{"gene":"NR3C2","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1987,"finding":"The human mineralocorticoid receptor (hMR/NR3C2) was cloned by low-stringency hybridization with the glucocorticoid receptor cDNA. Expression studies demonstrated that it encodes a 107-kDa polypeptide that binds aldosterone with high affinity, activates gene transcription in response to aldosterone, also binds glucocorticoids with high affinity, and can stimulate a glucocorticoid-responsive promoter, establishing functional kinship with the glucocorticoid receptor.","method":"cDNA cloning, radioligand binding assays, reporter gene transactivation in expression studies","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — original cloning paper with ligand binding and transcriptional activation assays, foundational study with 1752 citations","pmids":["3037703"],"is_preprint":false},{"year":1998,"finding":"Heterozygous loss-of-function mutations in NR3C2 (frameshift, premature stop, and splice-donor mutations) cause autosomal dominant pseudohypoaldosteronism type I (PHA1), demonstrating that haploinsufficiency of the mineralocorticoid receptor is sufficient to impair renal sodium reabsorption and blood pressure homeostasis in humans.","method":"Genetic linkage and mutation screening in PHA1 kindreds; mutations include frameshift, nonsense, and splice-site variants in NR3C2","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in human disease kindreds, multiple independent mutation types segregating with phenotype, replicated across multiple kindreds, 268 citations","pmids":["9662404"],"is_preprint":false},{"year":2000,"finding":"The S810L gain-of-function mutation in NR3C2 causes early-onset hypertension markedly exacerbated by pregnancy. Biochemical and structural studies showed this mutation confers constitutive receptor activity and altered ligand specificity: progesterone and other steroids lacking a 21-hydroxyl group, normally MR antagonists, become potent agonists. Structural analysis indicated the mutation creates a new van der Waals contact between helix 5 and helix 3, substituting for the normal 21-hydroxyl–helix 3 interaction required for wild-type activation.","method":"Mutation identification in hypertensive kindred; in vitro ligand binding and transactivation assays; X-ray crystallographic structural analysis; mutagenesis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — reconstitution/biochemical assays + crystal structure + mutagenesis in a single study, 441 citations","pmids":["10884226"],"is_preprint":false},{"year":2005,"finding":"Crystal structures of the NR3C2 ligand-binding domain bound to agonists and antagonists, combined with mutagenesis, revealed that maximal receptor activation requires a ligand-mediated hydrogen bond network involving Asn770 (which stabilizes the loop preceding the AF-2 helix and contacts the hormone) and Thr945 on helix 10. The naturally occurring S810L mutant was shown structurally to activate by stabilizing a helix 3/helix 5 interaction that bypasses this hydrogen bond network requirement.","method":"X-ray crystallography of MR LBD with multiple ligands; site-directed mutagenesis; transactivation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple crystal structures + mutagenesis + functional assays in one study, 165 citations","pmids":["15967794"],"is_preprint":false},{"year":2005,"finding":"Human coronary artery and aortic vascular smooth muscle cells express functional NR3C2 (MR) mRNA and protein. Endogenous vascular smooth muscle MR mediates aldosterone-dependent gene transcription that is blocked by spironolactone. Angiotensin II also activates MR-mediated gene transcription in these cells via AT1 receptor signaling. Aldosterone via MR upregulates genes involved in vascular fibrosis, inflammation, and calcification.","method":"RT-PCR, Western blot, reporter gene transactivation, microarray, pharmacological blockade (spironolactone, losartan), aldosterone synthase inhibition","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (mRNA, protein, reporter gene, microarray) with pharmacological and molecular controls, 296 citations","pmids":["15718497"],"is_preprint":false},{"year":2005,"finding":"Cardiac-specific overexpression of human NR3C2 (MR) in transgenic mice causes ion channel remodeling, prolonged ventricular repolarization, and severe life-threatening ventricular arrhythmias. These effects were prevented by the MR antagonist spironolactone, establishing a direct causal role for cardiac MR signaling in arrhythmogenesis.","method":"Conditional transgenic mouse model with cardiac-specific MR overexpression; electrophysiology; pharmacological rescue with spironolactone","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 — clean transgenic gain-of-function with defined electrophysiological phenotype and pharmacological rescue, 213 citations","pmids":["15939817"],"is_preprint":false},{"year":2006,"finding":"Molecular characterization of six NR3C2 mutations causing autosomal dominant PHA1 revealed distinct mechanisms: a frameshift mutation (c.2871dupC) abolished aldosterone binding and transactivation via major conformational change; two nonsense mutations produced truncated proteins; missense S818L prevented aldosterone binding, transactivation, and nuclear translocation; and missense E972G showed reduced ligand-binding affinity and only 9% of wild-type transcriptional activity. Fluorescence-labeled MR subcellular translocation assays and proteolysis experiments mapped critical residues for MR structure and function.","method":"Aldosterone binding assays, reporter gene transactivation assays, fluorescence microscopy for nuclear translocation, limited proteolysis, 3D structural modeling","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal mechanistic assays (binding, transactivation, localization, proteolysis, modeling) on naturally occurring disease mutants","pmids":["16954160"],"is_preprint":false},{"year":2006,"finding":"The common NR3C2 polymorphism I180V (MR180V) causes a mild loss of function specifically for cortisol as ligand (higher EC50 for cortisol-driven transactivation) without affecting aldosterone-driven transactivation. In vivo, carriers of the 180V allele showed enhanced salivary and plasma cortisol and heart rate responses to psychosocial stress, consistent with reduced cortisol-mediated MR dampening of the HPA axis.","method":"In vitro transactivation assays with cortisol and aldosterone on MR180I vs. MR180V; human psychosocial stress challenge (Trier Social Stress Test); salivary and plasma cortisol measurements","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro functional characterization combined with in vivo human physiological challenge, 151 citations","pmids":["17018659"],"is_preprint":false},{"year":2007,"finding":"Two novel NR3C2 mutations causing PHA1 in Italian patients—a nonsense mutation (Y134X) and a frameshift (2125delA)—were functionally characterized and showed complete absence of aldosterone binding and transactivation. These data extend the spectrum of loss-of-function NR3C2 mutations and identify functionally important regions of the mineralocorticoid receptor protein.","method":"NR3C2 gene sequencing, aldosterone binding assays, reporter gene transactivation assays, microsatellite analysis","journal":"European journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — binding and transactivation assays on disease mutants, single lab","pmids":["17287415"],"is_preprint":false},{"year":2008,"finding":"Human coronary artery and aortic endothelial cells express functional NR3C2 (MR) and the cortisol-inactivating enzyme 11βHSD2. Aldosterone activates endogenous EC MR to upregulate ICAM1 mRNA and protein expression; this was blocked by spironolactone and by siRNA knockdown of MR. Aldosterone-induced ICAM1 surface expression promoted leukocyte–endothelial adhesion, an effect inhibited by spironolactone and ICAM1 blocking antibody.","method":"RT-PCR, Western blot, reporter gene transactivation, siRNA knockdown, ELISA, cell adhesion assays, pharmacological blockade","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including siRNA knockdown + functional adhesion assay, 231 citations","pmids":["18467630"],"is_preprint":false},{"year":2013,"finding":"Phosphorylation of NR3C2 at Ser843 in the ligand-binding domain prevents ligand binding and receptor activation. In the kidney, MR-S843-P is found exclusively in intercalated cells of the distal nephron. Angiotensin II and WNK4 signaling decrease MR-S843-P levels during volume depletion, whereas hyperkalemia increases MR-S843-P. Dephosphorylation of MR-S843-P leads to aldosterone-dependent