Affinage

NR4A1

Nuclear receptor subfamily 4immunitygroup A member 1 · UniProt P22736

Length
598 aa
Mass
64.5 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

NR4A1 (Nur77/TR3) is an immediate-early orphan nuclear receptor that integrates transcriptional, cytoplasmic, and organelle-targeted activities to govern cell fate decisions—apoptosis, proliferation, inflammation, and metabolic reprogramming—across lymphoid, myeloid, endothelial, and epithelial lineages. In the nucleus, NR4A1 acts as a sequence-specific transcription factor that activates targets such as CYP11B2, E2F1, Cebpa, and eNOS, while repressing NF-κB-dependent inflammatory genes through direct interaction with p65 and recruiting co-repressors such as CoREST to loci including Runx3 (PMID:14645496, PMID:25822914, PMID:29343483, PMID:25762306). Upon apoptotic stimuli, NR4A1 translocates to mitochondria where it binds the N-terminal loop of Bcl-2 and induces a conformational change that exposes the BH3 domain, converting Bcl-2 from a pro-survival to a pro-apoptotic protein; ubiquitinated mitochondrial NR4A1 further drives mitophagy by forming p62-dependent liquid-liquid phase-separated condensates (PMID:14980220, PMID:34645818). NR4A1 activity is tuned by multiple post-translational modifications—Akt phosphorylation at Ser-350 suppresses DNA binding and blocks mitochondrial targeting, JNK phosphorylation at Ser-95 triggers its degradation, and SUMO2/3 conjugation by PIAS3 followed by RNF4-mediated polyubiquitination controls its protein turnover—while interactions with LKB1, RXRα, Pin1, PRMT1, and FHL2 modulate its transcriptional output and subcellular routing (PMID:11274386, PMID:18713840, PMID:17023523, PMID:28622293, PMID:22983157, PMID:22002310).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1993 High

    Mapping the functional architecture of Nur77 established that its transactivation resides in the N-terminal domain, that the C-terminal domain regulates this activity, and that phosphorylation by pp90rsk at Ser-354 modifies the protein, providing the first molecular framework for understanding how signal-dependent phosphorylation tunes an orphan receptor.

    Evidence Deletion mapping, in vitro kinase assays, and in vivo radiolabeling in transfected cells

    PMID:8232315

    Open questions at the time
    • Physiological kinase hierarchy upstream of pp90rsk-Nur77 not defined
    • No structural data on how phosphorylation alters DNA binding
  2. 1994 High

    Dominant-negative Nur77 blocked TCR-induced apoptosis in T-cell hybridomas, establishing Nur77 as a necessary mediator of activation-induced cell death and positioning it as a central effector in thymic negative selection.

    Evidence Dominant-negative overexpression and EMSA in T-cell hybridomas

    PMID:8121493

    Open questions at the time
    • Downstream effector mechanism unknown at this stage
    • Redundancy with other NR4A family members not addressed
  3. 1996 High

    Genetic epistasis in transgenic mice showed Nur77-driven thymocyte apoptosis required Fas ligand, linking a nuclear receptor to the extrinsic death pathway and resolving a key downstream effector question.

    Evidence Nur77 transgenic crossed to gld/gld (FasL-mutant) mice; flow cytometry

    PMID:8643610

    Open questions at the time
    • Whether FasL is a direct transcriptional target of Nur77 not shown
    • Pathway may differ in peripheral T cells
  4. 1997 High

    The glucocorticoid receptor was shown to antagonize Nur77-dependent transactivation at the POMC NurRE without requiring GR DNA binding, revealing crosstalk between steroid and orphan receptor signaling on a physiological promoter.

    Evidence Reporter assays, in vitro binding, GR mutant analysis in endocrine and lymphoid cells

    PMID:9315653

    Open questions at the time
    • Whether GR-Nur77 antagonism operates genome-wide or is promoter-selective
    • In vivo significance in HPA axis not tested
  5. 2001 High

    Akt was identified as a kinase that phosphorylates Nur77 at Ser-350 in the DNA-binding domain, reducing transcriptional activity by up to 85%, revealing a direct mechanism by which PI3K/Akt survival signaling neutralizes Nur77 function.

    Evidence In vitro kinase assay, in vivo phosphorylation, site-directed mutagenesis, reporter assays

    PMID:11274386

    Open questions at the time
    • Whether Akt phosphorylation also influences Nur77 subcellular localization not tested here
    • Relative contribution of Ser-350 vs. other sites unclear
  6. 2003 High

    Several studies collectively established that Nur77 subcellular localization dictates its biological output: nuclear Nur77 drives proliferation via DNA binding and transactivation (e.g., E2F1 induction with Kd ~6 nM), while cytoplasmic/mitochondrial Nur77 triggers apoptosis through BAX recruitment and cytochrome c release, with JNK-mediated phosphorylation switching Nur77 from a nuclear mitogen to an apoptosis inducer.

    Evidence Confocal imaging, siRNA, GFP-Nur77 mutants, EMSA on E2F1 promoter, JNK kinase assays, colon cancer and prostate cancer cell systems

    PMID:12947120 PMID:14500374 PMID:14612408

    Open questions at the time
    • Nuclear export mechanism not molecularly defined
    • Relative contribution of BAX versus Bcl-2 pathways in different tissues unresolved
  7. 2004 High

    The direct Nur77–Bcl-2 interaction was mapped to the N-terminal loop of Bcl-2, demonstrating that Nur77 induces a conformational change exposing the Bcl-2 BH3 domain and converting Bcl-2 from anti- to pro-apoptotic—a landmark mechanism linking an orphan receptor to intrinsic apoptosis at mitochondria.

