Affinage

NR4A3

Nuclear receptor subfamily 4 group A member 3 · UniProt Q92570

Length
626 aa
Mass
68.2 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR4A3 (NOR-1) is a ligand-independent orphan nuclear receptor that acts as a sequence-specific transcriptional regulator induced rapidly by cell-activation signals, coordinating cell-fate, metabolic, and inflammatory programs across hematopoietic, immune, vascular, and endocrine tissues (PMID:17515897, PMID:33147449, PMID:38629274). As a transcription factor it binds defined response elements in target promoters and enhancers to activate or repress genes: it directly drives a hematopoietic-specific Cebpa enhancer and antagonizes NF-κB-regulated inflammatory loci to restrain HSC proliferation, and its loss together with NR4A1 produces lethal acute myeloid leukemia, establishing it as a myeloid tumor suppressor (PMID:17515897, PMID:29343483). In other settings it binds NBRE elements to control vitronectin in vascular smooth muscle and glycolytic genes ALDOA and PFKL, the latter feeding a glycolysis→histone-lactylation→PHOSPHO1 cascade that drives vascular calcification (PMID:28666984, PMID:38629274). Its expression is gated by upstream pathways including TCR/calcineurin–NFAT1 signaling, p53, the homeodomain factor Nkx6.1, PKA, and muscle contraction, and is further tuned post-transcriptionally by FTO-dependent m6A methylation and by multiple microRNAs (PMID:24706823, PMID:30455429, PMID:33147449, PMID:28066330, PMID:35059772). In immune cells NR4A3 governs differentiation and effector states: it controls CD103+ and monocyte-derived dendritic cell development and migration via FOXO1/CCR7 and IKKβ/IRF4/IRF8 axes, programs early CD8+ T cell memory-versus-effector fate through chromatin accessibility at bZIP motifs, and contributes to CAR-T exhaustion in an NFAT-driven program (PMID:27820700, PMID:31285338, PMID:32913051, PMID:36350986, PMID:28893954). In pancreatic β-cells it has dual roles — promoting Nkx6.1-driven proliferation and supporting mitochondrial respiration and insulin secretion, while also acting cytotoxically when cytokine-activated and translocated to mitochondria to impair glucose-stimulated insulin secretion (PMID:24706823, PMID:27221116, PMID:30696767, PMID:31936632). NR4A3 also engages apoptotic machinery, being a p53 target that induces PUMA/Bax and sequesters Bcl-2, and is oncogenically activated by enhancer hijacking at t(4;9) and by the EWSR1/NR4A3 fusion, where it cooperates physically with MYB to drive transformation (PMID:30664630, PMID:18855877, PMID:30455429, PMID:32867110).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 2007 High

    Established NR4A3 as a genetically required tumor suppressor in the myeloid lineage, answering whether the orphan receptor has a non-redundant role in hematopoietic homeostasis.

    Evidence Double Nr4a1/Nr4a3 knockout mice developing lethal AML with HSC expansion and defective apoptotic signaling

    PMID:17515897

    Open questions at the time
    • Redundancy with NR4A1 leaves NR4A3-specific transcriptional targets undefined in this study
    • Direct chromatin targets not yet identified
  2. 2018 High

    Resolved the molecular basis of NR4A tumor suppression by showing direct chromatin binding to activate Cebpa and antagonize NF-κB inflammatory genes.

    Evidence Conditional double knockout with ChIP and enhancer-binding assays in HSCs

    PMID:29343483

    Open questions at the time
    • Does not separate NR4A1 from NR4A3 contributions at each locus
    • Whether C/EBPα activation is direct or cooperative left open
  3. 2018 High

    Placed NR4A3 within the p53 apoptotic axis, identifying both an upstream regulator and a protein-level effector mechanism.

    Evidence ChIP of p53 at the NR4A3 promoter plus co-IP of NR4A3 with Bcl-2 and apoptosis assays in cancer cells

    PMID:30455429

    Open questions at the time
    • Bcl-2 sequestration shown by single co-IP without structural mapping
    • Cell-type generality of the p53→NR4A3 axis untested
  4. 2009 High

    Demonstrated that fusion-driven NR4A3 retains transactivation function by directly binding the PPARG promoter in chondrosarcoma.

    Evidence EMSA, reporter assays and identification of an NR4A3 response element for the EWSR1/NR4A3 fusion

    PMID:18855877

    Open questions at the time
    • Role of the C-terminally truncated isoform inferred, not functionally proven in vivo
    • Genome-wide fusion targets not mapped
  5. 2019 High

    Showed NR4A3 can be oncogenic through enhancer hijacking, contrasting its tumor-suppressor role in myeloid cells with a proliferative role in salivary gland tissue.

    Evidence Genomic characterization of t(4;9), RNA-seq and NR4A3 overexpression with proliferation readouts in mouse salivary gland cells

    PMID:30664630

    Open questions at the time
    • Why NR4A3 is oncogenic here versus tumor-suppressive in HSCs not mechanistically reconciled
    • Direct transformation targets in salivary cells not enumerated
  6. 2020 Medium

    Identified the protein partner that confers context-specific oncogenicity, showing NR4A3 physically cooperates with MYB to drive transformation.

    Evidence LBD-DBD interaction assay and cooperative transformation/invasion assays in acinic cell carcinoma models

    PMID:32867110

    Open questions at the time
    • Interaction shown in single lab without reciprocal in vivo validation
    • Cooperative gene set not linked to specific phenotypic drivers
  7. 2014 High

    Defined NR4A3 as the effector of Nkx6.1-driven β-cell proliferation through a cell-cycle activation network.