upregulation of the apical proton pump and Cl-/HCO3- exchangers in intercalated cells, revealing a phosphorylation-based mechanism that selectively gates MR activity to produce distinct homeostatic responses to volume depletion versus hyperkalemia.","method":"Phosphospecific antibodies, in vitro ligand-binding assays with phosphomimetic and phospho-null mutants, mouse genetic models, immunofluorescence, patch-clamp/electrophysiology","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1–2 — phosphospecific biochemistry + mutagenesis + in vivo mouse genetics + cellular functional assays, 150 citations","pmids":["24206662"],"is_preprint":false},{"year":2016,"finding":"MIF drives a signaling axis in pancreatic ductal adenocarcinoma (PDAC) by upregulating miR-301b, which directly targets and suppresses NR3C2. Loss of NR3C2 function promotes epithelial-to-mesenchymal transition and reduces sensitivity to gemcitabine. Genetic deletion of MIF in a genetically engineered mouse model disrupted the MIF–miR-301b–NR3C2 axis, reducing metastasis and prolonging survival, establishing NR3C2 as a tumor suppressor downstream of MIF in PDAC.","method":"miRNA target prediction and validation, NR3C2 overexpression/knockdown in cell lines, EMT marker analysis, gemcitabine sensitivity assay, genetically engineered mouse model of PDAC with MIF deletion, patient cohort correlation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple cell-line experiments + in vivo mouse genetic model + patient cohort validation, 256 citations","pmids":["27197190"],"is_preprint":false},{"year":2016,"finding":"In mice with mosaic deletion of NR3C2 (~20% of renal tubule cells), MR is essential for ENaC abundance and apical targeting as well as Na+-K+-ATPase expression in collecting system cells, but is dispensable for NCC abundance, phosphorylation, and Na+-K+-ATPase regulation in the distal convoluted tubule—even under dietary Na+ restriction. This cell-autonomous comparison established that aldosterone regulates ENaC directly through MR in the collecting system but controls NCC indirectly through systemic mechanisms.","method":"Mosaic MR-knockout mouse model (MR/X mice); immunofluorescence; Western blot for transport protein abundance and phosphorylation; dietary Na+ restriction challenge","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — elegant cell-autonomous genetic comparison with side-by-side MR+ and MR- cells in same physiological context, multiple ion transport proteins assessed","pmids":["26898302"],"is_preprint":false},{"year":2017,"finding":"miR-135b-5p directly targets the 3′UTR of NR3C2 and suppresses its expression in pancreatic cancer cells, thereby promoting cell migration, invasion, and EMT. Rescue experiments confirmed that NR3C2 mediates the pro-tumorigenic effects of miR-135b-5p.","method":"Transwell migration/invasion assays, EMT marker immunostaining and Western blot, GEO database analysis, target validation by luciferase reporter and rescue experiments","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct target validation by luciferase + rescue experiments, single lab","pmids":["29196101"],"is_preprint":false},{"year":2018,"finding":"miR-766 directly targets NR3C2 in hepatocellular carcinoma cells, suppressing its expression and thereby promoting HCC cell proliferation and metastasis in vitro and in vivo. Mechanistically, miR-766 regulation of NR3C2 affected the β-catenin signaling pathway.","method":"qRT-PCR, luciferase reporter assay, xenograft mouse model, Western blot, cell proliferation and invasion assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct target validation with luciferase and in vivo xenograft model demonstrating NR3C2 as functional mediator","pmids":["30130435"],"is_preprint":false},{"year":2021,"finding":"miR-301b-3p directly targets NR3C2 in breast cancer cells, as confirmed by dual-luciferase reporter assay. Overexpression of miR-301b-3p promoted breast cancer cell proliferation, migration, and invasion, while NR3C2 was downregulated in breast cancer cell lines; rescue experiments demonstrated that NR3C2 mediates these effects of miR-301b-3p.","method":"Dual-luciferase reporter assay, CCK-8 proliferation assay, Transwell migration/invasion assay, Western blot, rescue experiments","journal":"Journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 — direct target validation by luciferase + rescue experiments in cell lines, single lab","pmids":["33542733"],"is_preprint":false},{"year":2023,"finding":"NR3C2 inhibits colorectal cancer cell proliferation and induces G2/M cell cycle arrest by suppressing glucose metabolism: NR3C2 overexpression decreased HK2 and LDHA expression, reducing lactate production, glucose consumption, and ATP production. NR3C2 overexpression also reduced AMPK phosphorylation, placing NR3C2 upstream of AMPK in the regulation of glycolysis in CRC cells.","method":"Lentiviral overexpression/knockdown, MTT assay, colony formation, flow cytometry (cell cycle), lactate/glucose/ATP measurement, Western blot for AMPK phosphorylation, HK2, LDHA","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple metabolic assays with genetic perturbation and downstream pathway analysis, single lab","pmids":["36950803"],"is_preprint":false},{"year":2022,"finding":"NR3C2 overexpression in colon cancer cells inhibits proliferation, colony formation, migration, invasion, and angiogenesis (reduced VEGF secretion and tube formation). Mechanistically, NR3C2 overexpression suppressed the AKT/ERK signaling pathway, and pathway activators rescued the NR3C2-driven inhibition, placing NR3C2 as an upstream suppressor of AKT/ERK in colon cancer.","method":"CCK-8 assay, colony formation, wound healing, Transwell invasion, ELISA for VEGF, tube formation assay, Western blot for AKT/ERK phosphorylation","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple functional assays with pathway inhibitor/activator rescue, single lab","pmids":["35191517"],"is_preprint":false},{"year":2024,"finding":"In PDAC, NR3C2 suppresses glycolytic metabolism by interacting with the activator protein 1 (AP-1) transcription factor complex to downregulate HK1, HK2, and LDHA expression, thereby inhibiting glucose uptake and lactate efflux. Conversely, MIF activates glycolysis through MAPK-ERK signaling. The MIF/NR3C2 axis thus dually regulates glucose metabolism reprogramming in pancreatic cancer.","method":"Gene expression analysis in PDAC patient cohorts, in vitro metabolic assays (glucose uptake, lactate efflux), NR3C2 overexpression/knockdown, Western blot for HK1/HK2/LDHA, MAPK-ERK pathway inhibition, AP-1 co-immunoprecipitation/interaction studies, mouse PDAC models","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway characterization with in vitro and in vivo models plus AP-1 interaction studies, single lab","pmids":["38629149"],"is_preprint":false},{"year":2009,"finding":"The NR3C2 promoter region SNP MR-2G/C (rs2070951) affects in vitro transactivational capacity of MR in response to cortisol or dexamethasone in a sex-specific manner. Female subjects homozygous for the G allele showed greatest suppression of the cortisol awakening response after dexamethasone administration, while male GG subjects showed attenuated suppression, implicating this functional MR variant in HPA-axis glucocorticoid feedback.","method":"SNP genotyping, in vitro MR transactivation assays, dexamethasone suppression test with cortisol awakening response measurement in human subjects","journal":"Psychoneuroendocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — combines in vitro functional characterization of the SNP with human physiological challenge, 67 citations","pmids":["19665310"],"is_preprint":false},{"year":2020,"finding":"miR-454 directly targets NR3C2 in oral squamous cell carcinoma (OSCC) cells, as validated by GEO database expression analysis and co-transfection rescue experiments. Depletion of miR-454 decreased OSCC cell proliferation, colony formation, invasion, and migration, effects that were partially reversed by NR3C2 silencing, establishing NR3C2 as a functional downstream effector mediating miR-454's tumor-promoting activities.","method":"GEO database analysis, miR-454 mimic/inhibitor transfection, pcDNA3.1-NR3C2/si-NR3C2 co-transfection, cell proliferation, colony formation, Transwell assays","journal":"Journal of oral pathology & medicine","confidence":"Low","confidence_rationale":"Tier 3 — rescue co-transfection experiments without direct luciferase validation of the binding site, single lab","pmids":["32170966"],"is_preprint":false},{"year":2020,"finding":"LINC01128 acts as a competing endogenous RNA (ceRNA) for