    Evidence Reciprocal Co-IP, domain mutagenesis, mitochondrial fractionation, cytochrome c release assays in multiple cell types

    PMID:14980220

    Open questions at the time
    • No structural model of the Nur77–Bcl-2 complex
    • Signals specifying Nur77 mitochondrial targeting remain unclear
  8. 2006 High

    Multiple discoveries in 2006 expanded the regulatory network: JNK phosphorylation at Ser-95 was shown to trigger Nur77 ubiquitination and degradation, Nur77 was found to drive angiogenesis through transcriptional activity in endothelial cells, and Nur77 was shown to translocate to the ER to engage Bcl-2 and trigger ER-stress-associated apoptosis via caspase-4.

    Evidence In vitro kinase assays with Ser95 mutagenesis; HUVEC assays with dominant-negative mutants and Nur77−/− mice; ER fractionation and Ca²⁺/caspase assays

    PMID:16520388 PMID:17023523 PMID:17543302

    Open questions at the time
    • ER translocation signal on Nur77 not identified
    • Whether ER and mitochondrial Bcl-2 engagement are simultaneous or sequential unknown
  9. 2007 Medium

    Nur77 was shown to heterodimerize with RXRα, block p300-mediated RXRα acetylation, and—upon 9-cis retinoic acid stimulation—co-translocate with RXRα from the nucleus to mitochondria to induce apoptosis, integrating retinoid signaling with Nur77 mitochondrial function.

    Evidence Co-IP, acetylation assays, subcellular fractionation, confocal microscopy

    PMID:17761950

    Open questions at the time
    • Single lab; independent replication pending
    • RXRα–Nur77 stoichiometry and dynamics at mitochondria unknown
  10. 2008 High

    Two discoveries clarified protein-level regulation: Akt phosphorylation of cytoplasmic Nur77 was shown to block mitochondrial targeting (resolving the gap from 2001), and PRMT1 was found to stabilize Nur77 protein and enhance its DNA binding in a methyltransferase-independent manner while Nur77 reciprocally inhibited PRMT1 catalytic activity.

    Evidence Co-IP, kinase assays, confocal imaging, PRMT1 methyltransferase assays, Nur77−/− mice

    PMID:18713840 PMID:19095693

    Open questions at the time
    • In vivo significance of PRMT1–Nur77 reciprocal regulation not fully tested
    • How Akt access to cytoplasmic Nur77 is spatially regulated unclear
  11. 2011 High

    A burst of studies in 2011 defined NR4A1's roles across multiple tissues: it is cell-intrinsically required for Ly6C− patrolling monocyte survival; it suppresses NF-κB in macrophages; it disrupts β-catenin/TCF4 on Wnt target promoters (antagonized by GSK3β phosphorylation); FHL2 represses Nur77 DNA binding; Pin1 isomerizes phospho-Nur77 to stabilize it and promote cyclin D2 transactivation; it modulates endothelial permeability through eNOS and junction proteins; and Chk2 phosphorylation of Nur77 enables repression of anti-apoptotic genes BRE and RNF-7.

    Evidence Nr4a1−/− and chimeric mice, ChIP, domain mutagenesis, yeast two-hybrid, Pin1 binding assays, kinase assays, vascular permeability models

    PMID:21725321 PMID:21730126 PMID:21873734 PMID:22002310 PMID:22049082 PMID:22159226 PMID:22194622

    Open questions at the time
    • Relative importance of the many phosphorylation sites in integrating signals not systematically compared
    • Tissue-specific weighting of nuclear vs. cytoplasmic functions still unclear
  12. 2012 High

    Two studies revealed non-transcriptional signaling roles: Nur77 sequesters LKB1 in the nucleus to attenuate AMPK activation (reversed by the small molecule TMPA), and Nur77 forms a trimeric complex with TSC1/TSC2 that promotes TSC2 proteasomal degradation to activate mTORC1, driving cardiac hypertrophy.

    Evidence Co-IP, subcellular fractionation, AMPK assays, compound binding, Nr4a1−/− mice; trimeric complex Co-IP, proteasome inhibition, cardiac hypertrophy models

    PMID:22983157 PMID:23197407

    Open questions at the time
    • Whether LKB1 sequestration and TSC2 degradation are coordinated or context-exclusive unknown
    • Structural basis of trimeric TSC complex assembly not determined
  13. 2015 High

    NR4A1's anti-inflammatory mechanism was directly demonstrated: it physically blocks p65 binding to κB elements, and LPS-activated p38α phosphorylation of Nur77 relieves this block; separately, Nr4a1 suppresses Runx3 transcription in CD8+ T cells by recruiting CoREST, modulating T cell differentiation.

    Evidence Co-IP, ChIP, phosphorylation assays, sepsis model; Nr4a1−/− mice, ChIP for CoREST, flow cytometry

    PMID:25762306 PMID:25822914

    Open questions at the time
    • Whether p38α phosphosite on Nur77 overlaps with other kinase sites
    • CoREST recruitment mechanism to Runx3 not structurally resolved
  14. 2017 High

    The SUMO-ubiquitin degradation axis for NR4A1 was defined: PIAS3-mediated SUMO2/3 conjugation at two sites targets NR4A1 for RNF4-dependent polyubiquitination and proteasomal degradation, with SENP1 opposing this modification, providing a unified mechanism for post-translational Nur77 turnover that affects NF-κB signaling output.