    Evidence Islet gain/loss-of-function and knockout mice with E2F1, cyclin E1, APC/UBE2C and p21 readouts

    PMID:24706823

    Open questions at the time
    • Direct chromatin targets among cell-cycle genes not mapped
    • Reconciliation with anti-proliferative roles in HSCs unaddressed
  8. 2014 Medium

    Showed NR4A3 represses insulin gene expression in a domain-dependent manner, indicating direct transcriptional control of β-cell identity genes.

    Evidence Adenoviral overexpression with AF1/DBD deletion mutants in MIN6 cells and Pdx1/NeuroD1 readouts

    PMID:24638142

    Open questions at the time
    • Overexpression-only model; physiological relevance uncertain
    • Direct vs indirect repression of Pdx1/NeuroD1 not resolved
  9. 2016 High

    Established a positive role for NR4A3 in β-cell mitochondrial respiration and insulin secretion, complicating its overall metabolic role.

    Evidence β-cell-specific double knockout with Seahorse respiration, ATP, GSIS and Idh3g/Sdhb expression readouts

    PMID:27221116

    Open questions at the time
    • NR4A1 vs NR4A3 contributions not separated
    • Mechanism of dehydrogenase regulation (direct/indirect) unknown
  10. 2019 High

    Revealed an opposing cytotoxic role for NR4A3 in β-cells under inflammatory/glucotoxic conditions, linking it to type 2 diabetes pathology.

    Evidence Nr4a3 knockout mice, gain/loss-of-function in INS cells and human islets, apoptosis assays, diabetic islet expression

    PMID:30696767

    Open questions at the time
    • Reconciliation of pro-proliferative/pro-respiration versus pro-apoptotic roles unresolved
    • Stimulus-dependent target switch not defined
  11. 2020 Medium

    Provided a subcellular mechanism for NR4A3 cytotoxicity by showing cytokine-induced mitochondrial translocation impairs respiration.

    Evidence Subcellular fractionation and imaging with mitochondrial function and mitophagy readouts in β-cells

    PMID:31936632

    Open questions at the time
    • Translocation mechanism and mitochondrial binding partners unknown
    • Overexpression model from a single lab
  12. 2016 High

    Established NR4A3 as essential for CD103+ DC migration via an AKT-FOXO1-CCR7 axis and mitochondrial maintenance.

    Evidence Knockout and mixed-chimera studies with in vivo migration and FOXO1/AKT signaling analysis

    PMID:27820700

    Open questions at the time
    • Whether FOXO1 regulation is transcriptional or post-translational not fully resolved
    • Direct NR4A3 targets in DCs not mapped
  13. 2017 Medium

    Identified NR4A3 as a transcriptional regulator of DC activation through control of IKKβ, IRF4 and IRF8.

    Evidence siRNA knockdown in bone marrow-derived DCs with TLR stimulation, epistasis knockdowns and T cell co-culture

    PMID:28893954

    Open questions at the time
    • Knockdown-only without genetic confirmation
    • Direct binding to IKKβ/IRF loci not shown
  14. 2019 High

    Showed NR4A3 directs monocyte differentiation toward MoDCs, controlling anti-bacterial CD8+ T cell responses.

    Evidence Knockout mice, LPS stimulation, RNA-seq and in vivo infection/CD8 response assays

    PMID:31285338

    Open questions at the time
    • Transcriptional targets driving the MoDC-versus-macrophage switch not defined
    • Mechanism of lineage skewing unknown
  15. 2020 High

    Demonstrated NR4A3 programs early CD8+ T cell memory-versus-effector fate via chromatin accessibility at bZIP motifs.

    Evidence NR4A3-deficient mice, adoptive transfer, scRNA-seq, ATAC-seq and cytokine assays

    PMID:32913051

    Open questions at the time
    • Direct binding at bZIP motif regions versus indirect chromatin remodeling not separated
    • Relationship to Fos/Jun cofactors mechanistically open
  16. 2020 High

    Placed NR4A3 in an NFAT-driven exhaustion program reciprocal to BLIMP1, with translational relevance for CAR-T engineering.

    Evidence Single and double PRDM1/NR4A3 knockout CAR-T cells, scRNA-seq, in vivo tumor models and clinical samples

    PMID:36350986

    Open questions at the time
    • Direct NR4A3 targets in the exhaustion program not enumerated
    • Epistasis mechanism with PRDM1 incompletely defined
  17. 2020 High

    Defined the upstream signaling logic of NR4A3 induction, showing strict dependence on calcineurin and NFAT1 with cognate peptide:MHC requirement.

    Evidence Nr4a3-Timer/Tocky reporter mice, calcineurin inhibition, NFAT1 binding assays and TCR pathway inhibitors

    PMID:33147449

    Open questions at the time
    • Direct vs cooperative NFAT1 binding at Nr4a3 not structurally defined
    • Downstream consequences of differential signal strength not mapped
  18. 2017 Medium

    Extended NR4A3 induction to PKA signaling in neutrophils and linked it to survival.

    Evidence Human neutrophil gene arrays, PKA agonists, siRNA and zebrafish morpholino knockdown

    PMID:28637666

    Open questions at the time
    • NR4A3 versus NR4A2 contributions unresolved
    • Pro-survival transcriptional targets not identified
  19. 2014 Medium

    Defined a role for Nr4a3 in regulating mast cell mediator secretion and allergen responsiveness.

    Evidence Knockout-based functional studies with IgE receptor activation and tryptase/cytokine readouts

    PMID:24586680

    Open questions at the time
    • Direct targets controlling tryptase and cytokine genes not identified
    • Mechanism of negative regulation unknown
  20. 2017 Medium

    Showed NR4A3 demethylation at its promoter is the most exercise-responsive transcriptional event in skeletal muscle.