miR-4260, thereby upregulating NR3C2 expression in AML cells. Inhibition of miR-4260 reduced AML cell proliferation and increased apoptosis; mechanistically, LINC01128 competed with NR3C2 for miR-4260 binding. Reduced levels of both LINC01128 and NR3C2 were identified in AML, and rescue assays confirmed that LINC01128 suppresses AML progression through the miR-4260/NR3C2 axis.","method":"miR-4260 inhibitor transfection, LINC01128 overexpression/knockdown, cell proliferation/apoptosis assays, luciferase reporter assay for ceRNA interactions, rescue experiments","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 — ceRNA mechanism with luciferase validation, indirect regulation of NR3C2, single lab","pmids":["32338183"],"is_preprint":false},{"year":2020,"finding":"In pancreatic β-cells (INS-1), LINC-P21 acts as a ceRNA sponging miR-766-3p to upregulate NR3C2. Overexpression of NR3C2 inhibited INS-1 cell proliferation and glucose-stimulated insulin secretion, while NR3C2 knockdown had opposite effects, placing NR3C2 as a functional regulator of β-cell proliferation and insulin secretion downstream of the LINC-P21/miR-766-3p axis.","method":"CCK-8 proliferation assay, ELISA for insulin secretion, miR-766-3p mimic/inhibitor, NR3C2 overexpression/knockdown, luciferase reporter assay","journal":"Experimental and clinical endocrinology & diabetes","confidence":"Low","confidence_rationale":"Tier 3 — functional cell assays for NR3C2 in β-cells with luciferase validation, indirect mechanism via ceRNA, single lab","pmids":["33007789"],"is_preprint":false},{"year":2020,"finding":"CREB1 binds the miR-1204 promoter and activates its transcription (ChIP assay). miR-1204 directly targets and inhibits NR3C2 (luciferase reporter assay and RIP). In glioblastoma cells, miR-1204 overexpression promoted proliferation and suppressed apoptosis (CCK-8, TUNEL), and rescue experiments confirmed that NR3C2 mediates these effects, identifying a CREB1–miR-1204–NR3C2 axis in GBM.","method":"ChIP assay for CREB1 at miR-1204 promoter, RIP assay, luciferase reporter assay, CCK-8, colony formation, caspase-3 activity, TUNEL, rescue experiments","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2–3 — multi-method mechanistic dissection (ChIP, RIP, luciferase, rescue), single lab","pmids":["32280303"],"is_preprint":false}],"current_model":"NR3C2 encodes the human mineralocorticoid receptor (MR), a ligand-activated transcription factor that, upon binding aldosterone (and glucocorticoids), undergoes nuclear translocation and activates target gene transcription via a ligand-mediated hydrogen bond network involving Asn770 and Thr945 in its ligand-binding domain; receptor activity is gated by phosphorylation at Ser843 (preventing ligand binding) and regulated by cell-type-specific cofactors, with established roles in renal ENaC-dependent sodium reabsorption, cardiac ion channel regulation, vascular inflammation (ICAM1/leukocyte adhesion), tumor suppression (inhibiting EMT, glycolysis via AP-1/HK/LDHA, and AKT/ERK signaling), and HPA-axis cortisol feedback, while loss-of-function mutations cause pseudohypoaldosteronism type I and a gain-of-function S810L mutation causes pregnancy-exacerbated hypertension by converting progesterone into a potent agonist."},"narrative":{"teleology":[{"year":1987,"claim":"Cloning of NR3C2 established the mineralocorticoid receptor as a member of the nuclear receptor superfamily that binds both aldosterone and glucocorticoids with high affinity and activates transcription, resolving the molecular identity of the aldosterone effector.","evidence":"cDNA cloning by low-stringency hybridization with GR probe; radioligand binding and reporter gene assays in expression systems","pmids":["3037703"],"confidence":"High","gaps":["Endogenous target genes uncharacterized","Tissue-specific cofactor requirements unknown","Post-translational regulation not addressed"]},{"year":1998,"claim":"Identification of heterozygous loss-of-function NR3C2 mutations in pseudohypoaldosteronism type I kindreds proved that MR haploinsufficiency is sufficient to disrupt renal sodium balance, linking the receptor directly to human disease.","evidence":"Genetic linkage and mutation screening in multiple PHA1 kindreds; frameshift, nonsense, and splice-site mutations segregating with phenotype","pmids":["9662404"],"confidence":"High","gaps":["Genotype–phenotype severity correlation not systematically assessed","Compensatory mechanisms in heterozygous tissue undefined"]},{"year":2000,"claim":"Structural and biochemical characterization of the S810L mutation revealed how a single residue change converts MR antagonists (progesterone) into agonists, explaining pregnancy-exacerbated hypertension and establishing the helix 3–helix 5 interface as a critical determinant of ligand selectivity.","evidence":"X-ray crystallography of MR LBD, site-directed mutagenesis, transactivation and binding assays in a hypertensive kindred","pmids":["10884226"],"confidence":"High","gaps":["Full-length MR structure not resolved","Cofactor interactions with mutant receptor unknown"]},{"year":2005,"claim":"Crystal structures of the wild-type MR LBD with agonists and antagonists defined the Asn770–Thr945 hydrogen bond network as the activation switch, while parallel in vivo studies in cardiac-specific MR-overexpressing mice and vascular cells established critical roles for MR in arrhythmogenesis and vascular inflammation.","evidence":"X-ray crystallography with mutagenesis; cardiac-specific MR transgenic mice with electrophysiology and spironolactone rescue; RT-PCR, reporter assays, and microarray in human vascular smooth muscle cells","pmids":["15967794","15939817","15718497"],"confidence":"High","gaps":["Cardiac MR target ion channel genes not individually characterized","Vascular MR cofactors not identified","Structural basis of antagonist-bound state in full receptor context unclear"]},{"year":2006,"claim":"Functional characterization of additional PHA1-causing NR3C2 mutations mapped distinct mechanisms of receptor inactivation—loss of ligand binding, failure of nuclear translocation, and conformational disruption—building a structure–function map of critical MR residues.","evidence":"Aldosterone binding assays, reporter transactivation, fluorescence microscopy for nuclear translocation, limited proteolysis on six disease mutations","pmids":["16954160"],"confidence":"High","gaps":["No crystal structures for these individual mutants","Dominant-negative effects versus haploinsufficiency not distinguished for all mutants"]},{"year":2006,"claim":"The I180V polymorphism demonstrated that MR can have ligand-selective functional variation (reduced cortisol but not aldosterone sensitivity), establishing MR as a physiological mediator of cortisol-dependent HPA-axis feedback in humans.","evidence":"In vitro transactivation with cortisol versus aldosterone; Trier Social Stress Test with salivary/plasma cortisol in genotyped human subjects","pmids":["17018659"],"confidence":"High","gaps":["Brain-specific MR targets mediating stress feedback undefined","Sex-specific mechanisms not fully dissected"]},{"year":2008,"claim":"Demonstration that endothelial MR directly upregulates ICAM1 and promotes leukocyte adhesion provided a molecular mechanism for aldosterone-driven vascular inflammation, explaining clinical benefits of MR antagonism in cardiovascular disease.","evidence":"siRNA knockdown of MR in human coronary/aortic endothelial cells; ICAM1 expression and functional leukocyte adhesion assay with spironolactone blockade","pmids":["18467630"],"confidence":"High","gaps":["Broader endothelial MR transcriptome not defined","In vivo endothelial-specific MR knockout not performed in this study"]},{"year":2013,"claim":"Discovery of Ser843 phosphorylation as an inhibitory gate on MR ligand binding revealed how the same receptor produces distinct physiological outputs in different cell types: dephosphorylation by angiotensin II/WNK4 selectively activates MR in intercalated cells during volume depletion.","evidence":"Phosphospecific antibodies, phosphomimetic/phospho-null mutant binding assays, mouse genetic models, immunofluorescence in kidney","pmids":["24206662"],"confidence":"High","gaps":["Kinase responsible for Ser843 phosphorylation not identified","Whether Ser843 phosphorylation operates in non-renal tissues unknown"]},{"year":2016,"claim":"Mosaic MR-knockout mice proved that MR cell-autonomously controls ENaC expression and apical targeting in collecting duct cells but regulates NCC indirectly, resolving a long-standing question about direct versus systemic aldosterone signaling in the distal