    Evidence SUMOylation and ubiquitination assays, site-directed mutagenesis, PIAS3/SENP1 manipulation, NF-κB reporters

    PMID:28622293

    Open questions at the time
    • How SUMO-dependent degradation is coordinated with JNK/Ser95-dependent ubiquitination
    • In vivo validation of SUMO-site mutants not performed
  15. 2018 High

    NR4A1 was established as a metabolic regulator in macrophages (downregulating IDH to limit succinate accumulation and inflammatory output) and in hematopoietic stem cells (activating Cebpa via a hematopoietic-specific enhancer and antagonizing NF-κB to maintain quiescence).

    Evidence Nr4a1−/− macrophages with metabolomics and SDH epistasis; conditional NR4A1/NR4A3 double-KO with ChIP and gene profiling

    PMID:29343483 PMID:30134173

    Open questions at the time
    • Whether IDH regulation is direct transcriptional or indirect
    • NR4A1 versus NR4A3 individual contributions to HSC maintenance not fully separated
  16. 2021 High

    Ubiquitinated mitochondrial Nur77 was shown to undergo liquid-liquid phase separation, forming condensates through multivalent interactions between its N-terminal IDR and p62/SQSTM1 PB1 domain, coordinating mitophagy of damaged mitochondria—a fundamentally new biophysical mechanism for this receptor.

    Evidence In vitro phase separation reconstitution, domain mutagenesis, live-cell imaging, mitophagy flux assays

    PMID:34645818

    Open questions at the time
    • Whether phase separation occurs in vivo under physiological (non-overexpression) conditions
    • Ubiquitin chain type specificity for condensate formation not defined
  17. 2023 High

    Two studies revealed unexpected non-nuclear functions: NR4A1 localizes to P-bodies in activated microglia where it directly binds and destabilizes Tnf mRNA in an m6A-dependent manner, and Mst1 kinase phosphorylates Nur77 at Thr-366 to enhance transcriptional activity and promote embryo implantation via β3-integrin.

    Evidence Conditional microglial Nr4a1 KO, RNA-binding assays, m6A analysis, P-body colocalization; in vitro kinase/LC-MS/MS, phospho-specific antibody, mouse implantation model

    PMID:36623453 PMID:37486903

    Open questions at the time
    • Scope of NR4A1 RNA-binding targets beyond Tnf unknown
    • Whether m6A-dependent RNA decay is a general NR4A1 function outside microglia not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis of the Nur77–Bcl-2 and Nur77–p62 interactions, the hierarchy and crosstalk among the >8 documented phosphorylation events, the full spectrum of NR4A1 RNA targets, and how tissue-specific contexts select between its nuclear transcriptional, cytoplasmic signaling, mitochondrial apoptotic, and P-body RNA-regulatory functions.
  • No crystal or cryo-EM structure of any NR4A1 complex
  • Integrated phospho-signaling code not determined
  • RNA targetome outside Tnf unknown
  • Redundancy with NR4A2/NR4A3 incompletely resolved in most tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0098772 molecular function regulator activity 5 GO:0003677 DNA binding 4 GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 12 GO:0005739 mitochondrion 5 GO:0005829 cytosol 4 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-168256 Immune System 9 R-HSA-74160 Gene expression (Transcription) 8 R-HSA-162582 Signal Transduction 7 R-HSA-5357801 Programmed Cell Death 7 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-8953854 Metabolism of RNA 1 R-HSA-9612973 Autophagy 1
Partners
BCL2FHL2PIN1PRMT1RELASQSTM1STK11TP53

