{"gene":"NR3C2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2009,"finding":"miR-124 and miR-135a directly suppress NR3C2 (mineralocorticoid receptor) expression by binding to its 3'UTR, acting at the translational level without reducing mRNA levels; co-expression of both miRNAs showed no additive or synergistic repression.","method":"Luciferase reporter assay with NR3C2 3'UTR construct; mRNA level measurements","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assay with functional validation, single lab, two orthogonal methods (reporter + mRNA quantification)","pmids":["19944075"],"is_preprint":false},{"year":2007,"finding":"Two novel NR3C2 loss-of-function mutations (nonsense Y134X and frameshift 2125delA) in pseudohypoaldosteronism type 1 patients completely abolished aldosterone binding and transactivation activity of the mineralocorticoid receptor.","method":"Aldosterone-binding assays and reporter gene transactivation assays on mutant NR3C2 constructs","journal":"European journal of endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay plus transactivation reporter assay, two orthogonal functional methods in single lab","pmids":["17287415"],"is_preprint":false},{"year":2010,"finding":"NR3C2 haplotypes defined by SNPs MR-2G/C (rs2070951) and MRI180V (rs5522) modulate cortisol-induced gene transcription and protein expression in vitro; the structural variant MRI180V did not affect ligand binding.","method":"In vitro cortisol-induced gene transcription assays and protein expression measurements for different NR3C2 haplotypes","journal":"Psychoneuroendocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro transactivation and protein expression assays, two orthogonal methods, single lab","pmids":["21095064"],"is_preprint":false},{"year":2016,"finding":"MIF upregulates miR-301b, which directly targets and suppresses NR3C2 expression; NR3C2 functions as a tumor suppressor in pancreatic ductal adenocarcinoma by inhibiting epithelial-to-mesenchymal transition and enhancing gemcitabine sensitivity. Genetic deletion of MIF disrupted the MIF-miR-301b-NR3C2 axis, reducing metastasis in a mouse model.","method":"Cell line functional assays, genetically engineered mouse model, patient cohort expression analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell lines, mouse model, patient cohorts), replicated across independent cohorts","pmids":["27197190"],"is_preprint":false},{"year":2016,"finding":"NR3C2 (mineralocorticoid receptor) is required for ENaC expression and apical targeting, and for Na+-K+-ATPase expression in the collecting system, but is dispensable for NCC phosphorylation and expression in the distal convoluted tubule, established by comparing MR-positive and MR-negative cells side-by-side in the same mice.","method":"Conditional mosaic MR knockout mouse model (MR/X mice); immunofluorescence and protein quantification comparing MR-positive vs MR-negative cells in the same physiological context","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic loss-of-function with cell-autonomous comparison, multiple transport protein readouts, rigorous controls","pmids":["26898302"],"is_preprint":false},{"year":2018,"finding":"miR-766 directly targets NR3C2 and promotes HCC cell proliferation and metastasis in vitro and in vivo; miR-766 affects the β-catenin signaling pathway by suppressing NR3C2.","method":"Luciferase reporter assay confirming direct targeting; cell line proliferation and metastasis assays; xenograft mouse model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct targeting validated by luciferase assay plus in vivo xenograft, single lab","pmids":["30130435"],"is_preprint":false},{"year":2023,"finding":"NR3C2 overexpression in colorectal cancer cells inhibits glucose metabolism by decreasing HK2 and LDHA expression, and reduces AMPK phosphorylation, resulting in suppressed proliferation and G2/M cell cycle arrest.","method":"Lentiviral NR3C2 overexpression and knockdown; MTT, colony formation, flow cytometry; lactate production, glucose consumption, ATP production assays; western blotting for AMPK, HK2, LDHA","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in cell lines, single lab","pmids":["36950803"],"is_preprint":false},{"year":2022,"finding":"NR3C2 overexpression inhibits proliferation, migration, invasion, and angiogenesis of colon cancer cells by suppressing the AKT/ERK signaling pathway.","method":"CCK-8, colony formation, wound healing, Transwell assays; ELISA for VEGF; tube formation assay; western blotting for AKT/ERK pathway proteins","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal cell-based assays with defined pathway readout, single lab","pmids":["35191517"],"is_preprint":false},{"year":2024,"finding":"NR3C2 suppresses glycolytic gene expression (HK1, HK2, LDHA) and inhibits glucose uptake and lactate efflux in pancreatic cancer cells by interacting with activator protein 1 (AP-1); MIF promotes glycolysis via MAPK-ERK pathway activation, opposing NR3C2 function in a MIF/NR3C2 regulatory axis.","method":"In vitro cell line experiments; mouse models of PDAC; patient expression data; metabolic flux measurements; pathway inhibitor studies","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway placement with in vitro and in vivo evidence, single lab follow-up study","pmids":["38629149"],"is_preprint":false},{"year":2021,"finding":"miR-301b-3p directly targets NR3C2 (validated by dual-luciferase reporter assay) and promotes breast cancer cell proliferation, migration, and invasion; NR3C2 overexpression rescued the oncogenic effects of miR-301b-3p.","method":"Dual-luciferase reporter assay; CCK-8 proliferation assay; Transwell migration/invasion assay; rescue experiment with NR3C2 overexpression","journal":"Journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct targeting validated by reporter assay plus functional rescue, single lab","pmids":["33542733"],"is_preprint":false},{"year":2020,"finding":"miR-454 directly targets NR3C2 in oral squamous cell carcinoma; depletion of miR-454 reduces OSCC cell proliferation, colony formation, invasion, and migration, and NR3C2 silencing partially rescues these phenotypes.","method":"miR-454 mimic/inhibitor transfection; pcDNA3.1-NR3C2/si-NR3C2; cell proliferation, colony formation, Transwell assays; co-transfection rescue experiment","journal":"Journal of oral pathology & medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional cell assays with rescue, but targeting validated only by co-transfection without explicit luciferase assay mentioned","pmids":["32170966"],"is_preprint":false},{"year":2020,"finding":"CREB1 binds to the promoter of miR-1204 and activates its transcription; miR-1204 directly targets and inhibits NR3C2 (validated by luciferase reporter and RIP assay), promoting glioblastoma cell proliferation and suppressing apoptosis; NR3C2 participates as a tumor suppressor downstream.","method":"ChIP assay (CREB1-miR-1204 promoter interaction); RIP assay; luciferase reporter assay; CCK-8, colony formation, caspase-3, TUNEL assays; rescue experiments","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, RIP, luciferase, functional assays), single lab","pmids":["32280303"],"is_preprint":false},{"year":2022,"finding":"NR3C2 promoter hypermethylation leads to its downregulation in colon cancer; NR3C2 overexpression induced apoptosis and suppressed proliferation in colon cancer cells in vitro.","method":"DNA methylation analysis (TCGA/GSCA databases); TUNEL and CCK-8 assays with NR3C2 overexpression in cell lines","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — bioinformatics methylation inference plus single in vitro functional assay, single lab","pmids":["35604518"],"is_preprint":false},{"year":2020,"finding":"LINC-P21 acts as a competing endogenous RNA (ceRNA) that sponges miR-766-3p to upregulate NR3C2 in pancreatic β-cells; NR3C2 upregulation inhibits INS-1 cell proliferation and glucose-stimulated insulin secretion.","method":"Gain- and loss-of-function experiments; CCK-8 assay; ELISA for insulin secretion; miRNA target prediction and validation in INS-1 cells","journal":"Experimental and clinical endocrinology & diabetes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ceRNA mechanism inferred from expression manipulation, single lab, limited mechanistic validation","pmids":["33007789"],"is_preprint":false},{"year":2022,"finding":"In zebrafish, several glucocorticoid-target genes require a functional mineralocorticoid receptor (mr/NR3C2 ortholog) to be correctly transcribed, revealed by generating mr knockout lines and comparing GC-dependent gene expression; NR3C2/MR interacts with GR in transcriptional regulation.","method":"Zebrafish mr knockout line generation; RNA-seq gene expression profiling; comparison with gr knockout and gr point mutant lines","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function with transcriptome readout, ortholog model, multiple mutant lines","pmids":["35269817"],"is_preprint":false},{"year":2020,"finding":"lncRNA MALAT1 promotes hypertension by sponging hsa-miR-124-3p and hsa-miR-135a-5p, thereby upregulating NR3C2 protein in HUVECs; knockdown of MALAT1 increased miR-124-3p and miR-135a-5p levels