nephron.","evidence":"Mosaic MR-knockout mouse model with side-by-side comparison of MR+ and MR− cells; immunofluorescence and Western blot for ENaC, NCC, Na-K-ATPase under Na+ restriction","pmids":["26898302"],"confidence":"High","gaps":["Downstream MR transcriptional targets controlling ENaC trafficking not identified","Systemic mediator linking MR to NCC regulation uncharacterized"]},{"year":2016,"claim":"Identification of NR3C2 as a miR-301b target suppressed by MIF in PDAC, with genetic validation in mouse models, established MR as a tumor suppressor that inhibits EMT when expressed—extending MR biology beyond classical epithelial electrolyte transport.","evidence":"miRNA target validation, NR3C2 overexpression/knockdown, EMT marker analysis, MIF-knockout genetically engineered mouse PDAC model","pmids":["27197190"],"confidence":"High","gaps":["Direct MR transcriptional targets mediating EMT suppression in PDAC not defined","Whether MR ligands are required for tumor suppressor activity unclear"]},{"year":2022,"claim":"NR3C2 overexpression in colorectal and colon cancer models suppressed proliferation, glycolysis, and angiogenesis by downregulating HK2/LDHA and inhibiting AKT/ERK signaling, revealing specific metabolic and signaling pathways through which MR exerts tumor suppression.","evidence":"Lentiviral NR3C2 overexpression/knockdown in CRC cell lines; metabolic assays (glucose, lactate, ATP); Western blot for AMPK, AKT, ERK phosphorylation; VEGF ELISA and tube formation; pathway activator rescue","pmids":["36950803","35191517"],"confidence":"Medium","gaps":["Whether MR requires aldosterone/ligand binding to suppress glycolysis is untested","In vivo tumor models not included in all studies","AP-1 interaction mechanism from PDAC studies not confirmed in CRC"]},{"year":2024,"claim":"NR3C2 was shown to interact with the AP-1 complex to transcriptionally repress HK1/HK2/LDHA in PDAC, providing a direct transcriptional mechanism for MR-mediated glycolysis suppression and linking the MIF/MAPK-ERK and NR3C2/AP-1 pathways as opposing regulators of tumor glucose metabolism.","evidence":"AP-1 co-immunoprecipitation/interaction studies, NR3C2 overexpression/knockdown with metabolic assays, MAPK-ERK inhibition, mouse PDAC models","pmids":["38629149"],"confidence":"Medium","gaps":["Structural basis of MR–AP-1 interaction unknown","Whether this mechanism operates in non-pancreatic cancers untested","Ligand dependence of MR–AP-1 interaction not assessed"]},{"year":null,"claim":"Key unresolved questions include the identity of the kinase that phosphorylates MR at Ser843, the full-length MR structure in complex with cofactors, whether MR tumor-suppressive functions require ligand activation, and the tissue-specific MR interactome that dictates divergent physiological outputs across kidney, heart, vasculature, and tumors.","evidence":"","pmids":[],"confidence":"High","gaps":["Ser843 kinase identity unknown","Full-length MR structure unresolved","Ligand dependence of tumor suppressor activity untested","Tissue-specific cofactor complexes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3,4,6,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2,3,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,10]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,4,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,9,10,17]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,10,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,11,16]}],"complexes":[],"partners":["AP-1","ICAM1","ENAC","WNK4"],"other_free_text":[]},"mechanistic_narrative":"NR3C2 encodes the mineralocorticoid receptor (MR), a ligand-activated nuclear receptor that binds aldosterone and glucocorticoids with high affinity and translocates to the nucleus to regulate target gene transcription, functioning in renal sodium homeostasis, cardiovascular physiology, HPA-axis feedback, and tumor suppression [PMID:3037703, PMID:9662404, PMID:15939817]. Receptor activation depends on a ligand-mediated hydrogen bond network involving Asn770 and Thr945 in the ligand-binding domain and is gated by inhibitory phosphorylation at Ser843, which prevents ligand binding and is dynamically regulated by angiotensin II and WNK4 signaling to produce context-dependent responses in renal intercalated cells [PMID:15967794, PMID:24206662]. In the collecting duct, MR cell-autonomously controls ENaC abundance and apical targeting for sodium reabsorption; in vascular endothelial and smooth muscle cells, MR mediates aldosterone-dependent ICAM1 upregulation and proinflammatory gene programs [PMID:26898302, PMID:18467630, PMID:15718497]. Heterozygous loss-of-function NR3C2 mutations cause autosomal dominant pseudohypoaldosteronism type I, whereas the gain-of-function S810L mutation converts progesterone into an MR agonist and causes pregnancy-exacerbated hypertension [PMID:9662404, PMID:10884226]."},"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. 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NR3C2 acts as a tumor suppressor that inhibits epithelial-to-mesenchymal transition (EMT) and enhances sensitivity to gemcitabine. Genetic deletion of MIF in a mouse model disrupted this axis, reducing metastasis.\",\n      \"method\": \"Cell line functional assays, genetically engineered mouse model, miRNA target validation, multiple patient cohort analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (cell lines, mouse model, patient cohorts), replicated across multiple independent cohorts\",\n      \"pmids\": [\"27197190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NR3C2 missense and frameshift mutations causing pseudohypoaldosteronism type 1 (PHA1) were characterized: some abolish aldosterone binding and transcriptional activation; one mutation (S818L) prevents nuclear translocation; conformational changes in the ligand-binding domain underlie loss of function. The E972G mutation reduces ligand-binding affinity and retains only 9% of wild-type transcriptional activity.\",\n      \"method\": \"Aldosterone-binding assays, reporter gene transactivation assays, fluorescence-labeled receptor subcellular translocation imaging, proteolysis experiments, 3D structural modeling, NR3C2 gene sequencing\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding and transactivation assays plus subcellular localization and structural modeling, multiple mutations characterized in one study\",\n      \"pmids\": [\"16954160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Two novel NR3C2 mutations (Y134X nonsense and 2125delA frameshift) in Italian PHA1 patients abolish aldosterone binding and transactivation. Haploinsufficiency was excluded in one patient by microsatellite analysis, indicating other mechanisms.\",\n      \"method\": \"NR3C2 gene sequencing, aldosterone-binding assays, reporter gene transactivation assays, microsatellite analysis\",\n      \"journal\": \"European journal of endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding and transactivation assays with orthogonal genetic analysis\",\n      \"pmids\": [\"17287415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NR3C2 (mineralocorticoid receptor) is required for ENaC expression and apical targeting and Na+-K+-ATPase expression in the renal collecting system, but is dispensable for NCC regulation and Na+-K+-ATPase in the distal convoluted tubule, demonstrated by side-by-side comparison of MR-positive and MR-negative cells in the same physiological context.\",\n      \"method\": \"Conditional/mosaic MR knockout mouse model (MR/X mice), immunostaining, dietary Na+ restriction challenge, protein abundance measurement\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean mosaic KO with defined cellular phenotypes, orthogonal readouts (protein abundance, localization), direct cell-autonomous comparison\",\n      \"pmids\": [\"26898302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-135b-5p directly targets NR3C2 in pancreatic cancer cells, promoting migration, invasion, and EMT. NR3C2 was validated as a target by a series of functional and rescue experiments showing that the pro-tumorigenic effects of miR-135b-5p are mediated through NR3C2 suppression.\",\n      \"method\": \"Transwell assays, immunohistochemistry, Western blot, luciferase reporter assay, rescue experiments, real-time PCR, GEO database analysis\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation by luciferase assay plus rescue experiments in cell lines, single lab\",\n      \"pmids\": [\"29196101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-766 directly targets NR3C2 in hepatocellular carcinoma cells and promotes proliferation and metastasis. miR-766 affects β-catenin signaling pathway by targeting NR3C2, demonstrated in cell lines and a xenograft mouse model.