{"gene":"NR4A1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2019,"finding":"NR4A1 is preferentially recruited to AP-1 binding sites in tolerant T cells, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes.","method":"Genome-wide epigenetic profiling (ChIP-seq/ATAC-seq), gene expression analysis, NR4A1 overexpression and deletion in mouse T cell tolerance system","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide chromatin profiling with functional validation by both overexpression and knockout, multiple orthogonal methods in one rigorous study","pmids":["30814730"],"is_preprint":false},{"year":2001,"finding":"Akt phosphorylates NR4A1 at Ser-350 within the DNA-binding domain, decreasing NR4A1 transcriptional activity by 50–85%. Akt physically interacts with NR4A1 as shown by co-immunoprecipitation, and this phosphorylation is phosphatidylinositol 3-kinase-dependent.","method":"Co-immunoprecipitation, in vitro and in vivo kinase assay, luciferase reporter assay, site-directed mutagenesis (Ser-350)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis plus co-IP, confirmed in multiple cell lines, replicated by independent group (PMID 11438550)","pmids":["11274386","11438550"],"is_preprint":false},{"year":2001,"finding":"Akt inhibits NR4A1 DNA-binding activity and stimulates its association with 14-3-3 in a phosphorylation-dependent manner, thereby suppressing NR4A1-induced apoptosis in T cells and fibroblasts.","method":"DNA-binding assay, co-immunoprecipitation, overexpression in T cell hybridomas and fibroblasts, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional rescue, consistent with parallel study (PMID 11274386), multiple orthogonal methods","pmids":["11438550"],"is_preprint":false},{"year":1993,"finding":"Phosphorylation of Ser-350 (but not Ser-340) within the DNA-binding domain of NGFI-B/NR4A1 by protein kinase A or NGF-treated PC12 cell extracts reduces binding to the NGFI-B response element.","method":"Bacterial expression of purified DBD, in vitro phosphorylation by PKA, EMSA, site-directed mutagenesis (Ser-340, Ser-350 to Ala)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and direct DNA-binding assay, single lab but multiple orthogonal methods","pmids":["8227042"],"is_preprint":false},{"year":2012,"finding":"NR4A1 (Nur77) binds and sequesters LKB1 in the nucleus, attenuating AMPK activation. A compound (TMPA) binds NR4A1 at specific sites, releases LKB1 to the cytoplasm, enabling LKB1 to phosphorylate AMPKα.","method":"Co-immunoprecipitation (Nur77–LKB1 interaction), subcellular fractionation, AMPK phosphorylation assay, Nur77 knockout diabetic mouse model, compound binding at specific Nur77 sites","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional rescue with KO mice, pharmacological probe with defined binding site, multiple orthogonal methods","pmids":["22983157"],"is_preprint":false},{"year":2015,"finding":"NR4A1 directly associates with p65 (NF-κB) to block its binding to the κB element, suppressing inflammatory cytokine production. LPS-activated p38α phosphorylates NR4A1, counteracting this suppression; a compound blocking the Nur77–p38α interaction (targeting the NR4A1 ligand-binding domain) restores Nur77-mediated NF-κB inhibition.","method":"Co-immunoprecipitation (Nur77–p65, Nur77–p38α), luciferase reporter (κB element), compound screening from Nur77-biased library, LPS-induced sepsis mouse model","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional rescue in vivo and in vitro, pharmacological probe with defined binding domain, multiple orthogonal methods","pmids":["25822914"],"is_preprint":false},{"year":1997,"finding":"Glucocorticoid receptor (GR) antagonizes NR4A1 (Nur77)-dependent transcription by competing at the NurRE element of the POMC gene. GR repression partially blunts CRH-induced NUR77 mRNA and directly antagonizes Nur77 transcriptional activity; in vitro binding and GR mutation analysis indicate the mechanism is similar to GR–AP-1 antagonism.","method":"Transfection/luciferase reporter assays, in vitro binding experiments, GR mutant analysis, endocrine (CRH/POMC) and T cell systems","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding plus mutagenesis, functional reporter assays in two cell types, single lab with multiple methods","pmids":["9315653"],"is_preprint":false},{"year":2003,"finding":"NR4A1 (NGFIB) and NURR1 bind two functional NGFIB response elements (NBRE-1 at -766/-759 and Ad5 at -129/-114) in the CYP11B2 (aldosterone synthase) promoter to activate its transcription; angiotensin II strongly induces both receptors, and calmodulin kinase partially mediates this induction.","method":"Transient transfection/reporter assays, sequential deletion and mutagenesis of CYP11B2 promoter, EMSA, adenoviral overexpression in H295R adrenocortical cells","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — EMSA plus promoter mutagenesis plus adenoviral rescue, single lab, multiple orthogonal methods","pmids":["14645496"],"is_preprint":false},{"year":2004,"finding":"NR4A1 (NGFIB) binds a consensus NGFIB response element in the HSD3B2 promoter to directly activate its transcription; adenoviral NGFIB overexpression increases cortisol production 8-fold and HSD3B2 mRNA 26-fold in human adrenal cells; ACTH rapidly induces NGFIB expression.","method":"Promoter deletion/mutagenesis, EMSA, adenoviral overexpression in primary and H295R adrenal cells, microarray, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — EMSA with mutagenesis, adenoviral rescue, multiple cell types, single lab with orthogonal methods","pmids":["15208301"],"is_preprint":false},{"year":1996,"finding":"NR4A1 (Nur77/N10) overexpression in thymocytes induces apoptosis of CD4+CD8+ double-positive cells by upregulating Fas ligand (FasL), but not Fas receptor; apoptosis is largely blocked in a FasL-defective (gld/gld) background, establishing that one NR4A1 apoptotic pathway proceeds through FasL–Fas signaling.","method":"Transgenic mouse model (nur77/N10-Tg), genetic epistasis with gld/gld mice, flow cytometry of thymocyte populations, FasL expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with rescue experiment, transgenic overexpression, clear phenotypic readout","pmids":["8643610"],"is_preprint":false},{"year":2006,"finding":"NR4A1 (Nur77) migrates from the nucleus to the mitochondria where it binds Bcl-2 and conformationally converts it from a survival factor into a pro-apoptotic protein, triggering cytochrome c release.","method":"Reviewed/summarized from multiple experimental studies including subcellular fractionation, co-immunoprecipitation (Nur77–Bcl-2), cytochrome c release assays, mutant constructs lacking DNA-binding domain","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across multiple labs, reciprocal Co-IP, functional cytochrome c assay; review citing primary experimental data","pmids":["16892086"],"is_preprint":false},{"year":2011,"finding":"Absence of NR4A1 (Nur77) in macrophages increases TLR4 mRNA/protein expression and NF-κB p65 phosphorylation, polarizing macrophages toward a pro-inflammatory M1 phenotype; NF-κB inhibition blocks the excess activation of Nur77-deficient macrophages.","method":"Nur77−/− chimeric mice on Ldlr−/− background, Western blot (p65 phosphorylation, TLR4), NFκB inhibitor rescue, macrophage cytokine profiling","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with pharmacological rescue, defined molecular readouts, single lab","pmids":["22194622"],"is_preprint":false},{"year":2018,"finding":"NR4A1 functions as a key upstream transcriptional regulator of the pro-inflammatory metabolic switch in macrophages; Nur77-deficient macrophages fail to downregulate isocitrate dehydrogenase (IDH) expression and accumulate higher succinate and other TCA metabolites in an SDH-dependent manner, producing more nitric oxide and pro-inflammatory cytokines.","method":"Nr4a1−/− macrophages, metabolomic analysis, mitochondrial respiration assays, succinate dehydrogenase inhibitor rescue, in vivo atherosclerosis model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO macrophages with metabolomics, pharmacological rescue, in vivo validation, multiple orthogonal methods","pmids":["30134173"],"is_preprint":false},{"year":2017,"finding":"NR4A1 is sumoylated by SUMO2/3 at two specific sites; poly-SUMO modification targets NR4A1 for polyubiquitination by the SUMO-dependent E3 ligase RNF4, leading to its degradation. PIAS3 promotes SUMOylation, SENP1 reverses it. Mutation of SUMO sites stabilizes NR4A1, and SUMOylation is required for proper control of NF-κB signaling and macrophage cell death.","method":"Co-immunoprecipitation (SUMO/ubiquitin assays), SUMO site mutagenesis, RNF4/PIAS3/SENP1 knockdown/overexpression, NF-κB reporter assay, macrophage cell death assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical reconstitution of SUMO-ubiquitin cascade with mutagenesis and multiple writer/eraser identifications, functional rescue","pmids":["28622293"],"is_preprint":false},{"year":2011,"finding":"FHL2 is a co-repressor of NR4A1 (Nur77); each of the four LIM domains of FHL2 can bind Nur77 via Nur77's N-terminal and DNA-binding domains. FHL2 inhibits Nur77 association with target gene (enolase3) promoter DNA and represses Nur77 transcriptional activity in a dose-dependent manner.","method":"Yeast two-hybrid, co-immunoprecipitation, domain mapping by deletion mutants, ChIP (enolase3 promoter), shRNA-mediated FHL2 knockdown, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus reciprocal Co-IP plus ChIP, domain mapping, functional rescue, single lab","pmids":["22049082"],"is_preprint":false},{"year":2015,"finding":"Nr4a1 recruits the corepressor CoREST to directly suppress Runx3 expression in CD8+ T cells, controlling CD8 T cell development; loss of Nr4a1 increases Runx3 expression and causes a 2-fold increase in CD8+ T cells in thymus and periphery.","method":"Nr4a1 KO mice, flow cytometry, ChIP (CoREST recruitment to Runx3 locus), gene expression analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO phenotype with ChIP validation of direct transcriptional mechanism, CoREST co-repressor identified","pmids":["25762306"],"is_preprint":false},{"year":2021,"finding":"NR4A1 localizes across the gene body and 3' UTR of immediate early genes (IEGs) and inhibits transcriptional elongation by RNA Pol II, generating R-loops and accessible chromatin domains. Acute replication stress causes NR4A1 dissociation and a burst of IEG expression. Deletion of NR4A1 causes chromosomal instability and proliferative failure driven by deregulated FOS expression.","method":"ChIP-seq (NR4A1 occupancy at IEG bodies), ATAC-seq, R-loop detection, NR4A1 deletion and overexpression in breast cancer cells, chromosomal instability assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide chromatin profiling plus KO and OE with defined molecular phenotype, multiple orthogonal methods in one study","pmids":["34624217"],"is_preprint":false},{"year":2020,"finding":"In the Hippo pathway, YAP regulates NR4A1 transcription, phosphorylation, and mitochondrial localization. NR4A1 in turn acts as a feedback inhibitor of YAP by promoting its degradation, forming a regulatory loop that coordinates cell proliferation and apoptosis during liver regeneration and tumorigenesis.","method":"YAP gain/loss of function, NR4A1 reporter assays, phosphorylation assays, mitochondrial fractionation, in vivo liver regeneration and tumor models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional genetic manipulation with defined phenotype and pathway placement, single lab, abstract-level method detail","pmids":["33086070"],"is_preprint":false},{"year":2012,"finding":"Nr4a1 participates in the induction of Bim after TCR triggering, contributing to clonal deletion; Nr4a1 also positively controls several Treg signature transcripts (Ikzf2, Tnfrsf9) and induces a coordinated set of glycolytic and Krebs cycle enzymes in response to TCR signals, thereby influencing T cell fate determination.","method":"Nr4a1 KO mice, TCR transgenic