and decreased NR3C2 protein expression.","method":"Cell transfection; CCK-8 assay; qRT-PCR; western blot; dual-luciferase reporter assay; patient plasma expression correlation","journal":"Medical science monitor","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ceRNA axis in endothelial cells, single lab, mechanistic depth limited","pmids":["32222724"],"is_preprint":false},{"year":2021,"finding":"SOX2OT lncRNA silencing attenuates cerebral ischemia-reperfusion injury via the miR-135a-5p/NR3C2 axis; SOX2OT sponges miR-135a-5p, and miR-135a-5p directly targets NR3C2 3'UTR (validated by dual-luciferase assay); NR3C2 upregulation promotes oxidative stress, apoptosis, and inflammation in OGD/R injury.","method":"Dual-luciferase reporter assay; OGD/R PC12 cell model; MCAO/R rat model; MTT, TUNEL, LDH, MDA, SOD, ROS, cytokine measurements","journal":"Brain research bulletin","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ceRNA axis with luciferase validation, NR3C2 role inferred from lncRNA manipulation","pmids":["34022287"],"is_preprint":false},{"year":2020,"finding":"miR-135b-5p directly targets NR3C2 3'UTR (validated by dual-luciferase assay); elevated miR-135b-5p reduces NR3C2 expression and alleviates neuronal apoptosis and inflammation in post-stroke cognitive impairment rat model.","method":"Dual-luciferase reporter gene assay; MCAO rat model; RT-qPCR and western blot; behavioral tests, Nissl staining, flow cytometry, TUNEL","journal":"The International journal of neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, NR3C2 as downstream target with limited mechanistic follow-up on NR3C2 itself","pmids":["32713242"],"is_preprint":false}],"current_model":"NR3C2 (mineralocorticoid receptor/MR) is a ligand-activated nuclear receptor that binds aldosterone and cortisol to regulate transcription; it is essential for ENaC-mediated sodium reabsorption and Na+-K+-ATPase expression in the renal collecting system (but not for NCC in the distal convoluted tubule), and its activity is modulated by NR3C2 haplotype variants that alter ligand-induced transactivation; loss-of-function mutations abolish aldosterone binding and transactivation; in cancer contexts, NR3C2 acts as a tumor suppressor by inhibiting EMT, glycolysis (via HK1/HK2/LDHA suppression through AP-1 interaction), and AKT/ERK signaling, and it is post-transcriptionally downregulated by multiple miRNAs (miR-124, miR-135a, miR-301b, miR-766, miR-454, miR-1204, miR-135b-5p) that target its 3'UTR, while upstream inflammatory signaling via MIF suppresses NR3C2 through miR-301b induction."},"narrative":{"mechanistic_narrative":"NR3C2 encodes the mineralocorticoid receptor (MR), a ligand-activated nuclear receptor that binds aldosterone and cortisol to drive transcription, and it is central to renal electrolyte handling: in the collecting system MR is required for ENaC expression and apical targeting and for Na+-K+-ATPase expression, yet is dispensable for NCC phosphorylation in the distal convoluted tubule [PMID:26898302]. Loss-of-function mutations (Y134X nonsense, 2125delA frameshift) that completely abolish aldosterone binding and transactivation cause pseudohypoaldosteronism type 1, while common haplotype variants modulate the magnitude of cortisol-induced transactivation without necessarily altering ligand binding [PMID:17287415, PMID:21095064]. Beyond mineralocorticoid signaling, MR functions cooperatively with the glucocorticoid receptor, as glucocorticoid-target genes require a functional MR for correct transcription [PMID:35269817]. In cancer, NR3C2 acts as a tumor suppressor: its overexpression suppresses glycolytic gene expression (HK1, HK2, LDHA) — in pancreatic cancer through interaction with AP-1 — inhibits glucose uptake and lactate efflux, induces G2/M arrest and apoptosis, and restrains AKT/ERK signaling, thereby blocking proliferation, invasion, EMT, and angiogenesis [PMID:36950803, PMID:35191517, PMID:38629149]. NR3C2 is repressed in tumors by an upstream MIF axis that induces miR-301b [PMID:27197190, PMID:38629149] and by multiple 3'UTR-targeting microRNAs including miR-124, miR-135a, miR-766, miR-301b-3p, miR-454, and miR-1204 [PMID:19944075, PMID:30130435, PMID:33542733, PMID:32170966, PMID:32280303].","teleology":[{"year":2007,"claim":"Established that specific NR3C2 mutations cause disease by directly destroying receptor function, defining the molecular basis of pseudohypoaldosteronism type 1.","evidence":"Aldosterone-binding and reporter transactivation assays on Y134X and 2125delA mutant constructs","pmids":["17287415"],"confidence":"High","gaps":["Does