    Evidence Acute human exercise study and electrical pulse stimulation of C2C12 myotubes with bisulfite sequencing

    PMID:28066330

    Open questions at the time
    • Functional consequence of muscle NR4A3 induction not addressed
    • Demethylase responsible not identified
  21. 2017 Medium

    Demonstrated that NR4A3 activation is pro-apoptotic in lymphoma, supporting a tumor-suppressive function with therapeutic potential.

    Evidence Stable transduction and pharmacological activation in lymphoma lines with NSG xenografts and pro-apoptotic gene analysis

    PMID:28249906

    Open questions at the time
    • Direct binding at pro-apoptotic gene loci not shown
    • Single-lab study without genetic loss-of-function
  22. 2019 Medium

    Identified a pro-inflammatory, NF-κB-enhancing role for NR4A3 in osteoarthritis chondrocytes, contrasting its NF-κB-antagonizing role in HSCs.

    Evidence Reciprocal overexpression/knockdown in chondrocytes with IL-1β stimulation and NF-κB analysis

    PMID:31701670

    Open questions at the time
    • Direction of NF-κB regulation opposite to HSC findings unexplained
    • Direct targets not defined
  23. 2018 Medium

    Placed NR4A3 in trophoblast syncytialization as a cAMP/PKA-induced negative regulator opposing STAT5B.

    Evidence siRNA knockdown of STAT5B and NR4A3 in BeWo cells with fusion and syncytin2 readouts

    PMID:29377304

    Open questions at the time
    • Knockdown-only without genetic confirmation
    • Direct regulation of syncytin2/CGB not demonstrated
  24. 2016 Medium

    Identified intragenic CpG hypermethylation, not promoter methylation, as the mechanism silencing NR4A3 in AML.

    Evidence Bisulfite sequencing of AML cells, DNMT inhibitor restoration and histone mark analysis

    PMID:27697661

    Open questions at the time
    • Mechanistic link between exon 3 methylation and silencing not fully defined
    • Causality of histone mark loss versus methylation unresolved
  25. 2020 Medium

    Showed FTO-dependent m6A demethylation post-transcriptionally controls NR4A3 in vascular smooth muscle proliferation.

    Evidence MeRIP with FTO knockdown/overexpression and catalytic-mutant control under AngII stimulation

    PMID:35059772

    Open questions at the time
    • m6A reader mediating NR4A3 mRNA fate not identified
    • Effect on transcript stability versus translation not separated
  26. 2020 Medium

    Defined microRNA control of NR4A3 across immune and vascular contexts, linking its levels to Treg differentiation and PASMC proliferation.

    Evidence Dual-luciferase validation of miR-106b-5p, miR-638 and miR-146a targeting NR4A3 with in vivo disease models

    PMID:32057731 PMID:32323598 PMID:35922863

    Open questions at the time
    • Direct NR4A3 transcriptional targets (Foxp3, cyclin D1) not shown to be direct
    • Single-lab miRNA studies without orthogonal confirmation
  27. 2024 High

    Established a direct chromatin-to-metabolite mechanism by which NR4A3 drives vascular calcification through glycolysis and histone lactylation.

    Evidence Knockout mice, CUT&TAG at ALDOA/PFKL promoters, metabolic assays and PHOSPHO1 pharmacological rescue

    PMID:38629274

    Open questions at the time
    • Mechanism of NR4A3 activation in calcifying cells not defined
    • Specificity of lactylation-driven PHOSPHO1 induction not fully mapped
  28. 2024 Medium

    Showed NR4A3 protects diabetic atria by preserving mitochondrial Sdha-dependent metabolism, extending its metabolic guardian role to cardiac tissue.

    Evidence Knockout and AAV9 overexpression mouse models with RNA-seq, metabolomics and electrophysiology

    PMID:39098108

    Open questions at the time
    • Whether Sdha is a direct NR4A3 target not established
    • Tissue-specific reconciliation with β-cell cytotoxic roles open

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how NR4A3 switches between tumor-suppressive/pro-apoptotic, oncogenic, NF-κB-antagonizing and NF-κB-promoting, and metabolically protective versus cytotoxic outputs across tissues.
  • No unifying model of cofactor- or context-dependent target selection
  • Genome-wide direct target catalog across cell types lacking
  • Ligand/activation-state control of nuclear-versus-mitochondrial function undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Partners
BCL2EWSR1MYBNFAT1NR4A1P53