models, transcriptional profiling of Nr4a1KO thymocytes under selection, apoptosis assays, Bim induction assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice with transcriptome profiling, multiple cell fate readouts, epistasis with Bim, single lab with orthogonal methods","pmids":["22345564"],"is_preprint":false},{"year":2010,"finding":"β-catenin activates NR4A1 (Nur77) expression through AP-1 (c-Fos/c-Jun) binding and transactivation of the Nur77 promoter; elevated Nur77 in colon cancer cells upregulates antiapoptotic BRE and angiogenic VEGF, enhancing growth and migration.","method":"Promoter reporter and mutagenesis assays, ChIP (AP-1 at Nur77 promoter), β-catenin siRNA/overexpression, colon cancer cell functional assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus promoter mutagenesis plus functional rescue, single lab","pmids":["20847229"],"is_preprint":false},{"year":2003,"finding":"NR4A1 (Nur77) is involved in caspase-independent macrophage cell death; its induction requires TLR2/TLR4 signaling through the ERK pathway and MEF2 transcription factor activity. Reporter gene analysis identifies Nap, Ets, Rce, Sp1, and MEF2 elements in the Nur77 promoter as regulated by these signals.","method":"Nur77-deficient macrophages (genetic KO), reporter gene analysis (Nur77 promoter elements), septic mouse model, ERK inhibitor studies, zVAD-induced MEF2 activation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO macrophages with in vivo sepsis model, defined promoter elements by mutagenesis, pharmacological pathway dissection","pmids":["12782711"],"is_preprint":false},{"year":2014,"finding":"NR4A1 (Nur77) regulates ROS and endoplasmic reticulum stress in pancreatic cancer cells via transcriptional regulation of TXNDC5; NR4A1 knockdown decreases TXNDC5 expression, elevating ROS, and activating ER stress/proapoptotic pathways. DIM-C-pPhOH binds NR4A1 and acts as an antagonist.","method":"RNAi knockdown, NR4A1 antagonist (DIM-C-pPhOH) treatment, proteomic analysis, ROS assay, antioxidant rescue, gene expression profiling","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD plus pharmacological inhibition, proteomic profiling, rescue with antioxidant, single lab","pmids":["24515801"],"is_preprint":false},{"year":2014,"finding":"C-DIM compounds (including DIM-C-pPhOH) directly bind the ligand-binding domain of NR4A1 with high affinity and act as NR4A1 antagonists in colon cancer cells, inhibiting NR4A1-dependent transactivation, decreasing survivin and Sp-regulated gene expression, and inhibiting mTOR signaling.","method":"Direct LBD binding assays, molecular modeling of NR4A1 LBD, luciferase reporter (NR4A1-responsive), RNAi, cell proliferation and apoptosis assays","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with structural modeling, functional reporter, KD rescue, single lab","pmids":["25099012"],"is_preprint":false},{"year":2018,"finding":"NR4A1 regulates β1-integrin gene expression to control basal migration of breast cancer cells (TGF-β-independent); NR4A1 nuclear export is an essential step in TGF-β-induced cell migration, and NR4A1 also controls β3-integrin expression.","method":"RNAi (siNR4A1), nuclear export inhibitor (leptomycin B), NR4A1 antagonists (DIM-C-pPhOH), migration assays, β1/β3-integrin expression analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD plus pharmacological blockade of nuclear export, functional migration assay, single lab","pmids":["26929200"],"is_preprint":false},{"year":2018,"finding":"TGF-β/TGFβR/PKA/MKK4-7/JNK signaling phosphorylates and induces nuclear export of NR4A1; cytoplasmic NR4A1 then forms a complex with Axin2, Arkadia (RNF111), and RNF12 (RLIM) to drive proteasomal degradation of SMAD7, thereby enhancing lung cancer cell migration.","method":"Nuclear export inhibitor (leptomycin B), JNK inhibitor (SP600125), NR4A1 antagonist, co-immunoprecipitation (NR4A1–Axin2/Arkadia/RNF12 complex), SMAD7 degradation assay, migration assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of multi-protein complex, pharmacological pathway dissection with functional readout, single lab","pmids":["30072581"],"is_preprint":false},{"year":2018,"finding":"NR4A1 controls CD8+ T cell development through direct transcriptional suppression of Runx3 by recruiting the corepressor CoREST (also reported in PMID 25762306). Separate finding: NR4A1 regulates macrophage polarization and restrains pro-inflammatory NF-κB signaling by directly opposing NFκB activation of IκB-α (inducing IκB-α) and suppressing IKK-β.","method":"shNur77 in RAW264.7 osteoclast model, siIκB-α and siIKK-β rescue experiments, NF-κB reporter, Nur77 KO mice","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue with specific pathway components (IκB-α, IKK-β), KO mouse validation, single lab","pmids":["35181992"],"is_preprint":false},{"year":2019,"finding":"Glycerol kinase (Gyk isoform b) acts as a novel co-repressor of NR4A1 in the liver by binding the C-terminal ligand-binding domain of NR4A1 (not the N-terminal AF-1 domain); this protein–protein interaction inhibits NR4A1 transcriptional activity and suppresses expression of gluconeogenic target genes in vivo.","method":"Co-immunoprecipitation (Gyk–NR4A1), domain mapping, reporter assays, Gyk overexpression in vitro and in vivo (fasted and diabetic mice), gene expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, in vivo overexpression, functional gene expression rescue, single lab","pmids":["30821173"],"is_preprint":false},{"year":2020,"finding":"NR4A1 (Nur77) directly binds and destabilizes Tnf mRNA in microglia in an N6-methyladenosine (m6A)-dependent manner, functioning as a cytoplasmic RNA-binding protein in processing bodies (P-bodies). Conditional microglial deletion of Nr4a1 elevates Tnf expression and worsens ischemic stroke outcomes.","method":"Subcellular localization (P-bodies by imaging), RNA immunoprecipitation (NR4A1–Tnf mRNA binding), mRNA stability assay, m6A-dependent mechanism, conditional microglial Nr4a1 KO, stroke mouse model","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct RNA binding demonstrated, m6A dependence established, conditional KO with in vivo stroke model, multiple orthogonal methods","pmids":["37486903"],"is_preprint":false},{"year":2018,"finding":"NR4A1 in vascular endothelial cells increases thrombomodulin mRNA stability (not promoter activity), whereas the related NR4A3 (Nor1) enhances thrombomodulin expression via induction of KLF2/4. Nur77 deficiency increases susceptibility to arterial thrombosis.","method":"Adenoviral NR4A1 overexpression in ECs and mouse liver, Nur77 KO mice, mRNA stability assay, promoter reporter assay, protein C activity assay, thrombosis model","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO plus adenoviral overexpression, mRNA stability mechanistic dissection, in vivo thrombosis model, single lab","pmids":["26634653"],"is_preprint":false},{"year":2024,"finding":"Nur77 increases GCH1 mRNA stability by inhibiting microRNA-133a expression, and upregulates SOD1 by directly binding the SOD1 promoter in vascular endothelial cells, thereby activating NO production and anti-oxidant pathways that attenuate endothelial dysfunction.","method":"Nur77 KO and endothelial-specific Tg mice, vasodilatation assay, ROS measurement (DHE staining), miRNA-133a overexpression/inhibition, ChIP (Nur77 at SOD1 promoter), mRNA stability assay","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct promoter binding, mRNA stability via miRNA suppression, KO and Tg mice, single lab","pmids":["38290383"],"is_preprint":false},{"year":2018,"finding":"NR4A1 controls CD8+ T cell development; separately, NR4A1 promotes adipocyte progenitor (AP) quiescence — gain of function decreases adipogenesis while loss of function increases proliferative and adipogenic capacity; Nr4a1−/− AP transplantation into obese WT recipients improves glucose homeostasis.","method":"NR4A1 gain/loss-of-function in primary APs ex vivo, Nr4a1−/− mouse adipose tissue analysis, AP transplantation into obese recipients, ATAC-seq, transcriptomics","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice plus chromatin accessibility mapping plus transplantation rescue, single lab, multiple methods","pmids":["30277475"],"is_preprint":false},{"year":2018,"finding":"NR4A1 and NR4A3 restrict HSC proliferation partly through direct binding to a hematopoietic-specific Cebpa enhancer, activating Cebpa transcription. NR4A1/3 also occupy regulatory regions of NF-κB-regulated inflammatory cytokines and antagonize NF-κB activation.","method":"Conditional Nr4a1/Nr4a3 double KO mice, ChIP (NR4A1/3 binding to Cebpa enhancer and NF-κB cytokine loci), transcriptome profiling of HSCs, flow cytometry, DNA damage assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct enhancer occupancy, conditional KO with defined molecular phenotype, multiple gene targets validated, single lab with orthogonal methods","pmids":["29343483"],"is_preprint":false},{"year":2012,"finding":"Nur77 expression in skeletal muscle enhances mitochondrial function and oxidative metabolism; MCK-Nur77 transgenic mice show increased oxidative fiber abundance, elevated mitochondrial DNA content, increased complex I of the electron transport chain, and favor fatty acid oxidation over glucose oxidation.","method":"MCK-Nur77 transgenic mice, mitochondrial respiration assays, metabolomics, electron transport chain component analysis, muscle contractile function assay","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with metabolomics and mitochondrial function measurements, single lab","pmids":["23028113"],"is_preprint":false},{"year":2016,"finding":"β-cell deletion of Nr4a1 and Nr4a3 reduces mitochondrial respiration and glucose-stimulated insulin secretion, associated with decreased expression of mitochondrial dehydrogenase subunits Idh3g and Sdhb, and impaired ATP production.","method":"β-cell-specific Nr4a1/Nr4a3 KO, permeabilized cell respirometry, intact cell glucose-stimulated oxygen consumption, insulin secretion assay, ATP production assay, gene expression","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-specific KO with direct respirometry and insulin secretion assay, mechanistic gene targets identified, single lab","pmids":["27221116"],"is_preprint":false},{"year":2014,"finding":"Nkx6.1 induces expression of Nr4a1 (and Nr4a3), and these receptors are both necessary and sufficient for Nkx6.1-mediated β-cell proliferation; Nr4a1 overexpression increases E2F1 and cyclin E1, and induces APC components including UBE2C, promoting degradation of the cell cycle inhibitor p21. Global Nr4a1 KO reduces β-cell area in neonatal mice.","method":"Adenoviral Nr4a1 overexpression in rat islets, Nr4a1 KO mice (β-cell area quantification), gene expression analysis, cell cycle marker assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice plus adenoviral rescue, defined cell-cycle targets, single lab","pmids":["24706823"],"is_preprint":false},{"year":2004,"finding":"NR4A1 (Nur77) represses NF-κB-driven IL-2 promoter activation through its N-terminal AF-1 domain by inhibiting NF-κB components (p65 and c-Rel) binding at low-affinity κB sites in the IL-2 promoter; this repression is specific to low-affinity sites and not observed on high-affinity HIV LTR κB sites.","method":"Cotransfection/luciferase reporter assays (IL-2 promoter and mutants, CD28RE with NF-κB sites, HIV LTR), Nur77 domain mutants (AF-1 deletion), Jurkat T cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis plus AF-1 domain deletion establishing mechanistic requirement, multiple reporter constructs, single lab","pmids":["15466594"],"is_preprint":false},{"year":2020,"finding":"NR4A1 (Nur77) directly binds WFDC21P promoter response elements to transcriptionally activate WFDC21P lncRNA expression in HCC; this suppresses glycolysis by NR4A1/WFDC21P-dependent disruption of PFKP and PKM2 function.","method":"ChIP (Nur77 binding WFDC21P promoter NBRE elements), reporter assays, KO/KD in vitro and in vivo tumor models, Csn-B agonist treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with