not address how partial-function variants behave in vivo","No structural explanation of how each lesion disrupts ligand binding"]},{"year":2009,"claim":"Showed that NR3C2 is post-transcriptionally controlled, with miR-124 and miR-135a repressing it translationally via the 3'UTR without mRNA degradation.","evidence":"Luciferase reporter assay with NR3C2 3'UTR and mRNA-level quantification","pmids":["19944075"],"confidence":"Medium","gaps":["Physiological context of this repression not defined","No endogenous target validation beyond reporter"]},{"year":2010,"claim":"Demonstrated that common NR3C2 haplotypes tune receptor output, modulating cortisol-induced transcription independent of ligand binding.","evidence":"In vitro cortisol-induced transactivation and protein expression assays across haplotypes","pmids":["21095064"],"confidence":"Medium","gaps":["In vivo physiological consequence of haplotype differences unresolved","Mechanism by which MRI180V alters transactivation without affecting binding unknown"]},{"year":2016,"claim":"Genetically separated MR-dependent from MR-independent transport in the nephron, establishing MR as required for ENaC and Na+-K+-ATPase but not NCC.","evidence":"Conditional mosaic MR knockout mouse with cell-autonomous MR-positive vs MR-negative comparison","pmids":["26898302"],"confidence":"High","gaps":["Transcriptional targets mediating ENaC induction not enumerated","Does not resolve why NCC escapes MR control"]},{"year":2016,"claim":"Defined an inflammatory suppression axis in which MIF induces miR-301b to silence NR3C2, framing MR as a tumor suppressor restraining EMT and metastasis.","evidence":"PDAC cell assays, MIF-deletion mouse model, and patient cohort expression analysis","pmids":["27197190"],"confidence":"High","gaps":["Direct transcriptional targets of MR in this EMT program not identified","Receptor ligand dependence of tumor-suppressor activity unclear"]},{"year":2022,"claim":"Placed MR within glucocorticoid signaling by showing GR-target gene transcription depends on a functional MR ortholog.","evidence":"Zebrafish mr knockout lines with RNA-seq compared to gr mutants","pmids":["35269817"],"confidence":"Medium","gaps":["Direct MR-GR physical interaction at target promoters not demonstrated","Human relevance of the shared gene set not established"]},{"year":2024,"claim":"Mechanistically linked MR tumor suppression to metabolic control, showing NR3C2 represses glycolytic genes by interacting with AP-1, opposed by MIF-MAPK/ERK signaling.","evidence":"PDAC cell lines, mouse models, patient data, metabolic flux and pathway-inhibitor studies","pmids":["38629149"],"confidence":"Medium","gaps":["Whether MR-AP-1 binding is direct vs cofactor-mediated not resolved","Structural basis of MR/AP-1 cooperation unknown"]},{"year":2023,"claim":"Generalized MR's anti-glycolytic, growth-suppressive role to colorectal cancer via HK2/LDHA suppression, AMPK dephosphorylation, and cell-cycle arrest.","evidence":"Lentiviral overexpression/knockdown with metabolic, proliferation, and flow cytometry assays","pmids":["36950803"],"confidence":"Medium","gaps":["Mechanism connecting MR to AMPK phosphorylation not defined","No in vivo confirmation"]},{"year":null,"claim":"How ligand-dependent MR transcriptional activity is mechanistically integrated with its non-canonical tumor-suppressor functions (AP-1 interaction, metabolic and AKT/ERK control) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined MR cistrome bridging electrolyte and metabolic gene programs","Unknown whether tumor-suppressor activity requires aldosterone/cortisol ligand binding","Direct MR genomic binding sites for glycolytic gene repression not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,4,14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8]}],"complexes":[],"partners":["AP1","GR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08235","full_name":"Mineralocorticoid receptor","aliases":["Nuclear receptor subfamily 3 group C member 2"],"length_aa":984,"mass_kda":107.1,"function":"Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels","subcellular_location":"Cytoplasm; Nucleus; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P08235/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR3C2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NR3C2","total_profiled":1310},"omim":[{"mim_id":"615733","title":"rRNA METHYLTRANSFERASE AND RIBOSOME MATURATION FACTOR BUD23; BUD23","url":"https://www.omim.org/entry/615733"},{"mim_id":"614232","title":"11-@BETA-HYDROXYSTEROID DEHYDROGENASE, TYPE