\",\n      \"method\": \"Luciferase reporter assay, cell proliferation and metastasis assays in vitro and in vivo (xenograft), quantitative RT-PCR\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation (luciferase), in vivo xenograft confirmation, β-catenin pathway placement\",\n      \"pmids\": [\"30130435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR3C2 inhibits proliferation of colorectal cancer cells by suppressing glucose metabolism (reducing HK2 and LDHA expression), inhibiting glucose consumption, lactate production, and ATP generation, and reducing phosphorylation of AMPK.\",\n      \"method\": \"Lentiviral overexpression and knockdown in CRC cell lines, MTT/colony formation/flow cytometry, glucose metabolism assays, Western blot, RT-PCR\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype with metabolic mechanism and pathway placement (AMPK phosphorylation), single lab\",\n      \"pmids\": [\"36950803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR3C2 overexpression in colon cancer cells inhibits proliferation, migration, invasion, and angiogenesis through inhibition of the AKT/ERK signaling pathway and reduced VEGF expression.\",\n      \"method\": \"CCK-8, colony formation, wound healing, Transwell, ELISA for VEGF, tube formation assay, Western blot, RT-qPCR\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays with AKT/ERK pathway placement, single lab\",\n      \"pmids\": [\"35191517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR3C2 suppresses HK1, HK2, and LDHA expression to inhibit glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, NR3C2 interacts with activator protein 1 (AP-1) to regulate glycolysis, while MIF activates the MAPK-ERK pathway to upregulate glycolytic enzymes. The MIF/NR3C2 axis interactively controls metabolic reprogramming in PDAC.\",\n      \"method\": \"In vitro cell line assays, mouse models of PDAC, patient tumor data, metabolomics (pyruvate/lactate), gene expression analysis, MAPK-ERK and AP-1 pathway analysis\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo models, AP-1 interaction demonstrated, MAPK-ERK pathway placement, but single lab\",\n      \"pmids\": [\"38629149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-301b-3p directly targets NR3C2 in breast cancer cells, promoting proliferation, migration, and invasion, as validated by dual-luciferase reporter assay and rescue experiments showing NR3C2 mediates the effects of miR-301b-3p.\",\n      \"method\": \"Dual-luciferase reporter assay, CCK-8, Transwell assay, Western blot, RT-qPCR, rescue experiment\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation plus rescue experiments, single lab\",\n      \"pmids\": [\"33542733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA Gm11974 acts upstream of miR-766-3p, which directly targets NR3C2; the Gm11974/miR-766-3p/NR3C2 axis regulates apoptosis and cell death in cerebral ischemia-reperfusion injury modeled in N2a cells.\",\n      \"method\": \"Dual-luciferase reporter assay, trypan blue staining, TUNEL, JC-1, cell viability assay, cytoplasmic/nuclear fractionation\",\n      \"journal\": \"Artificial cells, nanomedicine, and biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single model system, mechanistic follow-up partial\",\n      \"pmids\": [\"31556305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"lncRNA SOX2OT acts as a ceRNA sponging miR-135a-5p, which targets NR3C2; SOX2OT silencing attenuates cerebral ischemia-reperfusion injury in vitro (OGD/R in PC12 cells) and in vivo (MCAO/R rats) through the miR-135a-5p/NR3C2 axis, reducing oxidative stress, apoptosis, and inflammation.\",\n      \"method\": \"Dual-luciferase reporter assay, RT-qPCR, MTT, TUNEL, LDH/MDA/SOD/ROS assays, MCAO/R rat model, neurological deficit scoring\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, ceRNA mechanism inferred, NR3C2 role shown by rescue but without direct mechanistic characterization of NR3C2 function\",\n      \"pmids\": [\"34022287\"],\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 then targets and inhibits NR3C2, a tumor suppressor in glioblastoma, promoting malignant cell proliferation and suppressing apoptosis.\",\n      \"method\": \"ChIP assay, RIP assay, luciferase reporter assay, CCK-8, colony formation, caspase-3 activity, TUNEL, RT-qPCR, Western blot\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, RIP, and luciferase assays providing direct evidence for transcriptional regulation and target validation, single lab\",\n      \"pmids\": [\"32280303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-454 targets NR3C2 in oral squamous cell carcinoma cells, and suppression of NR3C2 mediates the tumor-promoting effects of miR-454 on proliferation, colony formation, invasion, and migration.\",\n      \"method\": \"Co-transfection and rescue experiments in OSCC cell lines, cell proliferation/colony formation/Transwell assays, GEO database analysis\",\n      \"journal\": \"Journal of oral pathology & medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — target relationship inferred from rescue experiments without direct luciferase validation reported, single lab\",\n      \"pmids\": [\"32170966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA LINC01128 acts as a competing endogenous RNA (ceRNA) for miR-4260, thereby upregulating NR3C2. Reduced LINC01128 and NR3C2 levels promote AML progression, and restoring the LINC01128/miR-4260/NR3C2 axis suppresses AML cell proliferation and promotes apoptosis.\",\n      \"method\": \"miRNA inhibitor/mimic transfection, luciferase assay inferred from ceRNA mechanism, proliferation and apoptosis assays, RT-qPCR, rescue experiments\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ceRNA network inferred, single lab, rescue experiments performed but detailed mechanistic follow-up limited\",\n      \"pmids\": [\"32338183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA LINC-P21 sponges miR-766-3p to upregulate NR3C2 expression; elevated NR3C2 reduces insulin secretion and pancreatic β-cell proliferation. miR-766-3p directly targets NR3C2 in INS-1 cells, placing NR3C2 downstream in the LINC-P21/miR-766-3p/NR3C2 axis.\",\n      \"method\": \"CCK-8 cell proliferation assay, ELISA for insulin secretion, gain/loss of function experiments, miRNA target prediction and validation in INS-1 cells\",\n      \"journal\": \"Experimental and clinical endocrinology & diabetes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional effects and ceRNA axis shown but direct target validation details limited\",\n      \"pmids\": [\"33007789\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR3C2 (mineralocorticoid receptor) is a ligand-activated nuclear receptor that, upon aldosterone binding, translocates to the nucleus to regulate transcription of ion transport genes (including ENaC and Na+-K+-ATPase) in renal collecting duct cells; loss-of-function mutations in NR3C2 cause pseudohypoaldosteronism type 1 by abolishing aldosterone binding, nuclear translocation, or transcriptional activation. In cancer contexts, NR3C2 functions as a tumor suppressor that inhibits EMT, glycolytic reprogramming (suppressing HK1/HK2/LDHA via AP-1 interaction), and AKT/ERK and β-catenin signaling; its expression is frequently silenced by multiple oncogenic microRNAs (miR-301b, miR-135b-5p, miR-766, miR-454, miR-1204) downstream of inflammatory mediators such as MIF.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1987,\n      \"finding\": \"The human mineralocorticoid receptor (hMR/NR3C2) was cloned by low-stringency hybridization with the glucocorticoid receptor cDNA. Expression studies demonstrated that it encodes a 107-kDa polypeptide that binds aldosterone with high affinity, activates gene transcription in response to aldosterone, also binds glucocorticoids with high affinity, and can stimulate a glucocorticoid-responsive promoter, establishing functional kinship with the glucocorticoid receptor.\",\n      \"method\": \"cDNA cloning, radioligand binding assays, reporter gene transactivation in expression studies\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning paper with ligand binding and transcriptional activation assays, foundational study with 1752 citations\",\n      \"pmids\": [\"3037703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Heterozygous loss-of-function mutations in NR3C2 (frameshift, premature stop, and splice-donor mutations) cause autosomal dominant pseudohypoaldosteronism type I (PHA1), demonstrating that haploinsufficiency of the mineralocorticoid receptor is sufficient to impair renal sodium reabsorption and blood pressure homeostasis in humans.