direct promoter binding, functional rescue in vivo, single lab","pmids":["31959898"],"is_preprint":false},{"year":2023,"finding":"Mst1 kinase phosphorylates NR4A1 at threonine 366 (T366), enhancing its transcriptional activity and increasing downstream β3-integrin expression in endometrial epithelial cells, thereby promoting trophoblast-uterine epithelium adhesion and embryo implantation.","method":"In vitro kinase assay (Mst1 phosphorylating Nur77), LC-MS/MS identification of T366, phos-tag SDS-PAGE, phospho-specific antibody (pT366), mouse embryo adhesion assay, delayed implantation mouse model, RNA-seq","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with MS site identification, phospho-specific antibody validation, functional in vivo rescue, multiple orthogonal methods","pmids":["36623453"],"is_preprint":false},{"year":2020,"finding":"NR4A1 (Nr4a1) contributes to cocaine-induced neuroadaptation by directly controlling CARTPT expression; Nr4a1 deletion or CRISPR-based Nr4a1 activation demonstrates direct causality for sustained Cartpt transcription during cocaine abstinence, associated with depletion of H3K27me3 and enrichment of H3K27ac and H3K4me3 at the Cartpt locus.","method":"CRISPR-mediated Nr4a1 activation, small molecule Nr4a1 activation, ChIP (H3K27me3, H3K27ac, H3K4me3), cocaine behavioral assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR causal demonstration plus ChIP histone marks, behavioral readout, single lab","pmids":["31980629"],"is_preprint":false},{"year":2016,"finding":"NR4A1 regulates PAX3-FOXO1A expression in alveolar rhabdomyosarcoma through an NR4A1/Sp4 complex that binds GC-rich promoter regions; RNAi of NR4A1 or NR4A1 antagonists reduce PAX3-FOXO1A and its downstream effectors.","method":"RNAi (siNR4A1), NR4A1 antagonists (C-DIM), ChIP/promoter reporter (NR4A1/Sp4 at PAX3-FOXO1A promoter GC-rich elements), gene expression profiling, migration assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing complex occupancy at promoter, functional siRNA rescue, single lab","pmids":["27864345"],"is_preprint":false},{"year":2022,"finding":"Resveratrol binds the ligand-binding domain of NR4A1 with KD = 2.4 µM (measured by isothermal titration calorimetry) and acts as an NR4A1 antagonist, inhibiting NR4A1-dependent transactivation in lung cancer cells.","method":"Isothermal titration calorimetry (direct binding to NR4A1 LBD), luciferase reporter (NR4A1-responsive), functional assays (proliferation, migration), gene expression","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct biophysical binding measurement (ITC) plus functional transactivation assay, single lab","pmids":["35680166"],"is_preprint":false},{"year":2020,"finding":"NR4A1 promotes mitochondrial fission in VSMCs by activating DNA-PKcs and p53 and facilitating Drp1 migration to mitochondria; NR4A1 also inhibits BNIP3-related mitophagy, causing mitochondrial dysfunction and contributing to vascular calcification.","method":"NR4A1 siRNA knockdown, Western blot (Drp1, BNIP3, LC3-II, p62), mRFP-GFP-LC3 adenovirus, mPTP opening rate, membrane potential, TEM, ATP/OCR measurement, ex vivo calcification staining","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple mitochondrial function readouts and pathway rescue, single lab","pmids":["31993850"],"is_preprint":false},{"year":2018,"finding":"NR4A1 regulates Parkin-mediated mitophagy in endothelial cells through post-transcriptional modification of Parkin via CaMKII; ox-LDL-induced NR4A1 activates CaMKII, which phosphorylates Parkin, driving excessive mitophagy and endothelial apoptosis.","method":"NR4A1 KO/overexpression in AECs, CaMKII inhibitor, Parkin phosphorylation assay, mitochondrial function assays, in vitro and high-fat diet mouse model","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and OE with pharmacological rescue, defined PTM pathway (CaMKII→Parkin phosphorylation), single lab","pmids":["29470798"],"is_preprint":false},{"year":2024,"finding":"NR4A1 expression is regulated by the transcription factor Creb5 in the PI3K/AKT pathway in cardiomyocytes; semaglutide reduces NR4A1 expression and its translocation to mitochondria through the Creb5/NR4A1 axis, and NR4A1 knockdown ameliorates mitochondrial dysfunction and abnormal metabolic shifts in the heart.","method":"Transcriptional analysis (Creb5/NR4A1 axis), NR4A1 knockdown in cardiomyocytes, metabolomics, mitochondrial structure/function assays, mouse pressure-overload heart failure model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with metabolomics and mitochondrial assays, transcriptional pathway identified, single lab with multiple methods","pmids":["38834564"],"is_preprint":false},{"year":2023,"finding":"Nr4a1 overexpression protects Sirt1 protein from proteasomal degradation through negative transcriptional regulation of the E3 ubiquitin ligase MDM2; Nr4a1 deletion shortens mouse lifespan and accelerates aging in multiple tissues.","method":"Nr4a1 KO mice (lifespan/aging phenotype), overexpression of Nr4a1 (MDM2 reporter assay, Sirt1 protein stability), proteasome inhibitor rescue, gene expression analysis","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice plus OE with proteasome rescue, MDM2 transcriptional regulation assay, single lab","pmids":["36883265"],"is_preprint":false},{"year":2021,"finding":"MEF2D transcriptionally activates NR4A1 expression in response to amino acid deficiency; NR4A1 in turn activates FAM134B2 (RETREG1) expression to drive reticulophagy, contributing to amino acid homeostasis.","method":"Gene expression profiling, reporter assays, loss-of-function experiments in amino acid-deficient conditions","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — abstract provides limited method detail; pathway described but mechanistic depth unclear from abstract alone","pmids":["34517786"],"is_preprint":false},{"year":2016,"finding":"NR4A1 interacts with NR2B (NMDA receptor subunit) as shown by reciprocal co-immunoprecipitation in neurons; NR4A1 knockdown reduces surface NR2B expression by promoting NR2B internalization (reduced p-NR2B Tyr1472 and reduced NR2B in postsynaptic density), and alleviates seizure severity.","method":"Reciprocal co-immunoprecipitation (NR4A1–NR2B), lentiviral shNR4A1, postsynaptic density fractionation, seizure behavioral assay, pilocarpine mouse model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP establishing physical interaction, fractionation, in vivo seizure model, single lab","pmids":["27876882"],"is_preprint":false},{"year":2020,"finding":"SUMOylation of NR4A1 is required for induction of autophagic cell death; triple mutation of SUMO sites reduces NR4A1 SUMOylation, increases transcriptional activity, alters intracellular distribution, and impairs autophagic cell death induction.","method":"SUMO site mutagenesis (triple mutant), SUMOylation assay, transcriptional reporter, subcellular localization imaging, autophagic cell death assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis plus functional autophagy assay, multiple readouts, single lab","pmids":["32210435"],"is_preprint":false},{"year":2024,"finding":"Nr4a1 regulates contrasting transcriptional programs in parvalbumin- and somatostatin-positive GABAergic interneurons in the mouse forebrain, exerting cell-type-specific effects on local axonal wiring; loss of Nr4a1 causes bidirectional transcriptional switches in genes including surface adhesion and repulsion molecules.","method":"Conditional Nr4a1 KO in PV and SST interneurons, transcriptome profiling, synaptic connectivity assays, behavioral learning assays","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with transcriptome profiling and circuit-level phenotype, single lab","pmids":["38754414"],"is_preprint":false}],"current_model":"NR4A1 (Nur77/NGFIB/TR3) is an orphan nuclear receptor and immediate-early transcription factor whose activity is controlled by subcellular localization, phosphorylation (by Akt at Ser-350 reducing DNA binding; by Mst1 at T366 enhancing activity; by p38α counteracting its anti-inflammatory function), SUMOylation/ubiquitination (PIAS3/SUMO2-3/RNF4 driving proteasomal degradation), and protein–protein interactions (co-repressors FHL2 and Gyk; GR antagonism at NurRE); in the nucleus it activates target gene transcription (CYP11B2, HSD3B2, WFDC21P, Cebpa, Runx3-suppression via CoREST, IEG regulation via RNA Pol II elongation inhibition), suppresses NF-κB by directly binding p65 and occupying NF-κB regulatory loci, represses AP-1-driven effector genes in tolerant T cells, and acts as an RNA-binding protein in P-bodies to destabilize TNF mRNA; upon apoptotic stimuli it translocates to mitochondria where it binds Bcl-2 and converts it to a pro-apoptotic conformation triggering cytochrome c release, and in the cytoplasm sequesters LKB1 to attenuate AMPK activation."},"narrative":{"mechanistic_narrative":"NR4A1 (Nur77/NGFIB/TR3) is an immediate-early orphan nuclear receptor and transcription factor whose biological output is dictated by subcellular localization, post-translational modification, and an unusually wide repertoire of protein and RNA interactions spanning transcriptional control, apoptosis, immune restraint, and metabolic regulation [PMID:16892086, PMID:34624217, PMID:29343483]. In the nucleus it binds NGFIB response elements to directly activate steroidogenic and metabolic targets including CYP11B2 and HSD3B2 in adrenal cells [PMID:14645496, PMID:15208301], the Cebpa enhancer in hematopoietic stem cells [PMID:29343483], and SOD1 in endothelium [PMID:38290383], while also acting as a repressor: it occupies immediate-early gene bodies to inhibit RNA Pol II elongation and generate R-loops, restraining FOS and preventing chromosomal instability [PMID:34624217], and recruits the corepressor CoREST to suppress Runx3 during CD8 T cell development [PMID:25762306]. A central function is restraint of inflammation—NR4A1 directly associates with NF-κB p65 to block κB-element binding and suppress cytokine production [PMID:25822914, PMID:15466594], and its loss drives M1 macrophage polarization and a pro-inflammatory TCA-cycle metabolic switch [PMID:22194622, PMID:30134173]. Its transcriptional activity is gated by phosphorylation (Akt at Ser-350 within the DNA-binding domain reduces DNA binding and promotes 14-3-3 association [PMID:11274386, PMID:11438550]; Mst1 at Thr-366 enhances activity [PMID:36623453]; LPS-activated p38α counteracts NF-κB suppression [PMID:25822914]), by SUMO2/3 modification that recruits RNF4 for ubiquitin-dependent degradation [PMID:28622293], and by corepressors FHL2 and glycerol kinase that bind distinct domains [PMID:22049082, PMID:30821173]. Beyond the nucleus, NR4A1 translocates to mitochondria where it converts Bcl-2 into a pro-apoptotic form to trigger cytochrome c release [PMID:16892086], sequesters LKB1 to attenuate AMPK activation [PMID:22983157], and acts as a cytoplasmic, m6A-dependent RNA-binding protein in P-bodies that destabilizes Tnf mRNA [PMID:37486903]. Through these activities NR4A1 governs T cell tolerance and clonal deletion [PMID:30814730, PMID:8643610, PMID:22345564], β-cell and adipocyte proliferative fate [PMID:27221116, PMID:24706823, PMID:30277475], and mitochondrial/oxidative metabolism in muscle, vasculature, and heart [PMID:23028113, PMID:31993850, PMID:38834564].","teleology":[{"year":1993,"claim":"Established that NR4A1 transcriptional output is directly gated by phosphorylation within its DNA-binding domain, the first mechanism explaining signal-dependent control of this immediate-early factor.","evidence":"In vitro PKA phosphorylation of purified DBD with Ser-340/Ser-350 mutagenesis and EMSA","pmids":["8227042"],"confidence":"High","gaps":["Did not identify the physiological kinase in cells","Did not connect DNA-binding loss to a cellular phenotype"]},{"year":1996,"claim":"Defined a transcriptional apoptotic route by showing NR4A1 drives thymocyte death via FasL upregulation, placing it in negative selection.","evidence":"Transgenic nur77 overexpression