II; HSD11B2","url":"https://www.omim.org/entry/614232"},{"mim_id":"611192","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 11; ANKRD11","url":"https://www.omim.org/entry/611192"},{"mim_id":"605115","title":"HYPERTENSION, EARLY-ONSET, AUTOSOMAL DOMINANT, WITH SEVERE EXACERBATION IN PREGNANCY","url":"https://www.omim.org/entry/605115"},{"mim_id":"604503","title":"JUMONJI DOMAIN-CONTAINING PROTEIN 1C; JMJD1C","url":"https://www.omim.org/entry/604503"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NR3C2"},"hgnc":{"alias_symbol":["MR"],"prev_symbol":["MLR"]},"alphafold":{"accession":"P08235","domains":[{"cath_id":"3.30.50.10","chopping":"611-672","consensus_level":"high","plddt":91.3232,"start":611,"end":672},{"cath_id":"1.10.565.10","chopping":"736-977","consensus_level":"high","plddt":93.4955,"start":736,"end":977}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08235","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08235-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08235-F1-predicted_aligned_error_v6.png","plddt_mean":55.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR3C2","jax_strain_url":"https://www.jax.org/strain/search?query=NR3C2"},"sequence":{"accession":"P08235","fasta_url":"https://rest.uniprot.org/uniprotkb/P08235.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08235/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08235"}},"corpus_meta":[{"pmid":"8372185","id":"PMC_8372185","title":"MR appearance of hemorrhage in the brain.","date":"1993","source":"Radiology","url":"https://pubmed.ncbi.nlm.nih.gov/8372185","citation_count":594,"is_preprint":false},{"pmid":"27197190","id":"PMC_27197190","title":"A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27197190","citation_count":262,"is_preprint":false},{"pmid":"37582716","id":"PMC_37582716","title":"Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study.","date":"2023","source":"BMC psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/37582716","citation_count":246,"is_preprint":false},{"pmid":"18583413","id":"PMC_18583413","title":"MR imaging findings in hepatic encephalopathy.","date":"2008","source":"AJNR. 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Genetic deletion of MIF disrupted the MIF-miR-301b-NR3C2 axis, reducing metastasis in a mouse model.\",\n      \"method\": \"Cell line functional assays, genetically engineered mouse model, patient cohort expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell lines, mouse model, patient cohorts), replicated across independent cohorts\",\n      \"pmids\": [\"27197190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NR3C2 (mineralocorticoid receptor) is required for ENaC expression and apical targeting, and for Na+-K+-ATPase expression in the collecting system, but is dispensable for NCC phosphorylation and expression in the distal convoluted tubule, established by comparing MR-positive and MR-negative cells side-by-side in the same mice.\",\n      \"method\": \"Conditional mosaic MR knockout mouse model (MR/X mice); immunofluorescence and protein quantification comparing MR-positive vs MR-negative cells in the same physiological context\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic loss-of-function with cell-autonomous comparison, multiple transport protein readouts, rigorous controls\",\n      \"pmids\": [\"26898302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-766 directly targets NR3C2 and promotes HCC cell proliferation and metastasis in vitro and in vivo; miR-766 affects the β-catenin signaling pathway by suppressing NR3C2.\",\n      \"method\": \"Luciferase reporter assay confirming direct targeting; cell line proliferation and metastasis assays; xenograft mouse model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct targeting validated by luciferase assay plus in vivo xenograft, single lab\",\n      \"pmids\": [\"30130435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR3C2 overexpression in colorectal cancer cells inhibits glucose metabolism by decreasing HK2 and LDHA expression, and reduces AMPK phosphorylation, resulting in suppressed proliferation and G2/M cell cycle arrest.\",\n      \"method\": \"Lentiviral NR3C2 overexpression and knockdown; MTT, colony formation, flow cytometry; lactate production, glucose consumption, ATP production assays; western blotting for AMPK, HK2, LDHA\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in cell lines, single lab\",\n      \"pmids\": [\"36950803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR3C2 overexpression inhibits proliferation, migration, invasion, and angiogenesis of colon cancer cells by suppressing the AKT/ERK signaling pathway.