WT or A53T) reduces Nurr1 transcription by modulating the NF-κB binding site region (-605 to -418 bp) of the Nurr1 promoter; α-SYN downregulates NF-κB expression and decreases NF-κB binding to the Nurr1 promoter without affecting mRNA stability. Reporter assays with promoter deletion constructs, ChIP for NF-κB at Nurr1 promoter, mRNA stability assays, overexpression in cell lines Frontiers in molecular neuroscience Medium 32477062
2021 miR-409-3p directly targets Nr4a2 (validated by luciferase reporter assay); reduced Nr4a2 activates the NF-κB pathway, promoting microglial migration and activation; exosomal miR-409-3p from activated mast cells is transferred to microglia to mediate this effect. Luciferase 3'UTR reporter assay, Western blot for Nr4a2 and NF-κB, Transwell migration assays, fluorescent exosome transfer Journal of neuroinflammation Medium 33750404
2016 NR4A2 is part of a p53-miR-34 regulatory network: p53 activates endogenous miR-34 which suppresses NR4A2 through a validated miR-34 recognition element in the NR4A2 3'UTR; conversely, NR4A2 overexpression blocks p53 target gene induction including miR-34a, creating a feedback loop. 3'UTR reporter screen, miRNA recognition element mapping and mutagenesis, miR-34 overexpression, p53 pathway activation, cell proliferation assays Scientific reports Medium 27121375
2020 NR4A2 directly transactivates CDK4 gene expression by binding to the CDK4 promoter region, facilitating gastric cancer cell proliferation; H. pylori induces NR4A2 via the PI3K/AKT-Sp1 pathway, and Sp1 binds the Nurr1 promoter to activate its transcription. ChIP, luciferase reporter assays, siRNA knockdown and overexpression, in vivo xenograft EBioMedicine Medium 32114387
2021 NR4A2 promotes cytoprotective autophagy in pancreatic cancer cells via transcriptional regulation of ATG7 and ATG12; gemcitabine induces NR4A2 expression and the NR4A2-ATG7/ATG12 axis is required for gemcitabine-induced drug resistance. RNA-seq with CRISPR/Cas9 KO, KEGG pathway analysis, NR4A2 knockdown/overexpression, drug resistance assays Cancer research communications Medium 35582016
2019 NR4A2 transcriptional activity represses the TSP-1 promoter in synoviocytes independent of DNA binding; ectopic NR4A2 expression reduces TSP-1 mRNA/protein with concomitant increases in VEGF and IL-8; depletion of NR4A2 shifts the TSP-1/VEGF expression ratio. Promoter-luciferase assays with deletion analysis, stable NR4A2 overexpression and shRNA knockdown, ELISA, qRT-PCR The American journal of pathology Medium 23933487
2019 FoxM1 directly promotes Nurr1 transcription by binding to the Nurr1 promoter; FoxM1 inhibition downregulates Nurr1 expression and Ki-67, and FoxM1 overexpression promotes intestinal epithelial cell proliferation after hypoxia/reperfusion via Nurr1 activation. ChIP, luciferase reporter assays, siRNA knockdown, forced expression, in vivo I/R rat model Experimental & molecular medicine Medium 31704909

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 770 19345186
2002 Mutations in NR4A2 associated with familial Parkinson disease. Nature genetics 377 12496759
2005 The role of Nurr1 in the development of dopaminergic neurons and Parkinson's disease. Progress in neurobiology 265 16243425
2011 The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells. Nature communications 176 21468021
2003 Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells. Experimental cell research 140 12915123
2014 Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription. Kidney international 123 24940803
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
2009 Brn3a and Nurr1 mediate a gene regulatory pathway for habenula development. The Journal of neuroscience : the official journal of the Society for Neuroscience 100 19906978
2016 Nurr1-Based Therapies for Parkinson's Disease. CNS neuroscience & therapeutics 99 27012974
2005 RNR1, a 3'-5' exoribonuclease belonging to the RNR superfamily, catalyzes 3' maturation of chloroplast ribosomal RNAs in Arabidopsis thaliana. Nucleic acids research 99 15891117
2012 Differential roles for Nr4a1 and Nr4a2 in object location vs. object recognition long-term memory. Learning & memory (Cold Spring Harbor, N.Y.) 96 23161447
2019 Molecular Insights into NR4A2(Nurr1): an Emerging Target for Neuroprotective Therapy Against Neuroinflammation and Neuronal Cell Death. Molecular neurobiology 91 30684217
2018 Nurr1 (NR4A2) regulates Alzheimer's disease-related pathogenesis and cognitive function in the 5XFAD mouse model. Aging cell 83 30515963
2008 Inhibition of adipocyte differentiation by Nur77, Nurr1, and Nor1. Molecular endocrinology (Baltimore, Md.) 83 18945812