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Abrogation of both NR4A3 (Nor-1) and NR4A1 (Nur77) in mice leads to rapidly lethal acute myeloid leukemia (AML), involving abnormal expansion of hematopoietic stem cells and myeloid progenitors, decreased expression of AP-1 transcription factors JunB and c-Jun, and defective extrinsic apoptotic (Fas-L and TRAIL) signaling, identifying NR4A3 as a critical tumor suppressor of myeloid leukemogenesis. Genetic knockout (double Nr4a1/Nr4a3 knockout mice), flow cytometry, gene expression analysis, functional apoptosis assays Nature medicine High 17515897
2018 NR4A1 and NR4A3 restrict HSC proliferation through two direct mechanisms: (1) binding to a hematopoietic-specific Cebpa enhancer to activate C/EBPα transcription and drive an antiproliferative network; (2) occupying regulatory regions of NF-κB-regulated inflammatory cytokines to antagonize NF-κB signaling activation. Conditional knockout mouse (CDKO), molecular profiling, chromatin immunoprecipitation (ChIP), enhancer binding assays, NF-κB pathway analysis Blood High 29343483
2019 Enhancer hijacking via recurrent t(4;9)(q13;q31) chromosomal rearrangement translocates active enhancer regions from the SCPP gene cluster to the region upstream of NR4A3, causing NR4A3 overexpression in acinic cell carcinoma (AciCC). NR4A3 overexpression in mouse salivary gland cells increases expression of known NR4A3 target genes and stimulates cell proliferation. Genomic sequencing, chromatin analysis, RNA-seq, transcription factor binding motif analysis, NR4A3 overexpression in mouse salivary gland cells, cell proliferation assays Nature communications High 30664630
2009 The EWSR1/NR4A3 fusion protein in extraskeletal myxoid chondrosarcoma (EMC) activates transcription of PPARG through a DNA response element in the PPARG promoter. An endogenous NR4A3 isoform lacking the C-terminal domain is highly expressed in EWSR1/NR4A3-positive tumors and may negatively regulate the fusion protein's activity on the PPARG promoter. Expression microarray, western blot, immunohistochemistry, bioinformatic identification of NR4A3 response element, band-shift (EMSA) experiments, transient transfection/reporter assays, co-transfection experiments The Journal of pathology High 18855877
2014 NR4A3 is downstream of the homeodomain transcription factor Nkx6.1 in pancreatic β-cells and is both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Nr4a3 (with Nr4a1) increases expression of E2F1 and cyclin E1, and induces components of the anaphase-promoting complex (including UBE2C), resulting in degradation of the cell cycle inhibitor p21. Islet overexpression, siRNA knockdown, knockout mice, gene expression analysis, cell cycle analysis Proceedings of the National Academy of Sciences of the United States of America High 24706823
2016 Deletion of Nr4a1 and Nr4a3 in pancreatic β-cells impedes mitochondrial respiration and reduces glucose-stimulated insulin secretion, associated with decreased expression of mitochondrial dehydrogenase subunits Idh3g and Sdhb and reduced ATP production, without reducing mitochondrial content. β-cell-specific knockout, mitochondrial respiration assays (Seahorse), glucose-stimulated insulin secretion assays, gene expression analysis American journal of physiology. Endocrinology and metabolism High 27221116
2018 NR4A3 is a direct transcriptional target of p53: p53 directly binds the NR4A3 promoter and induces its transcription. NR4A3 overexpression promotes apoptosis by augmenting expression of pro-apoptotic genes PUMA and Bax. NR4A3 also physically interacts with anti-apoptotic Bcl-2 protein, sequestering it from inhibiting apoptosis. ChIP assay (p53 binding to NR4A3 promoter), reporter assays, NR4A3 overexpression and knockdown in cancer cells, apoptosis assays, co-immunoprecipitation (NR4A3-Bcl-2 interaction) Oncogene High 30455429
2016 NR4A3 is essential for migration of CD103+ dendritic cells to lymph nodes through regulation of CCR7 surface expression. Nr4a3-deficient CD103+ DCs show markedly reduced CCR7, mediated by reduced FOXO1 protein levels through an AKT-dependent mechanism. NR4A3 also maintains homeostatic mitochondrial function in CD103+ DCs. Nr4a3 knockout mice, mixed-chimera studies (cell-intrinsic defect), flow cytometry, in vivo DC migration assays, FOXO1/AKT signaling analysis, in vivo TLR7 agonist and bacterial infection models The Journal of clinical investigation High 27820700
2019 NR4A3 is required for the proper differentiation of monocyte-derived dendritic cells (MoDCs) but not other DC types. Nr4a3-/- mice show severely impaired generation of DC-SIGN+ MoDCs in response to LPS, resulting in inability to mount optimal CD8+ T cell responses to gram-negative bacteria. Transcriptomic analysis shows NR4A3 skews monocyte differentiation toward MoDCs at the expense of macrophages. Nr4a3 knockout mice, flow cytometry, LPS stimulation, RNA-seq/transcriptomic analysis, in vivo bacterial infection models, CD8+ T cell response assays Proceedings of the National Academy of Sciences of the United States of America High 31285338
2020 NR4A3 programs early CD8+ T cell differentiation fate: NR4A3-deficient murine CD8+ T cells preferentially differentiate into memory precursor and central memory cells while also producing more cytokines. This is mediated through early influence on the memory transcriptional program and chromatin accessibility at bZIP transcription factor motifs, impacting Fos/Jun target gene transcription. NR4A3-deficient mouse model, adoptive transfer experiments, single-cell transcriptomics, ATAC-seq (chromatin accessibility), cytokine production assays Proceedings of the National Academy of Sciences of the United States of America High 32913051