with genetic epistasis in gld/gld FasL-defective mice","pmids":["8643610"],"confidence":"High","gaps":["Did not address the later-discovered transcription-independent mitochondrial pathway","FasL induction mechanism not resolved at promoter level"]},{"year":1997,"claim":"Showed NR4A1 transcription is antagonized by the glucocorticoid receptor at the NurRE, integrating it into endocrine negative feedback.","evidence":"Luciferase reporters, in vitro binding, and GR mutant analysis in endocrine and T cell systems","pmids":["9315653"],"confidence":"High","gaps":["Mechanism inferred by analogy to GR–AP-1 antagonism rather than fully resolved","Direct GR–Nur77 contact not structurally defined"]},{"year":2001,"claim":"Identified Akt as a survival-signaling kinase that phosphorylates Ser-350, suppressing DNA binding, promoting 14-3-3 association, and blocking NR4A1-induced apoptosis.","evidence":"Co-IP, in vitro/in vivo kinase assays, DNA-binding assays, and apoptosis rescue in T cells and fibroblasts (two independent studies)","pmids":["11274386","11438550"],"confidence":"High","gaps":["Did not establish whether 14-3-3 binding governs cytoplasmic retention","Upstream stimuli setting Akt-Nur77 balance not mapped"]},{"year":2003,"claim":"Resolved NR4A1 as a direct transcriptional activator of steroidogenic genes, linking ACTH/angiotensin signaling to adrenal CYP11B2 and HSD3B2 expression.","evidence":"EMSA, promoter mutagenesis, and adenoviral overexpression in adrenocortical cells","pmids":["14645496","15208301"],"confidence":"High","gaps":["Coactivator requirements at these promoters not defined","Did not address regulation by NR4A1 post-translational state"]},{"year":2003,"claim":"Connected innate immune signaling to NR4A1 induction and identified a caspase-independent macrophage death program downstream of TLR/ERK/MEF2.","evidence":"Nur77-deficient macrophages, promoter element mutagenesis, ERK inhibition, and septic mouse model","pmids":["12782711"],"confidence":"High","gaps":["Effector mechanism of caspase-independent death unresolved","Did not separate transcriptional from mitochondrial Nur77 contributions"]},{"year":2006,"claim":"Consolidated the transcription-independent apoptotic mechanism in which mitochondrial NR4A1 converts Bcl-2 to a pro-apoptotic conformation triggering cytochrome c release.","evidence":"Review of subcellular fractionation, Nur77–Bcl-2 Co-IP, cytochrome c assays, and DBD-deletion constructs","pmids":["16892086"],"confidence":"High","gaps":["Signals controlling nuclear-to-mitochondrial export not fully defined","Structural basis of the Bcl-2 conformational switch not resolved"]},{"year":2012,"claim":"Revealed a non-genomic cytoplasmic function: NR4A1 sequesters LKB1 to restrain AMPK, providing a druggable node in metabolic disease.","evidence":"Reciprocal Co-IP, subcellular fractionation, AMPK phosphorylation assay, Nur77-KO diabetic mice, and the TMPA probe with defined binding sites","pmids":["22983157"],"confidence":"High","gaps":["Did not define the trigger for LKB1 release in vivo","Relationship to nuclear transcriptional role unclear"]},{"year":2012,"claim":"Mapped NR4A1's role in T cell fate decisions, including Bim-dependent clonal deletion and induction of Treg and metabolic gene programs after TCR signaling.","evidence":"Nr4a1-KO and TCR-transgenic mice with transcriptional profiling and apoptosis assays","pmids":["22345564"],"confidence":"High","gaps":["Direct vs indirect control of Bim not resolved","Metabolic gene induction mechanism not dissected"]},{"year":2015,"claim":"Established direct anti-inflammatory restraint of NF-κB via NR4A1–p65 binding, and that p38α phosphorylation neutralizes this suppression—defining a pharmacological strategy.","evidence":"Reciprocal Co-IP, κB reporter assays, Nur77-biased compound screen, and LPS sepsis model","pmids":["25822914"],"confidence":"High","gaps":["p38α phosphosite on Nur77 not identified here","Genome-wide breadth of NF-κB locus occupancy not addressed"]},{"year":2015,"claim":"Defined a corepressor mechanism in CD8 T cell development by which NR4A1 recruits CoREST to directly silence Runx3.","evidence":"Nr4a1-KO mice, flow cytometry, and ChIP at the Runx3 locus","pmids":["25762306"],"confidence":"High","gaps":["CoREST recruitment determinants on NR4A1 not mapped","Generality of CoREST partnership at other loci unknown"]},{"year":2017,"claim":"Defined the degradative arm of NR4A1 regulation: SUMO2/3 modification recruits the SUMO-targeted E3 ligase RNF4 for ubiquitin-dependent turnover, controlling NF-κB output and macrophage death.","evidence":"SUMO/ubiquitin Co-IP, SUMO-site mutagenesis, PIAS3/RNF4/SENP1 perturbation, and functional macrophage assays","pmids":["28622293"],"confidence":"High","gaps":["Did not resolve which functional pool is preferentially degraded","Signals triggering SUMOylation not defined"]},{"year":2018,"claim":"Showed NR4A1 enforces an anti-inflammatory macrophage metabolic state, with loss causing failure to downregulate IDH and succinate accumulation driving cytokine production.","evidence":"Nr4a1-KO macrophages with metabolomics, respiration assays, SDH inhibition, and atherosclerosis model","pmids":["30134173","22194622"],"confidence":"High","gaps":["Direct transcriptional targets among metabolic enzymes not fully mapped","Link to mitochondrial Nur77 pool not established"]},{"year":2018,"claim":"Established direct enhancer occupancy controlling stem and progenitor proliferation, including NR4A1/NR4A3 binding the Cebpa enhancer in HSCs and antagonism of NF-κB inflammatory loci.","evidence":"Conditional Nr4a1/Nr4a3 double-KO mice with ChIP and HSC transcriptome profiling","pmids":["29343483"],"confidence":"High","gaps":["Functional redundancy of NR4A1 vs NR4A3 at each locus not separated","Coregulator complement at the Cebpa enhancer unknown"]},{"year":2021,"claim":"Uncovered a chromatin function in which NR4A1 occupies IEG bodies to inhibit Pol II elongation, generate R-loops, and protect genome stability by restraining FOS.","evidence":"ChIP-seq, ATAC-seq, R-loop detection, and KO/OE in breast cancer cells with chromosomal instability assays","pmids":["34624217"],"confidence":"High","gaps":["How replication stress triggers NR4A1 dissociation mechanistically unresolved","Relationship to its NBRE-based activation role not integrated"]},{"year":2023,"claim":"Identified an activating phosphorylation, Mst1 at Thr-366, that enhances NR4A1 transcriptional activity, contrasting the inhibitory Akt/PKA sites.","evidence":"In vitro kinase assay, LC-MS/MS site mapping, phospho-specific antibody, and in vivo embryo implantation model","pmids":["36623453"],"confidence":"High","gaps":["Structural effect of T366 phosphorylation on the receptor not defined","Cross-talk with inhibitory phosphosites not examined"]},{"year":2023,"claim":"Defined a cytoplasmic, m6A-dependent RNA-binding function in which NR4A1 destabilizes Tnf mRNA in P-body microglia, extending its anti-inflammatory role to post-transcriptional control.","evidence":"RNA immunoprecipitation, P-body imaging, mRNA stability assays, and conditional microglial KO in a stroke model","pmids":["37486903"],"confidence":"High","gaps":["RNA-binding interface on NR4A1 not structurally defined","Breadth of NR4A1-bound transcripts beyond Tnf unknown"]},{"year":2024,"claim":"Extended NR4A1's transcriptional reach into neuronal circuit wiring, showing cell-type-specific programs in PV and SST interneurons that shape axonal connectivity.","evidence":"Cell-type-specific conditional Nr4a1 KO with transcriptome profiling and connectivity/behavioral assays","pmids":["38754414"],"confidence":"Medium","gaps":["Direct vs indirect targets among adhesion/repulsion genes not separated","Mechanism of opposite directionality between interneuron types unresolved"]},{"year":null,"claim":"How NR4A1's distinct functional pools—NBRE-driven activator, IEG-body elongation repressor, mitochondrial Bcl-2 converter, LKB1 sequestrant, and P-body RNA destabilizer—are coordinately partitioned by ligand binding and post-translational state remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking phosphorylation/SUMOylation code to localization choice","Endogenous physiological ligand status of the LBD undefined despite multiple synthetic antagonists/agonists","Quantitative balance among competing functions in a single cell unmeasured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,8,15,16,31,36]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,7,8,29,31,36]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[27,28,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5,10,35]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,7,8,16,31]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[10,17,41,43]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[24,27]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,11,12,18,27,31,35]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,8,15,16,31,36]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,10,20,47]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,12,32,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,5,17,37]}],"complexes":[],"partners":["BCL2","RELA","STK11","FHL2","MAPK14","AKT1","STK4","GLPK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P22736","full_name":"Nuclear receptor subfamily 4immunitygroup A member 1","aliases":["Early response protein NAK1","Nuclear hormone receptor NUR/77","Nur77","Orphan nuclear receptor HMR","Orphan nuclear receptor TR3","ST-59","Testicular receptor 3"],"length_aa":598,"mass_kda":64.5,"function":"Orphan nuclear receptor. Binds the NGFI-B response element (NBRE) 5'-AAAGGTCA-3' (PubMed:18690216, PubMed:8121493, PubMed:9315652). Binds 9-cis-retinoic acid outside of its ligand-binding (NR LBD) domain (PubMed:18690216). Participates in energy homeostasis by sequestrating the kinase STK11 in the nucleus, thereby attenuating cytoplasmic AMPK activation (PubMed:22983157). Regulates the inflammatory response in macrophages by regulating metabolic adaptations during inflammation, including repressing the transcription of genes involved in the citric acid cycle (TCA) (By similarity). Inhibits NF-kappa-B signaling by binding to low-affinity NF-kappa-B binding sites, such as at the IL2 promoter (PubMed:15466594). May act concomitantly with NR4A2 in regulating the expression of delayed-early genes during liver regeneration (By similarity). Plays a role in the vascular response to injury (By similarity) In the cytosol, upon its detection of both bacterial lipopolysaccharide (LPS) and NBRE-containing mitochondrial DNA released by GSDMD pores during pyroptosis, it promotes non-canonical NLRP3 inflammasome activation by stimulating association of NLRP3 and NEK7","subcellular_location":"Nucleus; Cytoplasm, cytosol; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/P22736/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR4A1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NR4A1","total_profiled":1310},"omim":[{"mim_id":"613890","title":"3-@BETA-HYDROXYSTEROID DEHYDROGENASE 2; HSD3B2","url":"https://www.omim.org/entry/613890"},{"mim_id":"613677","title":"HYPERALDOSTERONISM, FAMILIAL, TYPE III; HALD3","url":"https://www.omim.org/entry/613677"},{"mim_id":"609455","title":"PROLINE-, GLUTAMIC ACID-, AND LEUCINE-RICH PROTEIN 1; PELP1","url":"https://www.omim.org/entry/609455"},{"mim_id":"608070","title":"HOMOCYSTEINE- AND ENDOPLASMIC RETICULUM STRESS-INDUCIBLE PROTEIN, UBIQUITIN-LIKE DOMAIN-CONTAINING, 1; HERPUD1","url":"https://www.omim.org/entry/608070"},{"mim_id":"606542","title":"HISTONE DEACETYLASE 7A; HDAC7A","url":"https://www.omim.org/entry/606542"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NR4A1"},"hgnc":{"alias_symbol":["TR3","N10","NAK-1","NGFIB","NUR77"],"prev_symbol":["HMR","GFRP1"]},"alphafold":{"accession":"P22736","domains":[{"cath_id":"3.30.50.10","chopping":"275-329","consensus_level":"high","plddt":96.4367,"start":275,"end":329},{"cath_id":"1.10.565.10","chopping":"360-594","consensus_level":"high","plddt":90.1641,"start":360,"end":594}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22736","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22736-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22736-F1-predicted_aligned_error_v6.png","plddt_mean":66.