2000 Mutational and structural analyses of the ribonucleotide reductase inhibitor Sml1 define its Rnr1 interaction domain whose inactivation allows suppression of mec1 and rad53 lethality. Molecular and cellular biology 78 11074005
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
2015 Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease. EMBO molecular medicine 76 25759364
2015 Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis. The Journal of biological chemistry 75 25953901
2020 PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function. Nature chemical biology 74 32451509
2021 Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype. Clinical pharmacology and therapeutics 73 34032273
2008 Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines. Proceedings of the National Academy of Sciences of the United States of America 72 18550828
2013 Nuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signalling. PloS one 67 23437182
2001 Parathyroid hormone induces expression of the nuclear orphan receptor Nurr1 in bone cells. Endocrinology 65 11159837
2011 Ixr1 is required for the expression of the ribonucleotide reductase Rnr1 and maintenance of dNTP pools. PLoS genetics 63 21573136
2019 Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite. Cell chemical biology 57 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 54 33289551
2011 The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss. International journal of obesity (2005) 54 22143616
2011 Nuclear receptors Nur77 and Nurr1 modulate mesenchymal stromal cell migration. Stem cells and development 53 21480782
2020 The orphan nuclear receptor Nurr1 is responsive to non-steroidal anti-inflammatory drugs. Communications chemistry 52 36703399
2018 Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1. Structure (London, England : 1993) 46 30416039
2011 Nuclear orphan receptor NR4A2 modulates fatty acid oxidation pathways in colorectal cancer. The Journal of biological chemistry 46 21757690
2009 NGFI-B nuclear orphan receptor Nurr1 interacts with p53 and suppresses its transcriptional activity. Molecular cancer research : MCR 44 19671681
2012 Direct regulation of Pitx3 expression by Nurr1 in culture and in developing mouse midbrain. PloS one 43 22363463
2004 Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts. The Journal of biological chemistry 43 15485875
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 42 36948326
2018 Compensatory Expression of Nur77 and Nurr1 Regulates NF-κB-Dependent Inflammatory Signaling in Astrocytes. Molecular pharmacology 42 30111648
2009 A Nurr1 pathway for neuroprotection. Cell 42 19345183
2021 Exosomal miR-409-3p secreted from activated mast cells promotes microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway. Journal of neuroinflammation 41 33750404
2018 Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD Model. Molecular neurobiology 40 29429051
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
2010 Nurr1 regulates RET expression in dopamine neurons of adult rat midbrain. Journal of neurochemistry 39 20533997
2023 An optimized Nurr1 agonist provides disease-modifying effects in Parkinson's disease models. Nature communications 38 37463889
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 37 36577072
2016 Expression of mitochondrial genes MT-ND1, MT-ND6, MT-CYB, MT-COI, MT-ATP6, and 12S/MT-RNR1 in colorectal adenopolyps. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 36 27333991
2022 The role of NURR1 in metabolic abnormalities of Parkinson's disease. Molecular neurodegeneration 35 35761385
2019 Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases. Scientific reports 35 31664129
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
2020 α-Synuclein Negatively Regulates Nurr1 Expression Through NF-κB-Related Mechanism. Frontiers in molecular neuroscience 34 32477062
2016 Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease. Oncotarget 34 26862735
2018 NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder. Clinical genetics 33 29770430
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
2023 Development of a Potent Nurr1 Agonist Tool for In Vivo Applications. Journal of medicinal chemistry 32 37127285
2016 The orphan nuclear receptor NR4A2 is part of a p53-microRNA-34 network. Scientific reports 32 27121375
2020 Nurr1 performs its anti-inflammatory function by regulating RasGRP1 expression in neuro-inflammation. Scientific reports 31 32612143
2015 Age-and gender-related pattern of methylation in the MT-RNR1 gene. Epigenomics 30 26343273
2022 Medicinal Chemistry and Chemical Biology of Nurr1 Modulators: An Emerging Strategy in Neurodegeneration. Journal of medicinal chemistry 29 35797147
2021 Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review. Frontiers in molecular neuroscience 29 34880728