\",\n      \"method\": \"Genetic linkage and mutation screening in PHA1 kindreds; mutations include frameshift, nonsense, and splice-site variants in NR3C2\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in human disease kindreds, multiple independent mutation types segregating with phenotype, replicated across multiple kindreds, 268 citations\",\n      \"pmids\": [\"9662404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The S810L gain-of-function mutation in NR3C2 causes early-onset hypertension markedly exacerbated by pregnancy. Biochemical and structural studies showed this mutation confers constitutive receptor activity and altered ligand specificity: progesterone and other steroids lacking a 21-hydroxyl group, normally MR antagonists, become potent agonists. Structural analysis indicated the mutation creates a new van der Waals contact between helix 5 and helix 3, substituting for the normal 21-hydroxyl–helix 3 interaction required for wild-type activation.\",\n      \"method\": \"Mutation identification in hypertensive kindred; in vitro ligand binding and transactivation assays; X-ray crystallographic structural analysis; mutagenesis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution/biochemical assays + crystal structure + mutagenesis in a single study, 441 citations\",\n      \"pmids\": [\"10884226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structures of the NR3C2 ligand-binding domain bound to agonists and antagonists, combined with mutagenesis, revealed that maximal receptor activation requires a ligand-mediated hydrogen bond network involving Asn770 (which stabilizes the loop preceding the AF-2 helix and contacts the hormone) and Thr945 on helix 10. The naturally occurring S810L mutant was shown structurally to activate by stabilizing a helix 3/helix 5 interaction that bypasses this hydrogen bond network requirement.\",\n      \"method\": \"X-ray crystallography of MR LBD with multiple ligands; site-directed mutagenesis; transactivation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple crystal structures + mutagenesis + functional assays in one study, 165 citations\",\n      \"pmids\": [\"15967794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human coronary artery and aortic vascular smooth muscle cells express functional NR3C2 (MR) mRNA and protein. Endogenous vascular smooth muscle MR mediates aldosterone-dependent gene transcription that is blocked by spironolactone. Angiotensin II also activates MR-mediated gene transcription in these cells via AT1 receptor signaling. Aldosterone via MR upregulates genes involved in vascular fibrosis, inflammation, and calcification.\",\n      \"method\": \"RT-PCR, Western blot, reporter gene transactivation, microarray, pharmacological blockade (spironolactone, losartan), aldosterone synthase inhibition\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (mRNA, protein, reporter gene, microarray) with pharmacological and molecular controls, 296 citations\",\n      \"pmids\": [\"15718497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cardiac-specific overexpression of human NR3C2 (MR) in transgenic mice causes ion channel remodeling, prolonged ventricular repolarization, and severe life-threatening ventricular arrhythmias. These effects were prevented by the MR antagonist spironolactone, establishing a direct causal role for cardiac MR signaling in arrhythmogenesis.\",\n      \"method\": \"Conditional transgenic mouse model with cardiac-specific MR overexpression; electrophysiology; pharmacological rescue with spironolactone\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean transgenic gain-of-function with defined electrophysiological phenotype and pharmacological rescue, 213 citations\",\n      \"pmids\": [\"15939817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Molecular characterization of six NR3C2 mutations causing autosomal dominant PHA1 revealed distinct mechanisms: a frameshift mutation (c.2871dupC) abolished aldosterone binding and transactivation via major conformational change; two nonsense mutations produced truncated proteins; missense S818L prevented aldosterone binding, transactivation, and nuclear translocation; and missense E972G showed reduced ligand-binding affinity and only 9% of wild-type transcriptional activity. Fluorescence-labeled MR subcellular translocation assays and proteolysis experiments mapped critical residues for MR structure and function.\",\n      \"method\": \"Aldosterone binding assays, reporter gene transactivation assays, fluorescence microscopy for nuclear translocation, limited proteolysis, 3D structural modeling\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal mechanistic assays (binding, transactivation, localization, proteolysis, modeling) on naturally occurring disease mutants\",\n      \"pmids\": [\"16954160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The common NR3C2 polymorphism I180V (MR180V) causes a mild loss of function specifically for cortisol as ligand (higher EC50 for cortisol-driven transactivation) without affecting aldosterone-driven transactivation. In vivo, carriers of the 180V allele showed enhanced salivary and plasma cortisol and heart rate responses to psychosocial stress, consistent with reduced cortisol-mediated MR dampening of the HPA axis.\",\n      \"method\": \"In vitro transactivation assays with cortisol and aldosterone on MR180I vs. MR180V; human psychosocial stress challenge (Trier Social Stress Test); salivary and plasma cortisol measurements\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro functional characterization combined with in vivo human physiological challenge, 151 citations\",\n      \"pmids\": [\"17018659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Two novel NR3C2 mutations causing PHA1 in Italian patients—a nonsense mutation (Y134X) and a frameshift (2125delA)—were functionally characterized and showed complete absence of aldosterone binding and transactivation. These data extend the spectrum of loss-of-function NR3C2 mutations and identify functionally important regions of the mineralocorticoid receptor protein.\",\n      \"method\": \"NR3C2 gene sequencing, aldosterone binding assays, reporter gene transactivation assays, microsatellite analysis\",\n      \"journal\": \"European journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding and transactivation assays on disease mutants, single lab\",\n      \"pmids\": [\"17287415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human coronary artery and aortic endothelial cells express functional NR3C2 (MR) and the cortisol-inactivating enzyme 11βHSD2. Aldosterone activates endogenous EC MR to upregulate ICAM1 mRNA and protein expression; this was blocked by spironolactone and by siRNA knockdown of MR. Aldosterone-induced ICAM1 surface expression promoted leukocyte–endothelial adhesion, an effect inhibited by spironolactone and ICAM1 blocking antibody.\",\n      \"method\": \"RT-PCR, Western blot, reporter gene transactivation, siRNA knockdown, ELISA, cell adhesion assays, pharmacological blockade\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including siRNA knockdown + functional adhesion assay, 231 citations\",\n      \"pmids\": [\"18467630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Phosphorylation of NR3C2 at Ser843 in the ligand-binding domain prevents ligand binding and receptor activation. In the kidney, MR-S843-P is found exclusively in intercalated cells of the distal nephron. Angiotensin II and WNK4 signaling decrease MR-S843-P levels during volume depletion, whereas hyperkalemia increases MR-S843-P. Dephosphorylation of MR-S843-P leads to aldosterone-dependent upregulation of the apical proton pump and Cl-/HCO3- exchangers in intercalated cells, revealing a phosphorylation-based mechanism that selectively gates MR activity to produce distinct homeostatic responses to volume depletion versus hyperkalemia.\",\n      \"method\": \"Phosphospecific antibodies, in vitro ligand-binding assays with phosphomimetic and phospho-null mutants, mouse genetic models, immunofluorescence, patch-clamp/electrophysiology\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — phosphospecific biochemistry + mutagenesis + in vivo mouse genetics + cellular functional assays, 150 citations\",\n      \"pmids\": [\"24206662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MIF drives a signaling axis in pancreatic ductal adenocarcinoma (PDAC) by upregulating miR-301b, which directly targets and suppresses NR3C2. Loss of NR3C2 function promotes epithelial-to-mesenchymal transition and reduces sensitivity to gemcitabine. Genetic deletion of MIF in a genetically engineered mouse model disrupted the MIF–miR-301b–NR3C2 axis, reducing metastasis and prolonging survival, establishing NR3C2 as a tumor suppressor downstream of MIF in PDAC.