2020 NR4A3 and BLIMP1 (PRDM1) reciprocally regulate CAR T cell stemness and exhaustion. Dual knockout of PRDM1 and NR4A3 skews CAR T cell phenotypes from TIM-3+CD8+ toward TCF1+CD8+, countering exhaustion and improving antitumor responses in solid tumors — an effect not achieved by single knockouts alone. In PRDM1-deficient cells, NR4A3 is part of an NFAT-driven compensatory exhaustion program. PRDM1 and NR4A3 single and double knockout in CAR T cells, scRNA-seq, epigenetic profiling, in vivo mouse tumor models, clinical trial CAR T cell samples Science translational medicine High 36350986
2020 Nr4a1 and Nr4a3 reporter mice show differential sensitivity to TCR signal strength and duration. Nr4a2 and Nr4a3 expression is regulated downstream of calcineurin and requires NFAT1 (which directly binds Nr4a2 and Nr4a3 loci), while Nr4a1 shows redundancy for NFAT1. Nr4a3-Tocky requires cognate peptide:MHC interactions for expression, whereas Nr4a1-GFP responds to tonic signals during T cell development. Nr4a1-GFP and Nr4a3-Timer (Tocky) reporter mice, calcineurin inhibitor treatment, NFAT1 binding assays, TCR signaling pathway inhibitors (Src family kinase inhibitors), flow cytometry Cell reports High 33147449
2017 NR4A2 and NR4A3 are upregulated downstream of PKA activation in neutrophils (induced by adenosine, prostaglandin E2, and direct PKA agonists) and positively regulate neutrophil survival. Antisense knockdown of NR4A2 and NR4A3 homologs in zebrafish larvae significantly reduces absolute neutrophil number without affecting migration. Human neutrophil gene arrays, PKA agonists, siRNA knockdown, antisense morpholino knockdown in zebrafish, apoptosis/survival assays, flow cytometry Blood Medium 28637666
2017 NR4A3 knockdown in bone marrow-derived dendritic cells suppresses TLR-mediated upregulation of CD80, CD86, IL-10, IL-6, and IL-12, and reduces T cell proliferation and IL-2 production. Mechanistically, NR4A3 regulates DC activation via controlling expression of IKKβ, IRF4, and IRF8 — where IKKβ mediates IL-10/IL-6 induction and IRF4/IRF8 mediate IL-12 induction. siRNA knockdown in bone marrow-derived DCs, LPS/CpG/poly(I:C) stimulation, qRT-PCR, western blot, T cell co-culture assays Journal of immunology Medium 28893954
2017 NR4A3 (NOR-1) directly regulates vitronectin (VTN) in human vascular smooth muscle cells (VSMCs): NOR-1 binds the NBRE(-202/-195) site in the VTN promoter (identified by deletion/site-directed mutagenesis, EMSA, and ChIP). NOR-1-induced VTN secretion promotes VSMC migration. Lentiviral NOR-1 overexpression and siRNA silencing, deletion and site-directed mutagenesis, EMSA, ChIP, VTN blocking antibody experiments, cell migration assays FASEB journal High 28666984
2019 Nor1/Nr4a3 negatively regulates β-cell mass: Nor1 knockout mice display increased β-cell mass and improved glucose tolerance. Nor1 expression is increased by pro-inflammatory cytokines and elevated glucose in β-cells. Nor1 overexpression causes apoptosis in INS and human islet cells, while siRNA knockdown prevents cytokine-induced β-cell death. Nor1 expression is elevated in islets of type 2 diabetic individuals. Nr4a3 knockout mice, histological analysis, gain/loss-of-function (overexpression and siRNA) in INS cells and human islets, apoptosis assays, glucose tolerance tests The Journal of biological chemistry High 30696767
2020 Nor1/Nr4a3 is predominantly cytoplasmic in pancreatic β-cells and undergoes mitochondrial translocation upon activation by pro-inflammatory cytokines. Mitochondrial localization of Nor1 reduces glucose oxidation, lowers ATP production rates, inhibits glucose-stimulated insulin secretion, and provokes mitochondrial fragmentation via mitophagy. Subcellular fractionation, fluorescence microscopy, Nor1 overexpression in INS832/13 cells and human β-cells, mitochondrial function assays, western blot for mitophagy markers Cells Medium 31936632
2016 Muscle contraction (exercise) induces rapid demethylation at the Nr4a3 promoter preceded by hydroxymethylation: electrical pulse stimulation of C2C12 myotubes causes demethylation at 60 min and re-methylation at 120 min, with hydroxymethylation elevated immediately after stimulation. Nr4a3 was identified as the most exercise-responsive gene in acute exercise in humans. Acute human exercise study, electrical pulse stimulation (EPS) of C2C12 myotubes, targeted bisulfite sequencing, gene expression analysis Frontiers in endocrinology Medium 28066330
2014 NR4A3 overexpression in pancreatic MIN6 β-cells reduces insulin gene (Ins1, Ins2) transcription and insulin protein secretion. This effect requires both the AF1 activation domain and the DNA-binding domain of NR4A3. NR4A3 reduces insulin gene expression by downregulating transcriptional regulators Pdx1 and NeuroD1. Adenoviral overexpression of NR4A3 and deletion mutants in MIN6 cells, qPCR, insulin secretion assays, ER stress induction PloS one Medium 24638142
2018 NR4A3 knockdown in human BeWo trophoblast cells increases FSK-induced cell fusion and expression of CGB and syncytin2, whereas STAT5B knockdown decreases these. cAMP-PKA signaling upregulates both STAT5B and NR4A3, but NR4A3 acts as a negative regulator of syncytialization by decreasing syncytin2 expression, opposing STAT5B's positive effect. siRNA knockdown of STAT5B and NR4A3 in BeWo cells, microarray analysis, FSK stimulation, cell fusion assays, syncytialization marker expression Journal of cellular biochemistry Medium 29377304