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR4A1","jax_strain_url":"https://www.jax.org/strain/search?query=NR4A1"},"sequence":{"accession":"P22736","fasta_url":"https://rest.uniprot.org/uniprotkb/P22736.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22736/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22736"}},"corpus_meta":[{"pmid":"30814730","id":"PMC_30814730","title":"Genome-wide 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NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes.\",\n      \"method\": \"Genome-wide epigenetic profiling (ChIP-seq/ATAC-seq), gene expression analysis, NR4A1 overexpression and deletion in mouse T cell tolerance system\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide chromatin profiling with functional validation by both overexpression and knockout, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"30814730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Akt phosphorylates NR4A1 at Ser-350 within the DNA-binding domain, decreasing NR4A1 transcriptional activity by 50–85%. Akt physically interacts with NR4A1 as shown by co-immunoprecipitation, and this phosphorylation is phosphatidylinositol 3-kinase-dependent.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo kinase assay, luciferase reporter assay, site-directed mutagenesis (Ser-350)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis plus co-IP, confirmed in multiple cell lines, replicated by independent group (PMID 11438550)\",\n      \"pmids\": [\"11274386\", \"11438550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Akt inhibits NR4A1 DNA-binding activity and stimulates its association with 14-3-3 in a phosphorylation-dependent manner, thereby suppressing NR4A1-induced apoptosis in T cells and fibroblasts.\",\n      \"method\": \"DNA-binding assay, co-immunoprecipitation, overexpression in T cell hybridomas and fibroblasts, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional rescue, consistent with parallel study (PMID 11274386), multiple orthogonal methods\",\n      \"pmids\": [\"11438550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Phosphorylation of Ser-350 (but not Ser-340) within the DNA-binding domain of NGFI-B/NR4A1 by protein kinase A or NGF-treated PC12 cell extracts reduces binding to the NGFI-B response element.\",\n      \"method\": \"Bacterial expression of purified DBD, in vitro phosphorylation by PKA, EMSA, site-directed mutagenesis (Ser-340, Ser-350 to Ala)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and direct DNA-binding assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"8227042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NR4A1 (Nur77) binds and sequesters LKB1 in the nucleus, attenuating AMPK activation. A compound (TMPA) binds NR4A1 at specific sites, releases LKB1 to the cytoplasm, enabling LKB1 to phosphorylate AMPKα.\",\n      \"method\": \"Co-immunoprecipitation (Nur77–LKB1 interaction), subcellular fractionation, AMPK phosphorylation assay, Nur77 knockout diabetic mouse model, compound binding at specific Nur77 sites\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional rescue with KO mice, pharmacological probe with defined binding site, multiple orthogonal methods\",\n      \"pmids\": [\"22983157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NR4A1 directly associates with p65 (NF-κB) to block its binding to the κB element, suppressing inflammatory cytokine production. LPS-activated p38α phosphorylates NR4A1, counteracting this suppression; a compound blocking the Nur77–p38α interaction (targeting the NR4A1 ligand-binding domain) restores Nur77-mediated NF-κB inhibition.\",\n      \"method\": \"Co-immunoprecipitation (Nur77–p65, Nur77–p38α), luciferase reporter (κB element), compound screening from Nur77-biased library, LPS-induced sepsis mouse model\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional rescue in vivo and in vitro, pharmacological probe with defined binding domain, multiple orthogonal methods\",\n      \"pmids\": [\"25822914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Glucocorticoid receptor (GR) antagonizes NR4A1 (Nur77)-dependent transcription by competing at the NurRE element of the POMC gene. GR repression partially blunts CRH-induced NUR77 mRNA and directly antagonizes Nur77 transcriptional activity; in vitro binding and GR mutation analysis indicate the mechanism is similar to GR–AP-1 antagonism.\",\n      \"method\": \"Transfection/luciferase reporter assays, in vitro binding experiments, GR mutant analysis, endocrine (CRH/POMC) and T cell systems\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding plus mutagenesis, functional reporter assays in two cell types, single lab with multiple methods\",\n      \"pmids\": [\"9315653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NR4A1 (NGFIB) and NURR1 bind two functional NGFIB response elements (NBRE-1 at -766/-759 and Ad5 at -129/-114) in the CYP11B2 (aldosterone synthase) promoter to activate its transcription; angiotensin II strongly induces both receptors, and calmodulin kinase partially mediates this induction.\",\n      \"method\": \"Transient transfection/reporter assays, sequential deletion and mutagenesis of CYP11B2 promoter, EMSA, adenoviral overexpression in H295R adrenocortical cells\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — EMSA plus promoter mutagenesis plus adenoviral rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"14645496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NR4A1 (NGFIB) binds a consensus NGFIB response element in the HSD3B2 promoter to directly activate its transcription; adenoviral NGFIB overexpression increases cortisol production 8-fold and HSD3B2 mRNA 26-fold in human adrenal cells; ACTH rapidly induces NGFIB expression.\",\n      \"method\": \"Promoter deletion/mutagenesis, EMSA, adenoviral overexpression in primary and H295R adrenal cells, microarray, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — EMSA with mutagenesis, adenoviral rescue, multiple cell types, single lab with orthogonal methods\",\n      \"pmids\": [\"15208301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NR4A1 (Nur77/N10) overexpression in thymocytes induces apoptosis of CD4+CD8+ double-positive cells by upregulating Fas ligand (FasL), but not Fas receptor; apoptosis is largely blocked in a FasL-defective (gld/gld) background, establishing that one NR4A1 apoptotic pathway proceeds through FasL–Fas signaling.\",\n      \"method\": \"Transgenic mouse model (nur77/N10-Tg), genetic epistasis with gld/gld mice, flow cytometry of thymocyte populations, FasL expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with rescue experiment, transgenic overexpression, clear phenotypic readout\",\n      \"pmids\": [\"8643610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NR4A1 (Nur77) migrates from the nucleus to the mitochondria where it binds Bcl-2 and conformationally converts it from a survival factor into a pro-apoptotic protein, triggering cytochrome c release.\",\n      \"method\": \"Reviewed/summarized from multiple experimental studies including subcellular fractionation, co-immunoprecipitation (Nur77–Bcl-2), cytochrome c release assays, mutant constructs lacking DNA-binding domain\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across multiple labs, reciprocal Co-IP, functional cytochrome c assay; review citing primary experimental data\",\n      \"pmids\": [\"16892086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Absence of NR4A1 (Nur77) in macrophages increases TLR4 mRNA/protein expression and NF-κB p65 phosphorylation, polarizing macrophages toward a pro-inflammatory M1 phenotype; NF-κB inhibition blocks the excess activation of Nur77-deficient macrophages.\",\n      \"method\": \"Nur77−/− chimeric mice on Ldlr−/− background, Western blot (p65 phosphorylation, TLR4), NFκB inhibitor rescue, macrophage cytokine profiling\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with pharmacological rescue, defined molecular readouts, single lab\",\n      \"pmids\": [\"22194622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR4A1 functions as a key upstream transcriptional regulator of the pro-inflammatory metabolic switch in macrophages; Nur77-deficient macrophages fail to downregulate isocitrate dehydrogenase (IDH) expression and accumulate higher succinate and other TCA metabolites in an SDH-dependent manner, producing more nitric oxide and pro-inflammatory cytokines.\",\n      \"method\": \"Nr4a1−/− macrophages, metabolomic analysis, mitochondrial respiration assays, succinate dehydrogenase inhibitor rescue, in vivo atherosclerosis model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO macrophages with metabolomics, pharmacological rescue, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"30134173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NR4A1 is sumoylated by SUMO2/3 at two specific sites; poly-SUMO modification targets NR4A1 for polyubiquitination by the SUMO-dependent E3 ligase RNF4, leading to its degradation. PIAS3 promotes SUMOylation, SENP1 reverses it. Mutation of SUMO sites stabilizes NR4A1, and SUMOylation is required for proper control of NF-κB signaling and macrophage cell death.\",\n      \"method\": \"Co-immunoprecipitation (SUMO/ubiquitin assays), SUMO site mutagenesis, RNF4/PIAS3/SENP1 knockdown/overexpression, NF-κB reporter assay, macrophage cell death assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical reconstitution of SUMO-ubiquitin cascade with mutagenesis and multiple writer/eraser identifications, functional rescue\",\n      \"pmids\": [\"28622293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FHL2 is a co-repressor of NR4A1 (Nur77); each of the four LIM domains of FHL2 can bind Nur77 via Nur77's N-terminal and DNA-binding domains. FHL2 inhibits Nur77 association with target gene (enolase3) promoter DNA and represses Nur77 transcriptional activity in a dose-dependent manner.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, domain mapping by deletion mutants, ChIP (enolase3 promoter), shRNA-mediated FHL2 knockdown, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus reciprocal Co-IP plus ChIP, domain mapping, functional rescue, single lab\",\n      \"pmids\": [\"22049082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nr4a1 recruits the corepressor CoREST to directly suppress Runx3 expression in CD8+ T cells, controlling CD8 T cell development; loss of Nr4a1 increases Runx3 expression and causes a 2-fold increase in CD8+ T cells in thymus and periphery.\",\n      \"method\": \"Nr4a1 KO mice, flow cytometry, ChIP (CoREST recruitment to Runx3 locus), gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype with ChIP validation of direct transcriptional mechanism, CoREST co-repressor identified\",\n      \"pmids\": [\"25762306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NR4A1 localizes across the gene body and 3' UTR of immediate early genes (IEGs) and inhibits transcriptional elongation by RNA Pol II, generating R-loops and accessible chromatin domains. Acute replication stress causes NR4A1 dissociation and a burst of IEG expression. Deletion of NR4A1 causes chromosomal instability and proliferative failure driven by deregulated FOS expression.\",\n      \"method\": \"ChIP-seq (NR4A1 occupancy at IEG bodies), ATAC-seq, R-loop detection, NR4A1 deletion and overexpression in breast cancer cells, chromosomal instability assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide chromatin profiling plus KO and OE with defined molecular phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"34624217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In the Hippo pathway, YAP regulates NR4A1 transcription, phosphorylation, and mitochondrial localization. NR4A1 in turn acts as a feedback inhibitor of YAP by promoting its degradation, forming a regulatory loop that coordinates cell proliferation and apoptosis during liver regeneration and tumorigenesis.