\",\n      \"method\": \"miRNA target prediction and validation, NR3C2 overexpression/knockdown in cell lines, EMT marker analysis, gemcitabine sensitivity assay, genetically engineered mouse model of PDAC with MIF deletion, patient cohort correlation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell-line experiments + in vivo mouse genetic model + patient cohort validation, 256 citations\",\n      \"pmids\": [\"27197190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In mice with mosaic deletion of NR3C2 (~20% of renal tubule cells), MR is essential for ENaC abundance and apical targeting as well as Na+-K+-ATPase expression in collecting system cells, but is dispensable for NCC abundance, phosphorylation, and Na+-K+-ATPase regulation in the distal convoluted tubule—even under dietary Na+ restriction. This cell-autonomous comparison established that aldosterone regulates ENaC directly through MR in the collecting system but controls NCC indirectly through systemic mechanisms.\",\n      \"method\": \"Mosaic MR-knockout mouse model (MR/X mice); immunofluorescence; Western blot for transport protein abundance and phosphorylation; dietary Na+ restriction challenge\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — elegant cell-autonomous genetic comparison with side-by-side MR+ and MR- cells in same physiological context, multiple ion transport proteins assessed\",\n      \"pmids\": [\"26898302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-135b-5p directly targets the 3′UTR of NR3C2 and suppresses its expression in pancreatic cancer cells, thereby promoting cell migration, invasion, and EMT. Rescue experiments confirmed that NR3C2 mediates the pro-tumorigenic effects of miR-135b-5p.\",\n      \"method\": \"Transwell migration/invasion assays, EMT marker immunostaining and Western blot, GEO database analysis, target validation by luciferase reporter and rescue experiments\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct target validation by luciferase + rescue experiments, single lab\",\n      \"pmids\": [\"29196101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-766 directly targets NR3C2 in hepatocellular carcinoma cells, suppressing its expression and thereby promoting HCC cell proliferation and metastasis in vitro and in vivo. Mechanistically, miR-766 regulation of NR3C2 affected the β-catenin signaling pathway.\",\n      \"method\": \"qRT-PCR, luciferase reporter assay, xenograft mouse model, Western blot, cell proliferation and invasion assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct target validation with luciferase and in vivo xenograft model demonstrating NR3C2 as functional mediator\",\n      \"pmids\": [\"30130435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-301b-3p directly targets NR3C2 in breast cancer cells, as confirmed by dual-luciferase reporter assay. Overexpression of miR-301b-3p promoted breast cancer cell proliferation, migration, and invasion, while NR3C2 was downregulated in breast cancer cell lines; rescue experiments demonstrated that NR3C2 mediates these effects of miR-301b-3p.\",\n      \"method\": \"Dual-luciferase reporter assay, CCK-8 proliferation assay, Transwell migration/invasion assay, Western blot, rescue experiments\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct target validation by luciferase + rescue experiments in cell lines, single lab\",\n      \"pmids\": [\"33542733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR3C2 inhibits colorectal cancer cell proliferation and induces G2/M cell cycle arrest by suppressing glucose metabolism: NR3C2 overexpression decreased HK2 and LDHA expression, reducing lactate production, glucose consumption, and ATP production. NR3C2 overexpression also reduced AMPK phosphorylation, placing NR3C2 upstream of AMPK in the regulation of glycolysis in CRC cells.\",\n      \"method\": \"Lentiviral overexpression/knockdown, MTT assay, colony formation, flow cytometry (cell cycle), lactate/glucose/ATP measurement, Western blot for AMPK phosphorylation, HK2, LDHA\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple metabolic assays with genetic perturbation and downstream pathway analysis, single lab\",\n      \"pmids\": [\"36950803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR3C2 overexpression in colon cancer cells inhibits proliferation, colony formation, migration, invasion, and angiogenesis (reduced VEGF secretion and tube formation). Mechanistically, NR3C2 overexpression suppressed the AKT/ERK signaling pathway, and pathway activators rescued the NR3C2-driven inhibition, placing NR3C2 as an upstream suppressor of AKT/ERK in colon cancer.\",\n      \"method\": \"CCK-8 assay, colony formation, wound healing, Transwell invasion, ELISA for VEGF, tube formation assay, Western blot for AKT/ERK phosphorylation\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple functional assays with pathway inhibitor/activator rescue, single lab\",\n      \"pmids\": [\"35191517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In PDAC, NR3C2 suppresses glycolytic metabolism by interacting with the activator protein 1 (AP-1) transcription factor complex to downregulate HK1, HK2, and LDHA expression, thereby inhibiting glucose uptake and lactate efflux. Conversely, MIF activates glycolysis through MAPK-ERK signaling. The MIF/NR3C2 axis thus dually regulates glucose metabolism reprogramming in pancreatic cancer.\",\n      \"method\": \"Gene expression analysis in PDAC patient cohorts, in vitro metabolic assays (glucose uptake, lactate efflux), NR3C2 overexpression/knockdown, Western blot for HK1/HK2/LDHA, MAPK-ERK pathway inhibition, AP-1 co-immunoprecipitation/interaction studies, mouse PDAC models\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway characterization with in vitro and in vivo models plus AP-1 interaction studies, single lab\",\n      \"pmids\": [\"38629149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The NR3C2 promoter region SNP MR-2G/C (rs2070951) affects in vitro transactivational capacity of MR in response to cortisol or dexamethasone in a sex-specific manner. Female subjects homozygous for the G allele showed greatest suppression of the cortisol awakening response after dexamethasone administration, while male GG subjects showed attenuated suppression, implicating this functional MR variant in HPA-axis glucocorticoid feedback.\",\n      \"method\": \"SNP genotyping, in vitro MR transactivation assays, dexamethasone suppression test with cortisol awakening response measurement in human subjects\",\n      \"journal\": \"Psychoneuroendocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — combines in vitro functional characterization of the SNP with human physiological challenge, 67 citations\",\n      \"pmids\": [\"19665310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-454 directly targets NR3C2 in oral squamous cell carcinoma (OSCC) cells, as validated by GEO database expression analysis and co-transfection rescue experiments. Depletion of miR-454 decreased OSCC cell proliferation, colony formation, invasion, and migration, effects that were partially reversed by NR3C2 silencing, establishing NR3C2 as a functional downstream effector mediating miR-454's tumor-promoting activities.\",\n      \"method\": \"GEO database analysis, miR-454 mimic/inhibitor transfection, pcDNA3.1-NR3C2/si-NR3C2 co-transfection, cell proliferation, colony formation, Transwell assays\",\n      \"journal\": \"Journal of oral pathology & medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — rescue co-transfection experiments without direct luciferase validation of the binding site, single lab\",\n      \"pmids\": [\"32170966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LINC01128 acts as a competing endogenous RNA (ceRNA) for miR-4260, thereby upregulating NR3C2 expression in AML cells. Inhibition of miR-4260 reduced AML cell proliferation and increased apoptosis; mechanistically, LINC01128 competed with NR3C2 for miR-4260 binding. Reduced levels of both LINC01128 and NR3C2 were identified in AML, and rescue assays confirmed that LINC01128 suppresses AML progression through the miR-4260/NR3C2 axis.