\",\n      \"method\": \"CCK-8, colony formation, wound healing, Transwell assays; ELISA for VEGF; tube formation assay; western blotting for AKT/ERK pathway proteins\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal cell-based assays with defined pathway readout, single lab\",\n      \"pmids\": [\"35191517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR3C2 suppresses glycolytic gene expression (HK1, HK2, LDHA) and inhibits glucose uptake and lactate efflux in pancreatic cancer cells by interacting with activator protein 1 (AP-1); MIF promotes glycolysis via MAPK-ERK pathway activation, opposing NR3C2 function in a MIF/NR3C2 regulatory axis.\",\n      \"method\": \"In vitro cell line experiments; mouse models of PDAC; patient expression data; metabolic flux measurements; pathway inhibitor studies\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway placement with in vitro and in vivo evidence, single lab follow-up study\",\n      \"pmids\": [\"38629149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-301b-3p directly targets NR3C2 (validated by dual-luciferase reporter assay) and promotes breast cancer cell proliferation, migration, and invasion; NR3C2 overexpression rescued the oncogenic effects of miR-301b-3p.\",\n      \"method\": \"Dual-luciferase reporter assay; CCK-8 proliferation assay; Transwell migration/invasion assay; rescue experiment with NR3C2 overexpression\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct targeting validated by reporter assay plus functional rescue, single lab\",\n      \"pmids\": [\"33542733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-454 directly targets NR3C2 in oral squamous cell carcinoma; depletion of miR-454 reduces OSCC cell proliferation, colony formation, invasion, and migration, and NR3C2 silencing partially rescues these phenotypes.\",\n      \"method\": \"miR-454 mimic/inhibitor transfection; pcDNA3.1-NR3C2/si-NR3C2; cell proliferation, colony formation, Transwell assays; co-transfection rescue experiment\",\n      \"journal\": \"Journal of oral pathology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional cell assays with rescue, but targeting validated only by co-transfection without explicit luciferase assay mentioned\",\n      \"pmids\": [\"32170966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CREB1 binds to the promoter of miR-1204 and activates its transcription; miR-1204 directly targets and inhibits NR3C2 (validated by luciferase reporter and RIP assay), promoting glioblastoma cell proliferation and suppressing apoptosis; NR3C2 participates as a tumor suppressor downstream.\",\n      \"method\": \"ChIP assay (CREB1-miR-1204 promoter interaction); RIP assay; luciferase reporter assay; CCK-8, colony formation, caspase-3, TUNEL assays; rescue experiments\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, RIP, luciferase, functional assays), single lab\",\n      \"pmids\": [\"32280303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR3C2 promoter hypermethylation leads to its downregulation in colon cancer; NR3C2 overexpression induced apoptosis and suppressed proliferation in colon cancer cells in vitro.\",\n      \"method\": \"DNA methylation analysis (TCGA/GSCA databases); TUNEL and CCK-8 assays with NR3C2 overexpression in cell lines\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — bioinformatics methylation inference plus single in vitro functional assay, single lab\",\n      \"pmids\": [\"35604518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LINC-P21 acts as a competing endogenous RNA (ceRNA) that sponges miR-766-3p to upregulate NR3C2 in pancreatic β-cells; NR3C2 upregulation inhibits INS-1 cell proliferation and glucose-stimulated insulin secretion.\",\n      \"method\": \"Gain- and loss-of-function experiments; CCK-8 assay; ELISA for insulin secretion; miRNA target prediction and validation in INS-1 cells\",\n      \"journal\": \"Experimental and clinical endocrinology & diabetes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ceRNA mechanism inferred from expression manipulation, single lab, limited mechanistic validation\",\n      \"pmids\": [\"33007789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In zebrafish, several glucocorticoid-target genes require a functional mineralocorticoid receptor (mr/NR3C2 ortholog) to be correctly transcribed, revealed by generating mr knockout lines and comparing GC-dependent gene expression; NR3C2/MR interacts with GR in transcriptional regulation.