2019 NR4A3 acts pro-inflammatory in osteoarthritis chondrocytes: NR4A3 overexpression enhances IL-1β-induced expression of matrix-degrading enzymes (MMP-3, MMP-9, iNOS, COX-2) and NF-κB activation, while NR4A3 knockdown reduces these effects. NR4A3 overexpression also enhances starvation-induced chondrocyte apoptosis. Lentiviral NR4A3 overexpression, siRNA knockdown in chondrocytes, IL-1β stimulation, western blot, qRT-PCR, NF-κB pathway analysis, apoptosis assays Journal of cellular and molecular medicine Medium 31701670
2014 Nuclear receptor Nr4a3 regulates mast cell cytokine/chemokine secretion following high-affinity IgE receptor activation and negatively affects mast cell tryptase transcript and protein levels, as well as the mast cell's responsiveness to allergen. Nr4a3 knockout-based functional studies in mast cells, IgE receptor activation assays, cytokine/chemokine measurement, tryptase expression analysis PloS one Medium 24586680
2016 Intragenic DNA hypermethylation at CpG sites in exon 3 of NR4A3 (but not the promoter region) silences NR4A3 expression in AML. A DNA methyltransferase inhibitor restores NR4A3 expression following reduction in methylation at intragenic CpG sites. Exon 3 contains histone marks (H3K4me1, H2A.Z) in non-malignant cells that are absent in leukemia cells with CpG hypermethylation. Bisulfite sequencing of AML cell lines and primary AML cells, DNA methyltransferase inhibitor treatment, ChIP-seq/in silico histone mark analysis Leukemia research Medium 27697661
2017 NR4A3 overexpression or pharmacological activation in aggressive lymphoma cell lines induces apoptosis, abrogates tumor growth in NSG xenograft mouse models, and drives apoptosis by inducing pro-apoptotic genes BAK, PUMA, BIK, BIM, BID, and TRAIL (similar to NR4A1). Stable NR4A3 transduction of lymphoma cell lines, NSG xenograft mouse model, pharmacological NR4A3 activation, transcript analysis, apoptosis assays Cancer research Medium 28249906
2020 Oncogenic NR4A3 interacts physically with the MYB DNA-binding domain via its ligand-binding domain in acinic cell carcinoma. Co-expression of NR4A3 and MYB cooperatively regulates a distinct gene set and is more potent at inducing transformation (anchorage-independent growth, invasiveness) than either alone. RNA-seq of AciCC samples, protein-protein interaction assay (LBD-DBD binding), transformation assays, anchorage-independent growth, invasion assays Cancers Medium 32867110
2020 miR-106b-5p negatively regulates NR4A3 expression (validated by dual-luciferase reporter assay), and NR4A3 regulates Treg differentiation via Foxp3. Reduced NR4A3 (by miR-106b-5p) leads to decreased Foxp3 and TGF-β expression, contributing to Treg/Th17 imbalance in immune thrombocytopenic purpura. qRT-PCR, western blot, dual-luciferase reporter assay for miR-106b-5p/NR4A3 interaction, siRNA knockdown of NR4A3, in vivo miR-106b-5p silencing in ITP mouse model Cell cycle Medium 32323598
2022 MSC-derived extracellular vesicles deliver miR-146a, which directly targets Nr4a3 (validated by dual-luciferase assay): miR-146a mimic decreases Nr4a3 expression while inhibition promotes it. Upregulation of miR-146a by MSC-EVs decreases Nr4a3 expression and reduces LPS-induced pro-inflammatory cytokines in microglia (BV2 cells), contributing to retinal protection. Dual-luciferase assay, miR-146a mimic/inhibitor transfection, qPCR, western blot, co-culture of photoreceptors with microglia, in vivo rd10 mouse model Stem cell research & therapy Medium 35922863
2024 NR4A3 promotes vascular calcification via histone lactylation: NR4A3 directly binds promoter regions of glycolysis genes ALDOA and PFKL to drive their transcriptional initiation, enhancing glycolytic rate and lactate production. Increased lactate promotes histone lactylation, which in turn activates PHOSPHO1 transcription to drive calcium deposition. NR4A3 deficiency inhibits this cascade and reduces vascular calcification. NR4A3 knockout mice, vascular calcification models, RNA-seq, CUT&TAG (chromatin binding analysis), metabolic assays, NR4A3 overexpression, Phospho1 pharmacological inhibition and overexpression, in vivo and in vitro calcium deposition assays Circulation research High 38629274
2020 FTO (fat mass and obesity-associated demethylase) regulates NR4A3 mRNA m6A methylation: FTO knockdown increases methylation of NR4A3 mRNA, while FTO (but not catalytically mutated FTO) overexpression reduces NR4A3 mRNA methylation. DHA suppresses AngII-induced VSMC proliferation/inflammation by inhibiting the FTO/NR4A3 axis. m6A-RNA immunoprecipitation (MeRIP) assay, FTO knockdown/overexpression, AngII stimulation of VSMCs, cell proliferation assays (CCK-8, BrdU), western blot, qRT-PCR Inflammation research Medium 35059772
2020 NR4A3 promotes pulmonary arterial smooth muscle cell (PASMC) proliferation via the cyclin D1 pathway. miR-638 directly targets NR4A3 (validated by luciferase reporter assay), and resveratrol prevents MCT-induced pulmonary vascular remodeling by upregulating miR-638 and thereby reducing NR4A3 expression. Luciferase reporter assay for miR-638/NR4A3, loss-/gain-of-function (miR-638 mimic/antagomir), NR4A3 overexpression, MCT rat model of pulmonary hypertension, PASMC proliferation assays Microvascular research Medium 32057731
2024 NR4A3 protects against diabetes-induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress, acting through preserving transcriptional expression of Sdha. NR4A3 deficiency exacerbates atrial hypertrophy, fibrosis, and susceptibility to atrial fibrillation. Nr4a3 knockout mice (HFD/STZ model), AAV9-Nr4a3 overexpression in db/db mice, RNA-seq, metabolomics, electrophysiological studies, histological analysis EBioMedicine Medium 39098108