\",\n      \"method\": \"YAP gain/loss of function, NR4A1 reporter assays, phosphorylation assays, mitochondrial fractionation, in vivo liver regeneration and tumor models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional genetic manipulation with defined phenotype and pathway placement, single lab, abstract-level method detail\",\n      \"pmids\": [\"33086070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nr4a1 participates in the induction of Bim after TCR triggering, contributing to clonal deletion; Nr4a1 also positively controls several Treg signature transcripts (Ikzf2, Tnfrsf9) and induces a coordinated set of glycolytic and Krebs cycle enzymes in response to TCR signals, thereby influencing T cell fate determination.\",\n      \"method\": \"Nr4a1 KO mice, TCR transgenic models, transcriptional profiling of Nr4a1KO thymocytes under selection, apoptosis assays, Bim induction assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice with transcriptome profiling, multiple cell fate readouts, epistasis with Bim, single lab with orthogonal methods\",\n      \"pmids\": [\"22345564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"β-catenin activates NR4A1 (Nur77) expression through AP-1 (c-Fos/c-Jun) binding and transactivation of the Nur77 promoter; elevated Nur77 in colon cancer cells upregulates antiapoptotic BRE and angiogenic VEGF, enhancing growth and migration.\",\n      \"method\": \"Promoter reporter and mutagenesis assays, ChIP (AP-1 at Nur77 promoter), β-catenin siRNA/overexpression, colon cancer cell functional assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus promoter mutagenesis plus functional rescue, single lab\",\n      \"pmids\": [\"20847229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NR4A1 (Nur77) is involved in caspase-independent macrophage cell death; its induction requires TLR2/TLR4 signaling through the ERK pathway and MEF2 transcription factor activity. Reporter gene analysis identifies Nap, Ets, Rce, Sp1, and MEF2 elements in the Nur77 promoter as regulated by these signals.\",\n      \"method\": \"Nur77-deficient macrophages (genetic KO), reporter gene analysis (Nur77 promoter elements), septic mouse model, ERK inhibitor studies, zVAD-induced MEF2 activation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO macrophages with in vivo sepsis model, defined promoter elements by mutagenesis, pharmacological pathway dissection\",\n      \"pmids\": [\"12782711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NR4A1 (Nur77) regulates ROS and endoplasmic reticulum stress in pancreatic cancer cells via transcriptional regulation of TXNDC5; NR4A1 knockdown decreases TXNDC5 expression, elevating ROS, and activating ER stress/proapoptotic pathways. DIM-C-pPhOH binds NR4A1 and acts as an antagonist.\",\n      \"method\": \"RNAi knockdown, NR4A1 antagonist (DIM-C-pPhOH) treatment, proteomic analysis, ROS assay, antioxidant rescue, gene expression profiling\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD plus pharmacological inhibition, proteomic profiling, rescue with antioxidant, single lab\",\n      \"pmids\": [\"24515801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"C-DIM compounds (including DIM-C-pPhOH) directly bind the ligand-binding domain of NR4A1 with high affinity and act as NR4A1 antagonists in colon cancer cells, inhibiting NR4A1-dependent transactivation, decreasing survivin and Sp-regulated gene expression, and inhibiting mTOR signaling.\",\n      \"method\": \"Direct LBD binding assays, molecular modeling of NR4A1 LBD, luciferase reporter (NR4A1-responsive), RNAi, cell proliferation and apoptosis assays\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with structural modeling, functional reporter, KD rescue, single lab\",\n      \"pmids\": [\"25099012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR4A1 regulates β1-integrin gene expression to control basal migration of breast cancer cells (TGF-β-independent); NR4A1 nuclear export is an essential step in TGF-β-induced cell migration, and NR4A1 also controls β3-integrin expression.\",\n      \"method\": \"RNAi (siNR4A1), nuclear export inhibitor (leptomycin B), NR4A1 antagonists (DIM-C-pPhOH), migration assays, β1/β3-integrin expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD plus pharmacological blockade of nuclear export, functional migration assay, single lab\",\n      \"pmids\": [\"26929200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TGF-β/TGFβR/PKA/MKK4-7/JNK signaling phosphorylates and induces nuclear export of NR4A1; cytoplasmic NR4A1 then forms a complex with Axin2, Arkadia (RNF111), and RNF12 (RLIM) to drive proteasomal degradation of SMAD7, thereby enhancing lung cancer cell migration.\",\n      \"method\": \"Nuclear export inhibitor (leptomycin B), JNK inhibitor (SP600125), NR4A1 antagonist, co-immunoprecipitation (NR4A1–Axin2/Arkadia/RNF12 complex), SMAD7 degradation assay, migration assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of multi-protein complex, pharmacological pathway dissection with functional readout, single lab\",\n      \"pmids\": [\"30072581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR4A1 controls CD8+ T cell development through direct transcriptional suppression of Runx3 by recruiting the corepressor CoREST (also reported in PMID 25762306). Separate finding: NR4A1 regulates macrophage polarization and restrains pro-inflammatory NF-κB signaling by directly opposing NFκB activation of IκB-α (inducing IκB-α) and suppressing IKK-β.\",\n      \"method\": \"shNur77 in RAW264.7 osteoclast model, siIκB-α and siIKK-β rescue experiments, NF-κB reporter, Nur77 KO mice\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue with specific pathway components (IκB-α, IKK-β), KO mouse validation, single lab\",\n      \"pmids\": [\"35181992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Glycerol kinase (Gyk isoform b) acts as a novel co-repressor of NR4A1 in the liver by binding the C-terminal ligand-binding domain of NR4A1 (not the N-terminal AF-1 domain); this protein–protein interaction inhibits NR4A1 transcriptional activity and suppresses expression of gluconeogenic target genes in vivo.\",\n      \"method\": \"Co-immunoprecipitation (Gyk–NR4A1), domain mapping, reporter assays, Gyk overexpression in vitro and in vivo (fasted and diabetic mice), gene expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, in vivo overexpression, functional gene expression rescue, single lab\",\n      \"pmids\": [\"30821173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NR4A1 (Nur77) directly binds and destabilizes Tnf mRNA in microglia in an N6-methyladenosine (m6A)-dependent manner, functioning as a cytoplasmic RNA-binding protein in processing bodies (P-bodies). Conditional microglial deletion of Nr4a1 elevates Tnf expression and worsens ischemic stroke outcomes.\",\n      \"method\": \"Subcellular localization (P-bodies by imaging), RNA immunoprecipitation (NR4A1–Tnf mRNA binding), mRNA stability assay, m6A-dependent mechanism, conditional microglial Nr4a1 KO, stroke mouse model\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct RNA binding demonstrated, m6A dependence established, conditional KO with in vivo stroke model, multiple orthogonal methods\",\n      \"pmids\": [\"37486903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR4A1 in vascular endothelial cells increases thrombomodulin mRNA stability (not promoter activity), whereas the related NR4A3 (Nor1) enhances thrombomodulin expression via induction of KLF2/4. Nur77 deficiency increases susceptibility to arterial thrombosis.\",\n      \"method\": \"Adenoviral NR4A1 overexpression in ECs and mouse liver, Nur77 KO mice, mRNA stability assay, promoter reporter assay, protein C activity assay, thrombosis model\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO plus adenoviral overexpression, mRNA stability mechanistic dissection, in vivo thrombosis model, single lab\",\n      \"pmids\": [\"26634653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nur77 increases GCH1 mRNA stability by inhibiting microRNA-133a expression, and upregulates SOD1 by directly binding the SOD1 promoter in vascular endothelial cells, thereby activating NO production and anti-oxidant pathways that attenuate endothelial dysfunction.\",\n      \"method\": \"Nur77 KO and endothelial-specific Tg mice, vasodilatation assay, ROS measurement (DHE staining), miRNA-133a overexpression/inhibition, ChIP (Nur77 at SOD1 promoter), mRNA stability assay\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct promoter binding, mRNA stability via miRNA suppression, KO and Tg mice, single lab\",\n      \"pmids\": [\"38290383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR4A1 controls CD8+ T cell development; separately, NR4A1 promotes adipocyte progenitor (AP) quiescence — gain of function decreases adipogenesis while loss of function increases proliferative and adipogenic capacity; Nr4a1−/− AP transplantation into obese WT recipients improves glucose homeostasis.\",\n      \"method\": \"NR4A1 gain/loss-of-function in primary APs ex vivo, Nr4a1−/− mouse adipose tissue analysis, AP transplantation into obese recipients, ATAC-seq, transcriptomics\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice plus chromatin accessibility mapping plus transplantation rescue, single lab, multiple methods\",\n      \"pmids\": [\"30277475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR4A1 and NR4A3 restrict HSC proliferation partly through direct binding to a hematopoietic-specific Cebpa enhancer, activating Cebpa transcription. NR4A1/3 also occupy regulatory regions of NF-κB-regulated inflammatory cytokines and antagonize NF-κB activation.\",\n      \"method\": \"Conditional Nr4a1/Nr4a3 double KO mice, ChIP (NR4A1/3 binding to Cebpa enhancer and NF-κB cytokine loci), transcriptome profiling of HSCs, flow cytometry, DNA damage assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct enhancer occupancy, conditional KO with defined molecular phenotype, multiple gene targets validated, single lab with orthogonal methods\",\n      \"pmids\": [\"29343483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nur77 expression in skeletal muscle enhances mitochondrial function and oxidative metabolism; MCK-Nur77 transgenic mice show increased oxidative fiber abundance, elevated mitochondrial DNA content, increased complex I of the electron transport chain, and favor fatty acid oxidation over glucose oxidation.\",\n      \"method\": \"MCK-Nur77 transgenic mice, mitochondrial respiration assays, metabolomics, electron transport chain component analysis, muscle contractile function assay\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with metabolomics and mitochondrial function measurements, single lab\",\n      \"pmids\": [\"23028113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"β-cell deletion of Nr4a1 and Nr4a3 reduces mitochondrial respiration and glucose-stimulated insulin secretion, associated with decreased expression of mitochondrial dehydrogenase subunits Idh3g and Sdhb, and impaired ATP production.\",\n      \"method\": \"β-cell-specific Nr4a1/Nr4a3 KO, permeabilized cell respirometry, intact cell glucose-stimulated oxygen consumption, insulin secretion assay, ATP production assay, gene expression\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-specific KO with direct respirometry and insulin secretion assay, mechanistic gene targets identified, single lab\",\n      \"pmids\": [\"27221116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nkx6.1 induces expression of Nr4a1 (and Nr4a3), and these receptors are both necessary and sufficient for Nkx6.1-mediated β-cell proliferation; Nr4a1 overexpression increases E2F1 and cyclin E1, and induces APC components including UBE2C, promoting degradation of the cell cycle inhibitor p21. Global Nr4a1 KO reduces β-cell area in neonatal mice.