\",\n      \"method\": \"Zebrafish mr knockout line generation; RNA-seq gene expression profiling; comparison with gr knockout and gr point mutant lines\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function with transcriptome readout, ortholog model, multiple mutant lines\",\n      \"pmids\": [\"35269817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA MALAT1 promotes hypertension by sponging hsa-miR-124-3p and hsa-miR-135a-5p, thereby upregulating NR3C2 protein in HUVECs; knockdown of MALAT1 increased miR-124-3p and miR-135a-5p levels and decreased NR3C2 protein expression.\",\n      \"method\": \"Cell transfection; CCK-8 assay; qRT-PCR; western blot; dual-luciferase reporter assay; patient plasma expression correlation\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ceRNA axis in endothelial cells, single lab, mechanistic depth limited\",\n      \"pmids\": [\"32222724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOX2OT lncRNA silencing attenuates cerebral ischemia-reperfusion injury via the miR-135a-5p/NR3C2 axis; SOX2OT sponges miR-135a-5p, and miR-135a-5p directly targets NR3C2 3'UTR (validated by dual-luciferase assay); NR3C2 upregulation promotes oxidative stress, apoptosis, and inflammation in OGD/R injury.\",\n      \"method\": \"Dual-luciferase reporter assay; OGD/R PC12 cell model; MCAO/R rat model; MTT, TUNEL, LDH, MDA, SOD, ROS, cytokine measurements\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ceRNA axis with luciferase validation, NR3C2 role inferred from lncRNA manipulation\",\n      \"pmids\": [\"34022287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-135b-5p directly targets NR3C2 3'UTR (validated by dual-luciferase assay); elevated miR-135b-5p reduces NR3C2 expression and alleviates neuronal apoptosis and inflammation in post-stroke cognitive impairment rat model.\",\n      \"method\": \"Dual-luciferase reporter gene assay; MCAO rat model; RT-qPCR and western blot; behavioral tests, Nissl staining, flow cytometry, TUNEL\",\n      \"journal\": \"The International journal of neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, NR3C2 as downstream target with limited mechanistic follow-up on NR3C2 itself\",\n      \"pmids\": [\"32713242\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR3C2 (mineralocorticoid receptor/MR) is a ligand-activated nuclear receptor that binds aldosterone and cortisol to regulate transcription; it is essential for ENaC-mediated sodium reabsorption and Na+-K+-ATPase expression in the renal collecting system (but not for NCC in the distal convoluted tubule), and its activity is modulated by NR3C2 haplotype variants that alter ligand-induced transactivation; loss-of-function mutations abolish aldosterone binding and transactivation; in cancer contexts, NR3C2 acts as a tumor suppressor by inhibiting EMT, glycolysis (via HK1/HK2/LDHA suppression through AP-1 interaction), and AKT/ERK signaling, and it is post-transcriptionally downregulated by multiple miRNAs (miR-124, miR-135a, miR-301b, miR-766, miR-454, miR-1204, miR-135b-5p) that target its 3'UTR, while upstream inflammatory signaling via MIF suppresses NR3C2 through miR-301b induction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR3C2 encodes the mineralocorticoid receptor (MR), a ligand-activated nuclear receptor that binds aldosterone and cortisol to drive transcription, and it is central to renal electrolyte handling: in the collecting system MR is required for ENaC expression and apical targeting and for Na+-K+-ATPase expression, yet is dispensable for NCC phosphorylation in the distal convoluted tubule [#4]. Loss-of-function mutations (Y134X nonsense, 2125delA frameshift) that completely abolish aldosterone binding and transactivation cause pseudohypoaldosteronism type 1, while common haplotype variants modulate the magnitude of cortisol-induced transactivation without necessarily altering ligand binding [#1, #2]. Beyond mineralocorticoid signaling, MR functions cooperatively with the glucocorticoid receptor, as glucocorticoid-target genes require a functional MR for correct transcription [#14]. In cancer, NR3C2 acts as a tumor suppressor: its overexpression suppresses glycolytic gene expression (HK1, HK2, LDHA) — in pancreatic cancer through interaction with AP-1 — inhibits glucose uptake and lactate efflux, induces G2/M arrest and apoptosis, and restrains AKT/ERK signaling, thereby blocking proliferation, invasion, EMT, and angiogenesis [#6, #7, #8]. NR3C2 is repressed in tumors by an upstream MIF axis that induces miR-301b [#3, #8] and by multiple 3'UTR-targeting microRNAs including miR-124, miR-135a, miR-766, miR-301b-3p, miR-454, and miR-1204 [#0, #5, #9, #10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that specific NR3C2 mutations cause disease by directly destroying receptor function, defining the molecular basis of pseudohypoaldosteronism type 1.