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators. Current opinion in cell biology 536 18640274
2003 Recognition of the DNA minor groove by pyrrole-imidazole polyamides. Current opinion in structural biology 522 12831879
2006 What does minor elevation of C-reactive protein signify? The American journal of medicine 282 16443421
2007 Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nature medicine 275 17515897
2012 The significant other: splicing by the minor spliceosome. Wiley interdisciplinary reviews. RNA 258 23074130
2013 L2, the minor capsid protein of papillomavirus. Virology 179 23689062
2006 Significance of the minor cytochrome P450 3A isoforms. Clinical pharmacokinetics 176 16430309
2019 Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands. Nature communications 165 30664630
1997 Targeting the minor groove of DNA. Current opinion in structural biology 160 9204277
2006 What drives proteins into the major or minor grooves of DNA? Journal of molecular biology 148 17055530
1995 Complexes of the minor groove of DNA. Annual review of biophysics and biomolecular structure 146 7663124
2022 BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion. Science translational medicine 116 36350986
2022 Transsulfuration, minor player or crucial for cysteine homeostasis in cancer. Trends in cell biology 101 35365367
2019 Nuclear NR4A3 Immunostaining Is a Specific and Sensitive Novel Marker for Acinic Cell Carcinoma of the Salivary Glands. The American journal of surgical pathology 98 31094928
2002 The immunogenomics of minor histocompatibility antigens. Immunological reviews 91 12493008
2014 Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors. Proceedings of the National Academy of Sciences of the United States of America 85 24706823
2024 Orphan Nuclear Receptor NR4A3 Promotes Vascular Calcification via Histone Lactylation. Circulation research 82 38629274
2013 The Merkel cell polyomavirus minor capsid protein. PLoS pathogens 80 23990782
2020 Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration. Cell reports 77 33147449
2014 Role of PRMTs in cancer: Could minor isoforms be leaving a mark? World journal of biological chemistry 76 24921003
2022 Mesenchymal stem cell-derived extracellular vesicles protect retina in a mouse model of retinitis pigmentosa by anti-inflammation through miR-146a-Nr4a3 axis. Stem cell research & therapy 75 35922863
2013 Minor groove binders as anti-infective agents. Pharmacology & therapeutics 75 23507040
2012 Full-length minor ampullate spidroin gene sequence. PloS one 75 23251707
2021 Structure of the activated human minor spliceosome. Science (New York, N.Y.) 73 33509932
2004 Minor histocompatibility antigens--big in tumour therapy. Trends in immunology 64 15102363
2017 Atomic Structures of Minor Proteins VI and VII in Human Adenovirus. Journal of virology 60 28978703
2002 Minor H antigens: genes and peptides. Transplant immunology 60 12216941
2015 The nuclear orphan receptor NR4A1 and NR4A3 as tumor suppressors in hematologic neoplasms. Current drug targets 58 25410408
2018 NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBPα and inflammatory signaling. Blood 57 29343483
2006 Minor proteins and enzymes of the Drosophila eggshell matrix. Developmental biology 55 16515779
2009 The EWSR1/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the PPARG nuclear receptor gene. The Journal of pathology 53 18855877
1997 Minor histocompatibility antigens. Current opinion in immunology 52 9368774
2018 Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis. Oncogene 49 30455429
2017 NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival. Blood 49 28637666
2014 Minor class splicing shapes the zebrafish transcriptome during development. Proceedings of the National Academy of Sciences of the United States of America 49 24516132
2002 Subcellular localization of chlorosome proteins in Chlorobium tepidum and characterization of three new chlorosome proteins: CsmF, CsmH, and CsmX. Biochemistry 47 11914082
2016 β-Cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion. American journal of physiology. Endocrinology and metabolism 45 27221116
2019 The orphan nuclear receptor NR4A3 controls the differentiation of monocyte-derived dendritic cells following microbial stimulation. Proceedings of the National Academy of Sciences of the United States of America 43 31285338
2018 Dengue virus NS2 and NS4: Minor proteins, mammoth roles. Biochemical pharmacology 41 29674002
2014 Major capsid reinforcement by a minor protein in herpesviruses and phage. Nucleic acids research 41 25053840
2022 Controlling Nuclease Degradation of Wireframe DNA Origami with Minor Groove Binders. ACS nano 40 35640255
2021 NR4A3: A Key Nuclear Receptor in Vascular Biology, Cardiovascular Remodeling, and Beyond. International journal of molecular sciences 39 34768801
2020 Evaluation of NR4A3 immunohistochemistry (IHC) and fluorescence in situ hybridization and comparison with DOG1 IHC for FNA diagnosis of acinic cell carcinoma. Cancer cytopathology 39 32809265
2017 Targeting DNA Minor Groove by Hybrid Molecules as Anticancer Agents. Current medicinal chemistry 38 28545367
2020 NR4A3 Immunohistochemistry Reliably Discriminates Acinic Cell Carcinoma from Mimics. Head and neck pathology 37 32910350
2019 The pro-inflammatory effect of NR4A3 in osteoarthritis. Journal of cellular and molecular medicine 37 31701670
2016 Muscle Contraction Induces Acute Hydroxymethylation of the Exercise-Responsive Gene Nr4a3. Frontiers in endocrinology 37 28066330
2020 Early programming of CD8+ T cell response by the orphan nuclear receptor NR4A3. Proceedings of the National Academy of Sciences of the United States of America 36 32913051
2018 Thermodynamics of DNA Minor Groove Binders. Journal of medicinal chemistry 36 30059627
2008 Oligodendroglial cells and neurotrophins: a polyphonic cantata in major and minor. Journal of molecular neuroscience : MN 36 18327658
2018 Regulation of human trophoblast cell syncytialization by transcription factors STAT5B and NR4A3. Journal of cellular biochemistry 35 29377304
2001 Minor H antigens: genes and peptides. European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics 35 11881817