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Nur77 (NR4A1) directly interacts with the N-terminal loop region of Bcl-2 at the mitochondria, inducing a conformational change in Bcl-2 that exposes its BH3 domain and converts Bcl-2 from an anti-apoptotic to a pro-apoptotic protein, triggering cytochrome c release and apoptosis. Co-immunoprecipitation, domain mapping, mitochondrial fractionation, confocal microscopy, functional apoptosis assays Cell High 14980220
1994 Nur77 is required for activation-induced apoptosis in T-cell hybridomas; a dominant-negative Nur77 blocks TCR-induced cell death, establishing Nur77 as a necessary mediator of this pathway. Dominant-negative overexpression, gel shift analysis (EMSA), subtractive hybridization Nature High 8121493
2001 Akt physically interacts with Nur77 and phosphorylates it at Ser-350 within its DNA-binding domain in a PI3K-dependent manner, reducing Nur77 transcriptional activity by 50–85%. Co-immunoprecipitation, in vitro kinase assay, in vivo phosphorylation assay, luciferase reporter assay, site-directed mutagenesis Proceedings of the National Academy of Sciences High 11274386
1993 Nur77 transactivation activity resides in its N-terminal domain; the C-terminal domain regulates this activity. Deletion of the domain immediately C-terminal to the zinc fingers abolishes DNA binding and nuclear localization. Nur77 is phosphorylated primarily at its N-terminal domain, and pp90rsk phosphorylates Ser-354 in vitro and in vivo. Deletion mapping, transactivation assays, in vitro phosphorylation with recombinant kinases, in vivo radiolabeling Molecular Endocrinology High 8232315
2003 TR3/Nur77 nuclear functions are controlled by subcellular localization: nuclear TR3 promotes cell proliferation via its DNA-binding and transactivation domains, while mitochondrial TR3 induces apoptosis independently of these domains. EGF/serum induces nuclear TR3 mitogenesis; MEKK1 activates JNK which phosphorylates TR3 and abolishes its DNA binding, blocking its mitogenic function. Confocal microscopy, siRNA knockdown, ectopic expression of TR3 mutants, BrdU incorporation, JNK kinase assays Molecular and Cellular Biology High 14612408
2012 Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. Compound TMPA binds Nur77 with high affinity, releasing LKB1 to the cytoplasm where it phosphorylates AMPKα. Co-immunoprecipitation, subcellular fractionation, AMPK activity assays, compound binding assays, knockout mouse validation Nature Chemical Biology High 22983157
2015 Nur77 directly associates with the p65 subunit of NF-κB to block its binding to the κB element, suppressing inflammatory cytokine production. LPS-activated p38α phosphorylates Nur77, counteracting this NF-κB suppression. Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assays, phosphorylation assays, compound screening Nature Chemical Biology High 25822914
1996 Nur77/N10 transgenic thymocytes undergo apoptosis through upregulation of Fas ligand (FasL) expression; crossing to gld/gld mice (FasL-mutant) rescues the apoptosis phenotype, demonstrating Nur77-driven thymocyte apoptosis requires the Fas/FasL pathway. Transgenic mouse model, genetic epistasis with gld mutation, flow cytometry for thymocyte populations, FasL expression analysis Proceedings of the National Academy of Sciences High 8643610
2011 NR4A1 controls the differentiation and survival of Ly6C- (patrolling) monocytes in a cell-intrinsic manner; Nr4a1-/- mice lack patrolling monocytes, and residual Ly6C- cells in knockout bone marrow are arrested in S phase and undergo apoptosis. Knockout mouse analysis, bone marrow transplantation (chimera), flow cytometry, cell cycle analysis Nature Immunology High 21725321
2018 Nur77 acts as an upstream transcriptional regulator of metabolic reprogramming in macrophages by downregulating isocitrate dehydrogenase (IDH) expression; Nur77-deficient macrophages accumulate higher succinate levels and produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner. Nr4a1-/- macrophages, metabolomics, IDH/SDH functional assays, cytokine measurements, atherosclerosis in vivo model Cell Reports High 30134173
2021 Ubiquitinated mitochondrial Nur77 forms membraneless condensates through liquid-liquid phase separation; multivalent interaction between Nur77's N-terminal IDR and the PB1 domain of p62/SQSTM1, and between Nur77's UBA-interacting region and p62's UBA domain, coordinates sequestration of damaged mitochondria for mitophagy. Phase separation assays, co-immunoprecipitation, domain mutagenesis, live-cell imaging, mitophagy flux assays Nature Communications High 34645818
2008 Akt phosphorylates cytoplasmic Nur77 through physical interaction with its N-terminus, blocking Nur77 mitochondrial targeting and disrupting the Nur77–Bcl-2 interaction required for apoptosis induction. Co-immunoprecipitation, kinase assays, confocal microscopy, subcellular fractionation, insulin stimulation Carcinogenesis High 18713840
1997 Glucocorticoid receptor (GR) antagonizes Nur77-dependent transcription at the NurRE element of the POMC gene by a mechanism similar to GR/AP-1 antagonism; GR also partly blunts CRH induction of Nur77 mRNA; in vitro binding and mutation analysis show GR antagonism of Nur77 does not require direct DNA binding by GR. Transfection/reporter assays, in vitro binding experiments, GR mutation analysis, Northern blotting Molecular and Cellular Biology High 9315653
2006 TR3/Nur77 translocates to the endoplasmic reticulum (ER) upon CD437 treatment, interacts with ER-associated Bcl-2, triggers early Ca²⁺ release from the ER, and induces apoptosis via ER-specific caspase-4 activation in parallel with mitochondrial stress and caspase-9 activation. Immunofluorescence, subcellular fractionation, co-immunoprecipitation, Ca²⁺ measurement, caspase activity assays Experimental Cell Research Medium 17543302