\",\n      \"evidence\": \"Aldosterone-binding and reporter transactivation assays on Y134X and 2125delA mutant constructs\",\n      \"pmids\": [\"17287415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address how partial-function variants behave in vivo\", \"No structural explanation of how each lesion disrupts ligand binding\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that NR3C2 is post-transcriptionally controlled, with miR-124 and miR-135a repressing it translationally via the 3'UTR without mRNA degradation.\",\n      \"evidence\": \"Luciferase reporter assay with NR3C2 3'UTR and mRNA-level quantification\",\n      \"pmids\": [\"19944075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of this repression not defined\", \"No endogenous target validation beyond reporter\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that common NR3C2 haplotypes tune receptor output, modulating cortisol-induced transcription independent of ligand binding.\",\n      \"evidence\": \"In vitro cortisol-induced transactivation and protein expression assays across haplotypes\",\n      \"pmids\": [\"21095064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo physiological consequence of haplotype differences unresolved\", \"Mechanism by which MRI180V alters transactivation without affecting binding unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetically separated MR-dependent from MR-independent transport in the nephron, establishing MR as required for ENaC and Na+-K+-ATPase but not NCC.\",\n      \"evidence\": \"Conditional mosaic MR knockout mouse with cell-autonomous MR-positive vs MR-negative comparison\",\n      \"pmids\": [\"26898302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets mediating ENaC induction not enumerated\", \"Does not resolve why NCC escapes MR control\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined an inflammatory suppression axis in which MIF induces miR-301b to silence NR3C2, framing MR as a tumor suppressor restraining EMT and metastasis.\",\n      \"evidence\": \"PDAC cell assays, MIF-deletion mouse model, and patient cohort expression analysis\",\n      \"pmids\": [\"27197190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of MR in this EMT program not identified\", \"Receptor ligand dependence of tumor-suppressor activity unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed MR within glucocorticoid signaling by showing GR-target gene transcription depends on a functional MR ortholog.\",\n      \"evidence\": \"Zebrafish mr knockout lines with RNA-seq compared to gr mutants\",\n      \"pmids\": [\"35269817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MR-GR physical interaction at target promoters not demonstrated\", \"Human relevance of the shared gene set not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mechanistically linked MR tumor suppression to metabolic control, showing NR3C2 represses glycolytic genes by interacting with AP-1, opposed by MIF-MAPK/ERK signaling.\",\n      \"evidence\": \"PDAC cell lines, mouse models, patient data, metabolic flux and pathway-inhibitor studies\",\n      \"pmids\": [\"38629149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MR-AP-1 binding is direct vs cofactor-mediated not resolved\", \"Structural basis of MR/AP-1 cooperation unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generalized MR's anti-glycolytic, growth-suppressive role to colorectal cancer via HK2/LDHA suppression, AMPK dephosphorylation, and cell-cycle arrest.\",\n      \"evidence\": \"Lentiviral overexpression/knockdown with metabolic, proliferation, and flow cytometry assays\",\n      \"pmids\": [\"36950803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting MR to AMPK phosphorylation not defined\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ligand-dependent MR transcriptional activity is mechanistically integrated with its non-canonical tumor-suppressor functions (AP-1 interaction, metabolic and AKT/ERK control) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined MR cistrome bridging electrolyte and metabolic gene programs\", \"Unknown whether tumor-suppressor activity requires aldosterone/cortisol ligand binding\", \"Direct MR genomic binding sites for glycolytic gene repression not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 4, 14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"AP1\",\n      \"GR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}