2020 Pharmacological potential of varinic-, minor-, and acidic phytocannabinoids. Pharmacological research 33 32416215
2017 The Orphan Nuclear Receptor NR4A3 Is Involved in the Function of Dendritic Cells. Journal of immunology (Baltimore, Md. : 1950) 33 28893954
2014 Efficient transformation and artificial miRNA gene silencing in Lemna minor. Plant biology (Stuttgart, Germany) 33 24989135
2016 The transcription factor NR4A3 controls CD103+ dendritic cell migration. The Journal of clinical investigation 31 27820700
1994 DNA recognition by lexitropsins, minor groove binding agents. Journal of molecular recognition : JMR 31 7826677
2020 miR-106b-5p induces immune imbalance of Treg/Th17 in immune thrombocytopenic purpura through NR4A3/Foxp3 pathway. Cell cycle (Georgetown, Tex.) 28 32323598
2019 The orphan nuclear receptor Nor1/Nr4a3 is a negative regulator of β-cell mass. The Journal of biological chemistry 28 30696767
2017 Minor collagens of the skin with not so minor functions. Journal of anatomy 27 31318053
2024 Mechanisms of minor pole-mediated spindle bipolarization in human oocytes. Science (New York, N.Y.) 26 39172836
2022 Head and Neck Acinic Cell Carcinoma: A New Grading System Proposal and Diagnostic Utility of NR4A3 Immunohistochemistry. The American journal of surgical pathology 26 35034042
2020 Resveratrol prevented experimental pulmonary vascular remodeling via miR-638 regulating NR4A3/cyclin D1 pathway. Microvascular research 26 32057731
2017 NR4A3 Suppresses Lymphomagenesis through Induction of Proapoptotic Genes. Cancer research 26 28249906
2022 Dihydroartemisinin alleviates AngII-induced vascular smooth muscle cell proliferation and inflammatory response by blocking the FTO/NR4A3 axis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 24 35059772
2021 Minor Intron Splicing from Basic Science to Disease. International journal of molecular sciences 24 34199764
2014 Elevation of NR4A3 expression and its possible role in modulating insulin expression in the pancreatic beta cell. PloS one 24 24638142
2021 SMARCA2-NR4A3 is a novel fusion gene of extraskeletal myxoid chondrosarcoma identified by RNA next-generation sequencing. Genes, chromosomes & cancer 23 34124809
2020 Oncogenic Orphan Nuclear Receptor NR4A3 Interacts and Cooperates with MYB in Acinic Cell Carcinoma. Cancers 23 32867110
2019 Radiotherapy in combination with hyperthermia suppresses lung cancer progression via increased NR4A3 and KLF11 expression. International journal of radiation biology 23 31498019
1991 Minor histocompatibility antigens. Immunology letters 23 1916933
2021 MiR-20a-5p Negatively Regulates NR4A3 to Promote Metastasis in Bladder Cancer. Journal of oncology 22 34925506
2020 Long non-coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3. Journal of cellular and molecular medicine 22 32125766
1991 Minor histocompatibility antigens. Trends in genetics : TIG 22 1887503
2019 An Integrated Model of Minor Intron Emergence and Conservation. Frontiers in genetics 21 31798628
2010 Replicated association of the NR4A3 gene with smoking behaviour in schizophrenia and in bipolar disorder. Genes, brain, and behavior 21 20659174
2024 NR4A3 prevents diabetes induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress. EBioMedicine 20 39098108
2017 The nuclear receptor NOR-1/NR4A3 regulates the multifunctional glycoprotein vitronectin in human vascular smooth muscle cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 28666984
2023 Minor intron splicing is critical for survival of lethal prostate cancer. Molecular cell 19 37295433
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
1989 Nutrient composition and protein quality of minor millets. Plant foods for human nutrition (Dordrecht, Netherlands) 19 2548175
2023 NR4A3 Expression Is Consistently Absent in Acinic Cell Carcinomas of the Breast: A Potential Nosologic Shift. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 18 36828363
2022 NR4A3 Immunostain Is a Highly Sensitive and Specific Marker for Acinic Cell Carcinoma in Cytologic and Surgical Specimens. American journal of clinical pathology 18 34508546
2021 Circ_0030586 inhibits cell proliferation and stemness in bladder cancer by inactivating the ERK signaling via miR-665/NR4A3 axis. Acta histochemica 18 34175686
2010 Histopathology of the minor duodenal papilla. Digestive surgery 18 20551659
2016 Possible role of intragenic DNA hypermethylation in gene silencing of the tumor suppressor gene NR4A3 in acute myeloid leukemia. Leukemia research 17 27697661
2012 Evidence for a minor gene-for-minor gene interaction explaining nonhypersensitive polygenic partial disease resistance. Phytopathology 17 22835013
2005 "Minor" hemoglobinopathies: a risk factor for asthma. European annals of allergy and clinical immunology 17 15984316
2014 Nuclear receptor 4a3 (nr4a3) regulates murine mast cell responses and granule content. PloS one 16 24586680
2024 Expanding the Spectrum of NR4A3 Fusion-Positive Gynecologic Leiomyosarcomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 15 38508521
2020 Disruption of Beta-Cell Mitochondrial Networks by the Orphan Nuclear Receptor Nor1/Nr4a3. Cells 15 31936632
2010 Cytotoxicity of Vinca minor. Pharmaceutical biology 15 20645762
1979 Stress and Protein Turnover in Lemna minor. Plant physiology 15 16661102
2020 Disrupted minor intron splicing is prevalent in Mendelian disorders. Molecular genetics & genomic medicine 14 32573973
2019 Minor Isozymes Tailor Yeast Metabolism to Carbon Availability. mSystems 14 30834327
2016 Selective anti-malarial minor groove binders. Bioorganic & medicinal chemistry letters 14 27212070
2022 NR4A3 fusions characterize a distinctive peritoneal mesothelial neoplasm of uncertain biological potential with pure adenomatoid/microcystic morphology. Genes, chromosomes & cancer 13 36524687
2002 Intergenic mRNAs. Minor gene products or tools of diversity? Histology and histopathology 13 11962767
2024 Potential Roles of Nr4a3-Mediated Inflammation in Immunological and Neurological Diseases. Molecular neurobiology 12 38261254
2022 Dysregulated minor intron splicing in cancer. Cancer science 12 35766428

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