2011 TR3/Nur77 regulates mTORC1 signaling in lung cancer cells: it suppresses p53 (via a p300/TR3/Sp1 complex on GC-rich promoters including survivin), and in p53 wild-type cells, siTR3 activates p53 which induces sestrin2, activating AMPKα and inhibiting mTORC1. RNA interference, Western blot, ChIP, luciferase reporter assays, xenograft tumor models Oncogene Medium 22081070
2006 TR3/Nur77 directly interacts with p53 (not MDM2), blocks p53 acetylation (reducing MDM2 transcription), and prevents MDM2-induced p53 ubiquitination, resulting in MDM2 ubiquitination and degradation; TR3 also enhances p53-mediated apoptosis by UV. Co-immunoprecipitation, GST pulldown, luciferase reporter, ubiquitination assay, acetylation assay EMBO Journal High 17139261
2003 In colon cancer cells, butyrate- and NSAID-induced apoptosis involves nucleus-to-cytoplasm translocation of TR3/Nur77, with cytoplasmic (not direct mitochondrial) localization triggering BAX recruitment to mitochondria and cytochrome c release. GFP-TR3 live-cell imaging, TR3 mutant constructs, cytochrome c release assays, BAX co-localization Cancer Research Medium 14500374
2011 TR3/Nur77 disrupts the association of β-catenin and TCF4 on chromatin and facilitates recruitment of transcriptional co-repressors to Wnt target gene promoters, suppressing Wnt signaling. GSK3β phosphorylates TR3, attenuating its inhibitory activity toward Wnt signaling in clinical colorectal cancers. ChIP, co-immunoprecipitation, reporter assays, knockout/transgenic mouse models, kinase assays on clinical samples Gut High 21873734
2012 TR3/Nur77 forms a trimeric complex with TSC1/TSC2 that specifically promotes TSC2 degradation via the ubiquitin/proteasome pathway, activating mTORC1 (but not mTORC2) and leading to increased protein synthesis and cardiac hypertrophy in response to angiotensin II. Co-immunoprecipitation, proteasome inhibition, TR3 knockout/knockdown mouse models, mTORC1 activity assays EMBO Molecular Medicine High 23197407
2017 NR4A1 is SUMOylated by SUMO2/3 at two specific sites; poly-SUMO modification targets NR4A1 for polyubiquitination by the SUMO-dependent E3 ligase RNF4 and subsequent proteasomal degradation. PIAS3 promotes SUMOylation and RNF4-mediated ubiquitination, while SENP1 de-conjugates SUMO; mutation of SUMO sites stabilizes NR4A1 and affects its regulation of NF-κB signaling. SUMOylation assays, ubiquitination assays, site-directed mutagenesis, PIAS3/SENP1 overexpression/knockdown, functional NF-κB reporter assays Cell Death and Differentiation High 28622293
2011 FHL2 physically interacts with Nur77 (identified by yeast two-hybrid and Co-IP); each of FHL2's four LIM domains binds Nur77, and both the N-terminal domain and DNA-binding domain of Nur77 are involved. FHL2 represses Nur77 transcriptional activity dose-dependently by inhibiting Nur77 binding to DNA, as shown by ChIP on the enolase3 promoter. Yeast two-hybrid, co-immunoprecipitation, domain mapping, ChIP, shRNA knockdown, reporter assays Journal of Biological Chemistry High 22049082
2011 TR3/Nur77 modulates vascular permeability by transcriptionally increasing endothelial nitric-oxide synthase expression and downregulating endothelial junction proteins; both effects require TR3 transcriptional activity (transactivation and DNA-binding domains). Nur77-/- mice, transgenic overexpression, dominant-negative TR3, in vivo vascular permeability assays, TR3 mutant analysis Proceedings of the National Academy of Sciences High 21730126
2006 TR3/Nur77 angiogenic activity in endothelial cells (proliferation, survival, tube formation) operates through its transactivation and DNA-binding domains (transcriptional activity); overexpression promotes angiogenesis in vivo while antisense inhibits VEGF-A-induced angiogenesis. Antisense/overexpression in HUVECs, dominant-negative mutants, endothelial-selective retroviral targeting in vivo, Nur77-/- mice with tumor models Journal of Experimental Medicine High 16520388
2008 PRMT1 physically interacts with TR3/Nur77 and stabilizes TR3 protein (delaying degradation), thereby enhancing TR3 DNA binding and transcriptional activity in a methyltransferase-independent manner. In turn, TR3 binding to the catalytic domain of PRMT1 inhibits PRMT1 methyltransferase activity, affecting STAT3 and Sam68 methylation. Co-immunoprecipitation, methyltransferase activity assays, protein stability assays, luciferase reporter assays, TR3 knockout mice with agonist Nucleic Acids Research High 19095693
2011 Pin1 binds phospho-Ser/Thr-Pro motifs on TR3 (at least three sites; key site Ser95-Pro), isomerizes them, stabilizes TR3 by retarding degradation, and enhances TR3 transactivation through phospho-Ser431 isomerization by ERK2. Pin1 also promotes TR3 targeting to the cyclin D2 promoter and recruitment of p300. Co-immunoprecipitation, in vitro Pin1 binding assays, protein stability assays, ChIP, proliferation/tumor growth assays Oncogene High 22002310
2006 JNK phosphorylates TR3 specifically at Ser95 (mediated through MKK4/MKK7 → JNK1), inducing TR3 ubiquitination and degradation, abolishing its mitogenic activity, and blocking TR3 DNA binding and transactivation. In vitro kinase assays, site-directed mutagenesis (Ser95), ubiquitination assays, reporter assays, co-immunoprecipitation Endocrinology High 17023523