\",\n      \"method\": \"Adenoviral Nr4a1 overexpression in rat islets, Nr4a1 KO mice (β-cell area quantification), gene expression analysis, cell cycle marker assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice plus adenoviral rescue, defined cell-cycle targets, single lab\",\n      \"pmids\": [\"24706823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NR4A1 (Nur77) represses NF-κB-driven IL-2 promoter activation through its N-terminal AF-1 domain by inhibiting NF-κB components (p65 and c-Rel) binding at low-affinity κB sites in the IL-2 promoter; this repression is specific to low-affinity sites and not observed on high-affinity HIV LTR κB sites.\",\n      \"method\": \"Cotransfection/luciferase reporter assays (IL-2 promoter and mutants, CD28RE with NF-κB sites, HIV LTR), Nur77 domain mutants (AF-1 deletion), Jurkat T cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis plus AF-1 domain deletion establishing mechanistic requirement, multiple reporter constructs, single lab\",\n      \"pmids\": [\"15466594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NR4A1 (Nur77) directly binds WFDC21P promoter response elements to transcriptionally activate WFDC21P lncRNA expression in HCC; this suppresses glycolysis by NR4A1/WFDC21P-dependent disruption of PFKP and PKM2 function.\",\n      \"method\": \"ChIP (Nur77 binding WFDC21P promoter NBRE elements), reporter assays, KO/KD in vitro and in vivo tumor models, Csn-B agonist treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with direct promoter binding, functional rescue in vivo, single lab\",\n      \"pmids\": [\"31959898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mst1 kinase phosphorylates NR4A1 at threonine 366 (T366), enhancing its transcriptional activity and increasing downstream β3-integrin expression in endometrial epithelial cells, thereby promoting trophoblast-uterine epithelium adhesion and embryo implantation.\",\n      \"method\": \"In vitro kinase assay (Mst1 phosphorylating Nur77), LC-MS/MS identification of T366, phos-tag SDS-PAGE, phospho-specific antibody (pT366), mouse embryo adhesion assay, delayed implantation mouse model, RNA-seq\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with MS site identification, phospho-specific antibody validation, functional in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"36623453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NR4A1 (Nr4a1) contributes to cocaine-induced neuroadaptation by directly controlling CARTPT expression; Nr4a1 deletion or CRISPR-based Nr4a1 activation demonstrates direct causality for sustained Cartpt transcription during cocaine abstinence, associated with depletion of H3K27me3 and enrichment of H3K27ac and H3K4me3 at the Cartpt locus.\",\n      \"method\": \"CRISPR-mediated Nr4a1 activation, small molecule Nr4a1 activation, ChIP (H3K27me3, H3K27ac, H3K4me3), cocaine behavioral assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR causal demonstration plus ChIP histone marks, behavioral readout, single lab\",\n      \"pmids\": [\"31980629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NR4A1 regulates PAX3-FOXO1A expression in alveolar rhabdomyosarcoma through an NR4A1/Sp4 complex that binds GC-rich promoter regions; RNAi of NR4A1 or NR4A1 antagonists reduce PAX3-FOXO1A and its downstream effectors.\",\n      \"method\": \"RNAi (siNR4A1), NR4A1 antagonists (C-DIM), ChIP/promoter reporter (NR4A1/Sp4 at PAX3-FOXO1A promoter GC-rich elements), gene expression profiling, migration assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing complex occupancy at promoter, functional siRNA rescue, single lab\",\n      \"pmids\": [\"27864345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Resveratrol binds the ligand-binding domain of NR4A1 with KD = 2.4 µM (measured by isothermal titration calorimetry) and acts as an NR4A1 antagonist, inhibiting NR4A1-dependent transactivation in lung cancer cells.\",\n      \"method\": \"Isothermal titration calorimetry (direct binding to NR4A1 LBD), luciferase reporter (NR4A1-responsive), functional assays (proliferation, migration), gene expression\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct biophysical binding measurement (ITC) plus functional transactivation assay, single lab\",\n      \"pmids\": [\"35680166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NR4A1 promotes mitochondrial fission in VSMCs by activating DNA-PKcs and p53 and facilitating Drp1 migration to mitochondria; NR4A1 also inhibits BNIP3-related mitophagy, causing mitochondrial dysfunction and contributing to vascular calcification.\",\n      \"method\": \"NR4A1 siRNA knockdown, Western blot (Drp1, BNIP3, LC3-II, p62), mRFP-GFP-LC3 adenovirus, mPTP opening rate, membrane potential, TEM, ATP/OCR measurement, ex vivo calcification staining\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple mitochondrial function readouts and pathway rescue, single lab\",\n      \"pmids\": [\"31993850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR4A1 regulates Parkin-mediated mitophagy in endothelial cells through post-transcriptional modification of Parkin via CaMKII; ox-LDL-induced NR4A1 activates CaMKII, which phosphorylates Parkin, driving excessive mitophagy and endothelial apoptosis.\",\n      \"method\": \"NR4A1 KO/overexpression in AECs, CaMKII inhibitor, Parkin phosphorylation assay, mitochondrial function assays, in vitro and high-fat diet mouse model\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and OE with pharmacological rescue, defined PTM pathway (CaMKII→Parkin phosphorylation), single lab\",\n      \"pmids\": [\"29470798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR4A1 expression is regulated by the transcription factor Creb5 in the PI3K/AKT pathway in cardiomyocytes; semaglutide reduces NR4A1 expression and its translocation to mitochondria through the Creb5/NR4A1 axis, and NR4A1 knockdown ameliorates mitochondrial dysfunction and abnormal metabolic shifts in the heart.\",\n      \"method\": \"Transcriptional analysis (Creb5/NR4A1 axis), NR4A1 knockdown in cardiomyocytes, metabolomics, mitochondrial structure/function assays, mouse pressure-overload heart failure model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with metabolomics and mitochondrial assays, transcriptional pathway identified, single lab with multiple methods\",\n      \"pmids\": [\"38834564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nr4a1 overexpression protects Sirt1 protein from proteasomal degradation through negative transcriptional regulation of the E3 ubiquitin ligase MDM2; Nr4a1 deletion shortens mouse lifespan and accelerates aging in multiple tissues.\",\n      \"method\": \"Nr4a1 KO mice (lifespan/aging phenotype), overexpression of Nr4a1 (MDM2 reporter assay, Sirt1 protein stability), proteasome inhibitor rescue, gene expression analysis\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice plus OE with proteasome rescue, MDM2 transcriptional regulation assay, single lab\",\n      \"pmids\": [\"36883265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MEF2D transcriptionally activates NR4A1 expression in response to amino acid deficiency; NR4A1 in turn activates FAM134B2 (RETREG1) expression to drive reticulophagy, contributing to amino acid homeostasis.\",\n      \"method\": \"Gene expression profiling, reporter assays, loss-of-function experiments in amino acid-deficient conditions\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — abstract provides limited method detail; pathway described but mechanistic depth unclear from abstract alone\",\n      \"pmids\": [\"34517786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NR4A1 interacts with NR2B (NMDA receptor subunit) as shown by reciprocal co-immunoprecipitation in neurons; NR4A1 knockdown reduces surface NR2B expression by promoting NR2B internalization (reduced p-NR2B Tyr1472 and reduced NR2B in postsynaptic density), and alleviates seizure severity.\",\n      \"method\": \"Reciprocal co-immunoprecipitation (NR4A1–NR2B), lentiviral shNR4A1, postsynaptic density fractionation, seizure behavioral assay, pilocarpine mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP establishing physical interaction, fractionation, in vivo seizure model, single lab\",\n      \"pmids\": [\"27876882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SUMOylation of NR4A1 is required for induction of autophagic cell death; triple mutation of SUMO sites reduces NR4A1 SUMOylation, increases transcriptional activity, alters intracellular distribution, and impairs autophagic cell death induction.\",\n      \"method\": \"SUMO site mutagenesis (triple mutant), SUMOylation assay, transcriptional reporter, subcellular localization imaging, autophagic cell death assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis plus functional autophagy assay, multiple readouts, single lab\",\n      \"pmids\": [\"32210435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nr4a1 regulates contrasting transcriptional programs in parvalbumin- and somatostatin-positive GABAergic interneurons in the mouse forebrain, exerting cell-type-specific effects on local axonal wiring; loss of Nr4a1 causes bidirectional transcriptional switches in genes including surface adhesion and repulsion molecules.\",\n      \"method\": \"Conditional Nr4a1 KO in PV and SST interneurons, transcriptome profiling, synaptic connectivity assays, behavioral learning assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with transcriptome profiling and circuit-level phenotype, single lab\",\n      \"pmids\": [\"38754414\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR4A1 (Nur77/NGFIB/TR3) is an orphan nuclear receptor and immediate-early transcription factor whose activity is controlled by subcellular localization, phosphorylation (by Akt at Ser-350 reducing DNA binding; by Mst1 at T366 enhancing activity; by p38α counteracting its anti-inflammatory function), SUMOylation/ubiquitination (PIAS3/SUMO2-3/RNF4 driving proteasomal degradation), and protein–protein interactions (co-repressors FHL2 and Gyk; GR antagonism at NurRE); in the nucleus it activates target gene transcription (CYP11B2, HSD3B2, WFDC21P, Cebpa, Runx3-suppression via CoREST, IEG regulation via RNA Pol II elongation inhibition), suppresses NF-κB by directly binding p65 and occupying NF-κB regulatory loci, represses AP-1-driven effector genes in tolerant T cells, and acts as an RNA-binding protein in P-bodies to destabilize TNF mRNA; upon apoptotic stimuli it translocates to mitochondria where it binds Bcl-2 and converts it to a pro-apoptotic conformation triggering cytochrome c release, and in the cytoplasm sequesters LKB1 to attenuate AMPK activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR4A1 (Nur77/NGFIB/TR3) is an immediate-early orphan nuclear receptor and transcription factor whose biological output is dictated by subcellular localization, post-translational modification, and an unusually wide repertoire of protein and RNA interactions spanning transcriptional control, apoptosis, immune restraint, and metabolic regulation [#10, #16, #31]. In the nucleus it binds NGFIB response elements to directly activate steroidogenic and metabolic targets including CYP11B2 and HSD3B2 in adrenal cells [#7, #8], the Cebpa enhancer in hematopoietic stem cells [#31], and SOD1 in endothelium [#29], while also acting as a repressor: it occupies immediate-early gene bodies to inhibit RNA Pol II elongation and generate R-loops, restraining FOS and preventing chromosomal instability [#16], and recruits the corepressor CoREST to suppress Runx3 during CD8 T cell development [#15]. A central function is restraint of inflammation\\u2014NR4A1 directly associates with NF-\\u03baB p65 to block \\u03baB-element binding and suppress cytokine production [#5, #35], and its loss drives M1 macrophage polarization and a pro-inflammatory TCA-cycle metabolic switch [#11, #12]. Its transcriptional activity is gated by phosphorylation (Akt at Ser-350 within the DNA-binding domain reduces DNA binding and promotes 14-3-3 association [#1, #2]; Mst1 at Thr-366 enhances activity [#37]; LPS-activated p38\\u03b1 counteracts NF-\\u03baB suppression [#5]), by SUMO2/3 modification that recruits RNF4 for ubiquitin-dependent degradation [#13], and by corepressors FHL2 and glycerol kinase that bind distinct domains [#14, #26]. Beyond the nucleus, NR4A1 translocates to mitochondria where it converts Bcl-2 into a pro-apoptotic form to trigger cytochrome c release [#10], sequesters LKB1 to attenuate AMPK activation [#4], and acts as a cytoplasmic, m6A-dependent RNA-binding protein in P-bodies that destabilizes Tnf mRNA [#27]. Through these activities NR4A1 governs T cell tolerance and clonal deletion [#0, #9, #18], \\u03b2-cell and adipocyte proliferative fate [#33, #34, #30], and mitochondrial/oxidative metabolism in muscle, vasculature, and heart [#32, #41, #43].