2013 Tumor necrosis factor inhibition modulates thrombospondin-1 expression in human inflammatory joint disease through altered NR4A2 activity. The American journal of pathology 29 23933487
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 Nuclear receptor 4A2 (NR4A2) is a druggable target for glioblastomas. Journal of neuro-oncology 28 31754919
2016 Nurr1 promotes intestinal regeneration after ischemia/reperfusion injury by inhibiting the expression of p21 (Waf1/Cip1). Journal of molecular medicine (Berlin, Germany) 28 27553040
2006 Characterization of the Nurr1 ligand-binding domain co-activator interaction surface. Journal of molecular endocrinology 28 17032747
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
2022 CB2 receptor activation inhibits the phagocytic function of microglia through activating ERK/AKT-Nurr1 signal pathways. Acta pharmacologica Sinica 27 35132190
2008 Altered expression of 12S/MT-RNR1, MT-CO2/COX2, and MT-ATP6 mitochondrial genes in prostate cancer. The Prostate 27 18409190
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 26 37384814
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
2020 HPV-induced Nurr1 promotes cancer aggressiveness, self-renewal, and radioresistance via ERK and AKT signaling in cervical cancer. Cancer letters 25 33010383
2015 Role of Nurr1 in the Generation and Differentiation of Dopaminergic Neurons from Stem Cells. Neurotoxicity research 25 26678495
2005 Dopamine neurons express multiple isoforms of the nuclear receptor nurr1 with diminished transcriptional activity. Journal of neurochemistry 25 16313515
2022 Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson's Disease. International journal of molecular sciences 24 36555826
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
2021 Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1. Experimental & molecular medicine 23 33479411
2019 NURR1 Impairment in Multiple Sclerosis. International journal of molecular sciences 23 31574937
2015 Orphan nuclear receptor NR4A2 induces transcription of the immunomodulatory peptide hormone prolactin. Journal of inflammation (London, England) 22 25717285
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 21 35797416
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 21 31811028
2013 Sen1p contributes to genomic integrity by regulating expression of ribonucleotide reductase 1 (RNR1) in Saccharomyces cerevisiae. PloS one 21 23741394
2019 Transplantation of Nurr1-overexpressing neural stem cells and microglia for treating parkinsonian rats. CNS neuroscience & therapeutics 20 31087449
2013 Nurr1 expression is regulated by voltage-dependent calcium channels and calcineurin in cultured hippocampal neurons. Neuroscience letters 20 24291696
2021 Hepatic stellate cells promote intrahepatic cholangiocarcinoma progression via NR4A2/osteopontin/Wnt signaling axis. Oncogene 19 33742120
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
2019 Hydroxychloroquine antiparkinsonian potential: Nurr1 modulation versus autophagy inhibition. Behavioural brain research 19 30797853
2019 The transcription factor FoxM1 activates Nurr1 to promote intestinal regeneration after ischemia/reperfusion injury. Experimental & molecular medicine 19 31704909
2017 Activated Notch signaling augments cell growth in hepatocellular carcinoma via up-regulating the nuclear receptor NR4A2. Oncotarget 19 28423575
2021 Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson's Disease. A Systematic Review. Frontiers in aging neuroscience 18 33716718
2021 Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1. ACS chemical biology 18 34165961
2020 The mutation frequencies of GJB2, GJB3, SLC26A4 and MT-RNR1 of patients with severe to profound sensorineural hearing loss in northwest China. International journal of pediatric otorhinolaryngology 18 32645618
2019 Epigenetic regulation of immediate-early gene Nr4a2/Nurr1 in the medial habenula during reinstatement of cocaine-associated behavior. Neuropharmacology 18 30998946
2021 Nuclear Receptor 4A2 (NR4A2/NURR1) Regulates Autophagy and Chemoresistance in Pancreatic Ductal Adenocarcinoma. Cancer research communications 17 35582016
2020 Orphan nuclear receptor Nurr1 promotes Helicobacter pylori-associated gastric carcinogenesis by directly enhancing CDK4 expression. EBioMedicine 17 32114387
2021 NR4A2 alleviates cardiomyocyte loss and myocardial injury in rats by transcriptionally suppressing CCR5 and inducing M2 polarization of macrophages. Microvascular research 16 34774582
2010 Cytokines induce NF-κB, Nurr1 and corticotropin-releasing factor gene transcription in hypothalamic 4B cells. Neuroimmunomodulation 16 20407282