2007 TR3/Nur77 interacts with RXRα and blocks p300-induced acetylation of RXRα at Lys145 by sequestering RXRα from p300. 9-cis retinoic acid enhances TR3-RXRα association and promotes co-translocation from nucleus to mitochondria, inducing apoptosis. Co-immunoprecipitation, acetylation assays, luciferase reporter, subcellular fractionation, confocal microscopy Molecular Endocrinology Medium 17761950
2003 PML physically interacts with the DNA-binding domain of Nur77 (amino acids 267–332; coiled-coil domain of PML) in vitro and in vivo, and represses Nur77 transcription by interfering with Nur77 DNA binding in a dose-dependent manner. GST pulldown, co-immunoprecipitation, EMSA, colocalization by confocal microscopy, domain mapping Oncogene Medium 12032831
2003 NGFI-B/NR4A1 binds to two functional NBRE elements in the CYP11B2 (aldosterone synthase) promoter and transactivates CYP11B2 expression in adrenocortical cells; angiotensin II strongly induces NGFI-B and NURR1 protein, and calmodulin kinase partially mediates this induction. Transient transfection/reporter assays, EMSAs, promoter deletion/mutagenesis, Western blotting, kinase inhibition Molecular Endocrinology High 14645496
2015 Nr4a1 directly suppresses Runx3 transcription in CD8+ T cells by recruiting the co-repressor CoREST to the Runx3 gene; loss of Nr4a1 increases Runx3 expression and causes a 2-fold increase in CD8+ T cell frequency. Nr4a1 knockout mice, ChIP (CoREST recruitment), RNA interference, flow cytometry Scientific Reports Medium 25762306
2018 NR4A1 and NR4A3 directly bind a hematopoietic-specific Cebpa enhancer to activate Cebpa transcription, restricting HSC proliferation; they also occupy regulatory regions of NF-κB-regulated inflammatory cytokines to antagonize NF-κB signaling and maintain HSC quiescence. Conditional double-knockout mice, ChIP, gene expression profiling, NF-κB signaling assays Blood High 29343483
2011 NR4A1 deletion in macrophages enhances TLR4 signaling and increases phosphorylation of the p65 subunit of NF-κB, polarizing macrophages to a pro-inflammatory M1 phenotype; NF-κB inhibition blocks the excess activation of Nur77-/- macrophages. Nr4a1-/- chimeric mice, Western blot for p65 phosphorylation, NF-κB inhibitor experiments, cytokine measurement Circulation Research Medium 22194622
2014 Nr4a1 mediates the anti-inflammatory effects of apoptotic cell phagocytosis in macrophages; Nr4a1 deletion prevents inhibition of NF-κB signaling and IL-12 repression normally induced by apoptotic cells, demonstrating Nr4a1 is required for tolerance to dying-self signals. Nr4a1-/- macrophages, NF-κB reporter assay, IL-12 measurement, in vivo pristane-induced lupus model Journal of Immunology Medium 24740500
2023 In activated microglia, NR4A1 localizes to cytoplasmic processing bodies (P-bodies) and functions as an RNA-binding protein that directly binds and destabilizes Tnf mRNA in an m6A-dependent manner, providing post-transcriptional regulation of TNF production. Conditional microglial Nr4a1 knockout, RNA-binding protein assays, m6A assays, P-body colocalization, ischemic stroke mouse model PLOS Biology High 37486903
2003 Nur77 is required for caspase-independent macrophage cell death downstream of TLR2/TLR4 signaling; ERK (downstream of TLR) and MEF2 transcription factor activity (upregulated by caspase inhibition) are both required for Nur77 induction and macrophage death. Nr4a1-/- macrophages, TLR2/4 signaling inhibitors, reporter gene analysis of Nur77 promoter, septic mouse model Journal of Experimental Medicine Medium 12782711
2011 TR3 transcriptionally regulates Nanog in gastric cancer stem cells; TR3 knockdown decreases Nanog and Oct-4 expression and suppresses stem-like properties including tumorsphere formation. siRNA knockdown, promoter reporter assays, tumorsphere assays, gene expression analysis Cancer Letters Low 23043761
2003 TR3 induces E2F1 expression by binding to a TR3 response element (TR3RE) in the E2F1 promoter (−316 to −324 bp) with a Kd of 6.29 nM; this transcriptional activation is required for TR3-mediated apoptosis in LNCaP prostate cancer cells. Promoter reporter assays, EMSA with Kd determination, dominant-negative TR3, antisense E2F1 Journal of Biological Chemistry Medium 12947120
2011 TR3/Nur77 participates in cisplatin-induced apoptosis through Chk2 kinase-mediated phosphorylation of TR3; phosphorylated TR3 binds to response elements on BRE and RNF-7 promoters, negatively regulating these anti-apoptotic genes. Co-immunoprecipitation, kinase assays, ChIP, apoptosis assays, Apc(min/+)/TR3-/- mouse models Carcinogenesis Medium 22159226
2023 Mst1 kinase phosphorylates Nur77 at threonine 366 (identified by in vitro kinase assay and LC-MS/MS), which increases Nur77 transcriptional activity and upregulates downstream target β3-integrin, promoting trophoblast-uterine epithelium adhesion and embryo implantation. In vitro kinase assay, LC-MS/MS phosphosite identification, phos-tag SDS-PAGE, specific phospho-antibody, reporter assays, mouse implantation model EBioMedicine High 36623453
2015 Nur77 increases thrombomodulin mRNA stability in vascular endothelial cells (without affecting promoter activity), while Nor1 increases thrombomodulin expression through induction of KLF2 and KLF4; Nur77 deficiency increases susceptibility to arterial thrombosis. Adenovirus-mediated overexpression, Nur77-/- mice, mRNA stability assays, reporter assays, thrombosis models Arteriosclerosis, Thrombosis, and Vascular Biology Medium 26634653
2024 NR4A1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in cardiomyocytes; semaglutide reduces NR4A1 expression and its translocation to mitochondria through the Creb5/NR4A1 axis in the PI3K/AKT pathway. NR4A1 knockdown, metabolomics, transcriptional analysis, confocal imaging, mouse heart failure model Nature Communications Medium 38834564