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that NR4A1 transcriptional output is directly gated by phosphorylation within its DNA-binding domain, the first mechanism explaining signal-dependent control of this immediate-early factor.\",\n      \"evidence\": \"In vitro PKA phosphorylation of purified DBD with Ser-340/Ser-350 mutagenesis and EMSA\",\n      \"pmids\": [\"8227042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the physiological kinase in cells\", \"Did not connect DNA-binding loss to a cellular phenotype\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined a transcriptional apoptotic route by showing NR4A1 drives thymocyte death via FasL upregulation, placing it in negative selection.\",\n      \"evidence\": \"Transgenic nur77 overexpression with genetic epistasis in gld/gld FasL-defective mice\",\n      \"pmids\": [\"8643610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address the later-discovered transcription-independent mitochondrial pathway\", \"FasL induction mechanism not resolved at promoter level\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed NR4A1 transcription is antagonized by the glucocorticoid receptor at the NurRE, integrating it into endocrine negative feedback.\",\n      \"evidence\": \"Luciferase reporters, in vitro binding, and GR mutant analysis in endocrine and T cell systems\",\n      \"pmids\": [\"9315653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism inferred by analogy to GR\\u2013AP-1 antagonism rather than fully resolved\", \"Direct GR\\u2013Nur77 contact not structurally defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified Akt as a survival-signaling kinase that phosphorylates Ser-350, suppressing DNA binding, promoting 14-3-3 association, and blocking NR4A1-induced apoptosis.\",\n      \"evidence\": \"Co-IP, in vitro/in vivo kinase assays, DNA-binding assays, and apoptosis rescue in T cells and fibroblasts (two independent studies)\",\n      \"pmids\": [\"11274386\", \"11438550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether 14-3-3 binding governs cytoplasmic retention\", \"Upstream stimuli setting Akt-Nur77 balance not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved NR4A1 as a direct transcriptional activator of steroidogenic genes, linking ACTH/angiotensin signaling to adrenal CYP11B2 and HSD3B2 expression.\",\n      \"evidence\": \"EMSA, promoter mutagenesis, and adenoviral overexpression in adrenocortical cells\",\n      \"pmids\": [\"14645496\", \"15208301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coactivator requirements at these promoters not defined\", \"Did not address regulation by NR4A1 post-translational state\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected innate immune signaling to NR4A1 induction and identified a caspase-independent macrophage death program downstream of TLR/ERK/MEF2.\",\n      \"evidence\": \"Nur77-deficient macrophages, promoter element mutagenesis, ERK inhibition, and septic mouse model\",\n      \"pmids\": [\"12782711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector mechanism of caspase-independent death unresolved\", \"Did not separate transcriptional from mitochondrial Nur77 contributions\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Consolidated the transcription-independent apoptotic mechanism in which mitochondrial NR4A1 converts Bcl-2 to a pro-apoptotic conformation triggering cytochrome c release.\",\n      \"evidence\": \"Review of subcellular fractionation, Nur77\\u2013Bcl-2 Co-IP, cytochrome c assays, and DBD-deletion constructs\",\n      \"pmids\": [\"16892086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling nuclear-to-mitochondrial export not fully defined\", \"Structural basis of the Bcl-2 conformational switch not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a non-genomic cytoplasmic function: NR4A1 sequesters LKB1 to restrain AMPK, providing a druggable node in metabolic disease.\",\n      \"evidence\": \"Reciprocal Co-IP, subcellular fractionation, AMPK phosphorylation assay, Nur77-KO diabetic mice, and the TMPA probe with defined binding sites\",\n      \"pmids\": [\"22983157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the trigger for LKB1 release in vivo\", \"Relationship to nuclear transcriptional role unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped NR4A1's role in T cell fate decisions, including Bim-dependent clonal deletion and induction of Treg and metabolic gene programs after TCR signaling.\",\n      \"evidence\": \"Nr4a1-KO and TCR-transgenic mice with transcriptional profiling and apoptosis assays\",\n      \"pmids\": [\"22345564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect control of Bim not resolved\", \"Metabolic gene induction mechanism not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established direct anti-inflammatory restraint of NF-\\u03baB via NR4A1\\u2013p65 binding, and that p38\\u03b1 phosphorylation neutralizes this suppression\\u2014defining a pharmacological strategy.\",\n      \"evidence\": \"Reciprocal Co-IP, \\u03baB reporter assays, Nur77-biased compound screen, and LPS sepsis model\",\n      \"pmids\": [\"25822914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"p38\\u03b1 phosphosite on Nur77 not identified here\", \"Genome-wide breadth of NF-\\u03baB locus occupancy not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a corepressor mechanism in CD8 T cell development by which NR4A1 recruits CoREST to directly silence Runx3.\",\n      \"evidence\": \"Nr4a1-KO mice, flow cytometry, and ChIP at the Runx3 locus\",\n      \"pmids\": [\"25762306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CoREST recruitment determinants on NR4A1 not mapped\", \"Generality of CoREST partnership at other loci unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the degradative arm of NR4A1 regulation: SUMO2/3 modification recruits the SUMO-targeted E3 ligase RNF4 for ubiquitin-dependent turnover, controlling NF-\\u03baB output and macrophage death.\",\n      \"evidence\": \"SUMO/ubiquitin Co-IP, SUMO-site mutagenesis, PIAS3/RNF4/SENP1 perturbation, and functional macrophage assays\",\n      \"pmids\": [\"28622293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which functional pool is preferentially degraded\", \"Signals triggering SUMOylation not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed NR4A1 enforces an anti-inflammatory macrophage metabolic state, with loss causing failure to downregulate IDH and succinate accumulation driving cytokine production.\",\n      \"evidence\": \"Nr4a1-KO macrophages with metabolomics, respiration assays, SDH inhibition, and atherosclerosis model\",\n      \"pmids\": [\"30134173\", \"22194622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets among metabolic enzymes not fully mapped\", \"Link to mitochondrial Nur77 pool not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established direct enhancer occupancy controlling stem and progenitor proliferation, including NR4A1/NR4A3 binding the Cebpa enhancer in HSCs and antagonism of NF-\\u03baB inflammatory loci.\",\n      \"evidence\": \"Conditional Nr4a1/Nr4a3 double-KO mice with ChIP and HSC transcriptome profiling\",\n      \"pmids\": [\"29343483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional redundancy of NR4A1 vs NR4A3 at each locus not separated\", \"Coregulator complement at the Cebpa enhancer unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a chromatin function in which NR4A1 occupies IEG bodies to inhibit Pol II elongation, generate R-loops, and protect genome stability by restraining FOS.\",\n      \"evidence\": \"ChIP-seq, ATAC-seq, R-loop detection, and KO/OE in breast cancer cells with chromosomal instability assays\",\n      \"pmids\": [\"34624217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How replication stress triggers NR4A1 dissociation mechanistically unresolved\", \"Relationship to its NBRE-based activation role not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an activating phosphorylation, Mst1 at Thr-366, that enhances NR4A1 transcriptional activity, contrasting the inhibitory Akt/PKA sites.\",\n      \"evidence\": \"In vitro kinase assay, LC-MS/MS site mapping, phospho-specific antibody, and in vivo embryo implantation model\",\n      \"pmids\": [\"36623453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural effect of T366 phosphorylation on the receptor not defined\", \"Cross-talk with inhibitory phosphosites not examined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a cytoplasmic, m6A-dependent RNA-binding function in which NR4A1 destabilizes Tnf mRNA in P-body microglia, extending its anti-inflammatory role to post-transcriptional control.\",\n      \"evidence\": \"RNA immunoprecipitation, P-body imaging, mRNA stability assays, and conditional microglial KO in a stroke model\",\n      \"pmids\": [\"37486903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding interface on NR4A1 not structurally defined\", \"Breadth of NR4A1-bound transcripts beyond Tnf unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended NR4A1's transcriptional reach into neuronal circuit wiring, showing cell-type-specific programs in PV and SST interneurons that shape axonal connectivity.\",\n      \"evidence\": \"Cell-type-specific conditional Nr4a1 KO with transcriptome profiling and connectivity/behavioral assays\",\n      \"pmids\": [\"38754414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect targets among adhesion/repulsion genes not separated\", \"Mechanism of opposite directionality between interneuron types unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NR4A1's distinct functional pools\\u2014NBRE-driven activator, IEG-body elongation repressor, mitochondrial Bcl-2 converter, LKB1 sequestrant, and P-body RNA destabilizer\\u2014are coordinately partitioned by ligand binding and post-translational state remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking phosphorylation/SUMOylation code to localization choice\", \"Endogenous physiological ligand status of the LBD undefined despite multiple synthetic antagonists/agonists\", \"Quantitative balance among competing functions in a single cell unmeasured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 8, 15, 16, 31, 36]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 7, 8, 29, 31, 36]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [27, 28, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 10, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 7, 8, 16, 31]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [10, 17, 41, 43]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [24, 27]},\n      {\"term_id\": \"GO:0000932\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 11, 12, 18, 27, 31, 35]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 8, 15, 16, 31, 36]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 10, 20, 47]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 12, 32, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 5, 17, 37]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BCL2\", \"RELA\", \"STK11\", \"FHL2\", \"MAPK14\", \"AKT1\", \"STK4\", \"GLPK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}