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 586 14980220
2011 The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nature immunology 506 21725321
1994 Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 503 8121493
2011 NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circulation research 372 22194622
2006 p53 and Nur77/TR3 - transcription factors that directly target mitochondria for cell death induction. Oncogene 212 16892086
2003 Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Molecular and cellular biology 172 14612408
2003 The orphan nuclear receptors NURR1 and NGFIB regulate adrenal aldosterone production. Molecular endocrinology (Baltimore, Md.) 164 14645496
2001 Akt phosphorylates and regulates the orphan nuclear receptor Nur77. Proceedings of the National Academy of Sciences of the United States of America 156 11274386
1997 Antagonism between Nur77 and glucocorticoid receptor for control of transcription. Molecular and cellular biology 156 9315653
2012 The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK. Nature chemical biology 153 22983157
2015 Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation. Nature chemical biology 143 25822914
2006 Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity. The Journal of experimental medicine 137 16520388
2002 Protective function of transcription factor TR3 orphan receptor in atherogenesis: decreased lesion formation in carotid artery ligation model in TR3 transgenic mice. Circulation 134 12234960
1993 Functional domains and phosphorylation of the orphan receptor Nur77. Molecular endocrinology (Baltimore, Md.) 120 8232315
2018 Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism. Cell reports 114 30134173
1996 Apoptosis of nur77/N10-transgenic thymocytes involves the Fas/Fas ligand pathway. Proceedings of the National Academy of Sciences of the United States of America 114 8643610
2007 Targeting Nur77 translocation. Expert opinion on therapeutic targets 104 17150035
2011 The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53. Oncogene 103 22081070
2010 Regulation of Nur77 expression by β-catenin and its mitogenic effect in colon cancer cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 101 20847229
2020 Lactate accelerates vascular calcification through NR4A1-regulated mitochondrial fission and BNIP3-related mitophagy. Apoptosis : an international journal on programmed cell death 100 31993850
2003 TR3/Nur77 in colon cancer cell apoptosis. Cancer research 97 14500374
2014 Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells. Molecular endocrinology (Baltimore, Md.) 93 25099012
2011 Targeting NR4A1 (TR3) in cancer cells and tumors. Expert opinion on therapeutic targets 87 21204731
2008 Inhibition of adipocyte differentiation by Nur77, Nurr1, and Nor1. Molecular endocrinology (Baltimore, Md.) 83 18945812
2024 Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis. Nature communications 76 38834564
2021 Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates. Nature communications 72 34645818
2012 Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization. Journal of lipid research 71 23028113
2003 Orphan nuclear receptor Nur77 is involved in caspase-independent macrophage cell death. The Journal of experimental medicine 71 12782711
2018 Characteristics of Nur77 and its ligands as potential anticancer compounds (Review). Molecular medicine reports 69 30272297
2011 The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling. Gut 67 21873734
2014 The nuclear receptor Nr4a1 mediates anti-inflammatory effects of apoptotic cells. Journal of immunology (Baltimore, Md. : 1950) 66 24740500
1998 Antisense TR3 orphan receptor can increase prostate cancer cell viability with etoposide treatment. Endocrinology 65 9564841
2016 NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration. Molecular and cellular biology 64 26929200
2006 p53 mediates the negative regulation of MDM2 by orphan receptor TR3. The EMBO journal 64 17139261
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
2015 Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma. PloS one 57 26035713
2011 Orphan nuclear transcription factor TR3/Nur77 regulates microvessel permeability by targeting endothelial nitric oxide synthase and destabilizing endothelial junctions. Proceedings of the National Academy of Sciences of the United States of America 57 21730126
2006 TR3 nuclear orphan receptor prevents cyclic stretch-induced proliferation of venous smooth muscle cells. The American journal of pathology 57 16723716
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
2021 Nuclear receptor Nur77: its role in chronic inflammatory diseases. Essays in biochemistry 52 34328179
2007 Involvement of TR3/Nur77 translocation to the endoplasmic reticulum in ER stress-induced apoptosis. Experimental cell research 50 17543302
2014 Non-genomic effects of the NR4A1/Nur77/TR3/NGFIB orphan nuclear receptor. Steroids 46 25555471
2021 Nr4A1 modulates inflammation-associated intestinal fibrosis and dampens fibrogenic signaling in myofibroblasts. American journal of physiology. Gastrointestinal and liver physiology 45 34288735
2017 SUMO-triggered ubiquitination of NR4A1 controls macrophage cell death. Cell death and differentiation 45 28622293
2018 Key Functions and Therapeutic Prospects of Nur77 in Inflammation Related Lung Diseases. The American journal of pathology 44 30414411
2012 The orphan receptor TR3 participates in angiotensin II-induced cardiac hypertrophy by controlling mTOR signalling. EMBO molecular medicine 43 23197407
2002 Induction of apoptosis by TPA and VP-16 is through translocation of TR3. World journal of gastroenterology 43 12046067
2004 A role for the NGFI-B family in adrenal zonation and adrenocortical disease. Endocrine research 41 15666793
2003 TR3 orphan nuclear receptor mediates apoptosis through up-regulating E2F1 in human prostate cancer LNCaP cells. The Journal of biological chemistry 41 12947120
2011 FHL2 protein is a novel co-repressor of nuclear receptor Nur77. The Journal of biological chemistry 40 22049082
2011 Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis. Oncogene 39 22002310
2008 Akt phosphorylates the TR3 orphan receptor and blocks its targeting to the mitochondria. Carcinogenesis 39 18713840
2006 Nur77 gene knockout alters dopamine neuron biochemical activity and dopamine turnover. Biological psychiatry 39 16893530
2022 Kallistatin/Serpina3c inhibits cardiac fibrosis after myocardial infarction by regulating glycolysis via Nr4a1 activation. Biochimica et biophysica acta. Molecular basis of disease 38 35577178
2021 PSPH promotes melanoma growth and metastasis by metabolic deregulation-mediated transcriptional activation of NR4A1. Oncogene 37 33674745
2008 A feedback regulatory loop between methyltransferase PRMT1 and orphan receptor TR3. Nucleic acids research 37 19095693
2020 Reactivation of NR4A1 Restrains Chondrocyte Inflammation and Ameliorates Osteoarthritis in Rats. Frontiers in cell and developmental biology 36 32258036
2022 Therapeutic potential of NR4A1 in cancer: Focus on metabolism. Frontiers in oncology 35 36052242
2014 Human-gyrovirus-Apoptin triggers mitochondrial death pathway--Nur77 is required for apoptosis triggering. Neoplasia (New York, N.Y.) 35 25246270
2017 Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells. Cell reports 34 28538176
2003 Regulation of NGFI-B expression during the ovulatory process. Molecular and cellular endocrinology 34 12770726
2015 The nuclear receptor nr4a1 controls CD8 T cell development through transcriptional suppression of runx3. Scientific reports 33 25762306
2014 Dual roles of orphan nuclear receptor TR3/Nur77/NGFI-B in mediating cell survival and apoptosis. International review of cell and molecular biology 33 25376494
2007 Orphan receptor TR3 attenuates the p300-induced acetylation of retinoid X receptor-alpha. Molecular endocrinology (Baltimore, Md.) 33 17761950
2016 PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1. Cancer research 31 27864345
2006 Regulation of the orphan receptor TR3 nuclear functions by c-Jun N terminal kinase phosphorylation. Endocrinology 30 17023523
2005 Selective allosteric ligand activation of the retinoid X receptor heterodimers of NGFI-B and Nurr1. Biochemical pharmacology 30 16288995
2002 Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions. Oncogene 30 12032831
2023 Noncanonical contribution of microglial transcription factor NR4A1 to post-stroke recovery through TNF mRNA destabilization. PLoS biology 29 37486903
2021 Orphan nuclear receptor 4A1 (NR4A1) and novel ligands. Essays in biochemistry 29 34096590
2018 TGFβ-Induced Lung Cancer Cell Migration Is NR4A1-Dependent. Molecular cancer research : MCR 29 30072581
2022 Nur77 Prevents Osteoporosis by Inhibiting the NF-κB Signalling Pathway and Osteoclast Differentiation. Journal of cellular and molecular medicine 28 35181992
2019 BI1071, a Novel Nur77 Modulator, Induces Apoptosis of Cancer Cells by Activating the Nur77-Bcl-2 Apoptotic Pathway. Molecular cancer therapeutics 28 30926635
2016 Nuclear receptor 4A1 (NR4A1) as a drug target for treating rhabdomyosarcoma (RMS). Oncotarget 28 27144436
2012 Orphan receptor TR3 is essential for the maintenance of stem-like properties in gastric cancer cells. Cancer letters 28 23043761
2011 Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis. Carcinogenesis 28 22159226
2021 NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth. Cancers 26 34072371
2018 Nuclear Receptor Nur77 Deficiency Alters Dendritic Cell Function. Frontiers in immunology 26 30123220
2016 NR4A1 Knockdown Suppresses Seizure Activity by Regulating Surface Expression of NR2B. Scientific reports 26 27876882
2014 Novel treatment option for MUC16-positive malignancies with the targeted TRAIL-based fusion protein Meso-TR3. BMC cancer 26 24447304
2023 Oxidative stress impairs the Nur77-Sirt1 axis resulting in a decline in organism homeostasis during aging. Aging cell 25 36883265
2023 Flavonoids Quercetin and Kaempferol Are NR4A1 Antagonists and Suppress Endometriosis in Female Mice. Endocrinology 25 37652054
2022 mPGES-2 blockade antagonizes β-cell senescence to ameliorate diabetes by acting on NR4A1. Nature metabolism 25 35228744
2022 Celastrol upregulated ATG7 triggers autophagy via targeting Nur77 in colorectal cancer. Phytomedicine : international journal of phytotherapy and phytopharmacology 25 35752079
2020 Bis-Indole-Derived Nuclear Receptor 4A1 (NR4A1, Nur77) Ligands as Inhibitors of Endometriosis. Endocrinology 24 32099996
2015 Antithrombotic Effects of Nur77 and Nor1 Are Mediated Through Upregulating Thrombomodulin Expression in Endothelial Cells. Arteriosclerosis, thrombosis, and vascular biology 24 26634653
2024 Nur77 improves ovarian function in reproductive aging mice by activating mitophagy and inhibiting apoptosis. Reproductive biology and endocrinology : RB&E 23 39044215
2019 MiR-506 Suppresses Colorectal Cancer Development by Inhibiting Orphan Nuclear Receptor NR4A1 Expression. Journal of Cancer 23 31293661
2015 Pgc-1α and Nr4a1 Are Target Genes of Circadian Melatonin and Dopamine Release in Murine Retina. Investigative ophthalmology & visual science 23 26393668
2024 Nur77 mitigates endothelial dysfunction through activation of both nitric oxide production and anti-oxidant pathways. Redox biology 22 38290383
2022 hUMSCs Transplantation Regulates AMPK/NR4A1 Signaling Axis to Inhibit Ovarian Fibrosis in POI Rats. Stem cell reviews and reports 22 36307672
2021 Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes. International journal of molecular sciences 22 33562500
2016 Regulation of Nuclear Receptor Nur77 by miR-124. PloS one 22 26840408
2023 Mst1-mediated phosphorylation of Nur77 improves the endometrial receptivity in human and mice. EBioMedicine 21 36623453
2019 Nuclear receptor 4A1 (NR4A1) antagonists induce ROS-dependent inhibition of mTOR signaling in endometrial cancer. Gynecologic oncology 21 31053403
2019 Inhibition of NR4A1 Promotes ROS Accumulation and IL24-Dependent Growth Arrest in Rhabdomyosarcoma. Molecular cancer research : MCR 21 31462501
2015 Calcium-dependent Nr4a1 expression in mouse Leydig cells requires distinct AP1/CRE and MEF2 elements. Journal of molecular endocrinology 21 26647388
2004 Nur77 induction and activation are necessary for interleukin-1 stimulation of proopiomelanocortin in AtT-20 corticotrophs. FEBS letters 21 15063754