\",\n      \"method\": \"miR-4260 inhibitor transfection, LINC01128 overexpression/knockdown, cell proliferation/apoptosis assays, luciferase reporter assay for ceRNA interactions, rescue experiments\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ceRNA mechanism with luciferase validation, indirect regulation of NR3C2, single lab\",\n      \"pmids\": [\"32338183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In pancreatic β-cells (INS-1), LINC-P21 acts as a ceRNA sponging miR-766-3p to upregulate NR3C2. Overexpression of NR3C2 inhibited INS-1 cell proliferation and glucose-stimulated insulin secretion, while NR3C2 knockdown had opposite effects, placing NR3C2 as a functional regulator of β-cell proliferation and insulin secretion downstream of the LINC-P21/miR-766-3p axis.\",\n      \"method\": \"CCK-8 proliferation assay, ELISA for insulin secretion, miR-766-3p mimic/inhibitor, NR3C2 overexpression/knockdown, luciferase reporter assay\",\n      \"journal\": \"Experimental and clinical endocrinology & diabetes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional cell assays for NR3C2 in β-cells with luciferase validation, indirect mechanism via ceRNA, single lab\",\n      \"pmids\": [\"33007789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CREB1 binds the miR-1204 promoter and activates its transcription (ChIP assay). miR-1204 directly targets and inhibits NR3C2 (luciferase reporter assay and RIP). In glioblastoma cells, miR-1204 overexpression promoted proliferation and suppressed apoptosis (CCK-8, TUNEL), and rescue experiments confirmed that NR3C2 mediates these effects, identifying a CREB1–miR-1204–NR3C2 axis in GBM.\",\n      \"method\": \"ChIP assay for CREB1 at miR-1204 promoter, RIP assay, luciferase reporter assay, CCK-8, colony formation, caspase-3 activity, TUNEL, rescue experiments\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multi-method mechanistic dissection (ChIP, RIP, luciferase, rescue), single lab\",\n      \"pmids\": [\"32280303\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR3C2 encodes the human mineralocorticoid receptor (MR), a ligand-activated transcription factor that, upon binding aldosterone (and glucocorticoids), undergoes nuclear translocation and activates target gene transcription via a ligand-mediated hydrogen bond network involving Asn770 and Thr945 in its ligand-binding domain; receptor activity is gated by phosphorylation at Ser843 (preventing ligand binding) and regulated by cell-type-specific cofactors, with established roles in renal ENaC-dependent sodium reabsorption, cardiac ion channel regulation, vascular inflammation (ICAM1/leukocyte adhesion), tumor suppression (inhibiting EMT, glycolysis via AP-1/HK/LDHA, and AKT/ERK signaling), and HPA-axis cortisol feedback, while loss-of-function mutations cause pseudohypoaldosteronism type I and a gain-of-function S810L mutation causes pregnancy-exacerbated hypertension by converting progesterone into a potent agonist.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NR3C2 encodes the mineralocorticoid receptor (MR), a ligand-activated nuclear receptor that translocates to the nucleus upon aldosterone binding and drives transcription of ion transport genes — including ENaC and Na⁺-K⁺-ATPase — in a cell-autonomous manner in the renal collecting duct [PMID:26898302, PMID:16954160]. Loss-of-function mutations that abolish aldosterone binding, impair nuclear translocation, or truncate the protein cause autosomal pseudohypoaldosteronism type 1 [PMID:16954160, PMID:17287415]. Beyond its classical renal role, NR3C2 acts as a tumor suppressor across multiple cancer types by inhibiting epithelial-to-mesenchymal transition, suppressing glycolytic reprogramming through interaction with AP-1 to repress HK1/HK2/LDHA, and attenuating AKT/ERK and β-catenin signaling; its expression is frequently silenced by oncogenic microRNAs (miR-301b, miR-135b-5p, miR-766, miR-1204) operating downstream of inflammatory mediators such as MIF [PMID:27197190, PMID:38629149, PMID:35191517, PMID:30130435]. NR3C2 suppression also promotes metabolic reprogramming by sustaining glucose uptake and lactate efflux, linking its loss to enhanced aerobic glycolysis in pancreatic and colorectal cancers [PMID:36950803, PMID:38629149].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing how point mutations disable NR3C2: missense and frameshift mutations were shown to abolish aldosterone binding, prevent nuclear translocation (S818L), or drastically reduce transcriptional activity (E972G), providing a molecular explanation for pseudohypoaldosteronism type 1.\",\n      \"evidence\": \"Aldosterone-binding assays, reporter gene transactivation, fluorescence-labeled receptor imaging, proteolysis and 3D modeling of multiple PHA1-causing NR3C2 mutations\",\n      \"pmids\": [\"16954160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of mutant LBDs\", \"Genotype–phenotype correlation across large PHA1 cohorts not established\", \"Co-activator/co-repressor interactions with mutant receptors not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extending the mutational spectrum: two additional truncating NR3C2 mutations confirmed loss of ligand binding and transactivation, while exclusion of haploinsufficiency in one patient pointed to dominant-negative or other pathogenic mechanisms.\",\n      \"evidence\": \"Gene sequencing, aldosterone-binding and transactivation assays, microsatellite analysis in Italian PHA1 families\",\n      \"pmids\": [\"17287415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dominant-negative mechanism not directly tested\", \"Functional consequence at the level of ENaC/Na-K-ATPase not measured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining cell-autonomous targets in the kidney: a mosaic conditional knockout demonstrated that NR3C2 is required for ENaC expression and apical targeting and Na⁺-K⁺-ATPase expression specifically in collecting duct cells but is dispensable in the distal convoluted tubule, resolving which nephron segments depend on MR signaling.\",\n      \"evidence\": \"Mosaic MR knockout mouse model with side-by-side comparison of MR-positive and MR-negative cells, immunostaining, dietary Na⁺ restriction\",\n      \"pmids\": [\"26898302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional targets beyond ENaC and Na-K-ATPase not cataloged\", \"Chromatin-level mechanism of target gene regulation not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealing NR3C2 as a tumor suppressor silenced by inflammation-driven miRNA: a MIF–miR-301b–NR3C2 axis was identified in pancreatic cancer, where NR3C2 loss promotes EMT and gemcitabine resistance, validated across cell lines, a genetically engineered mouse model, and patient cohorts.\",\n      \"evidence\": \"miRNA target validation, MIF-knockout mouse model, multiple patient cohort analysis, functional assays in PDAC cell lines\",\n      \"pmids\": [\"27197190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of NR3C2 mediating EMT suppression unknown\", \"Whether aldosterone/ligand binding is required for tumor-suppressive function not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirming miRNA-mediated NR3C2 silencing generalizes in pancreatic cancer: miR-135b-5p was validated as a second direct NR3C2-targeting miRNA promoting migration, invasion, and EMT, with rescue experiments confirming NR3C2 as the functional mediator.\",\n      \"evidence\": \"Luciferase reporter assay, Transwell assays, rescue experiments in pancreatic cancer cell lines\",\n      \"pmids\": [\"29196101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overlap or redundancy with miR-301b targeting not examined\", \"In vivo validation absent\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking NR3C2 loss to oncogenic β-catenin signaling: miR-766 was shown to directly target NR3C2 in hepatocellular carcinoma, with NR3C2 suppression activating β-catenin signaling and promoting proliferation and metastasis in vitro and in vivo.\",\n      \"evidence\": \"Luciferase reporter assay, xenograft mouse model, HCC cell line functional assays\",\n      \"pmids\": [\"30130435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which NR3C2 restrains β-catenin not defined\", \"Whether NR3C2 acts through transcriptional or non-genomic routes unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadening the tissue scope of NR3C2 tumor suppression: NR3C2 was identified as a miRNA-regulated tumor suppressor in glioblastoma (targeted by CREB1-driven miR-1204), oral squamous cell carcinoma (targeted by miR-454), and AML (regulated via lncRNA LINC01128/miR-4260 ceRNA axis), consistently inhibiting proliferation and promoting apoptosis.\",\n      \"evidence\": \"ChIP, RIP, luciferase reporter assays, rescue experiments, proliferation and apoptosis assays across GBM, OSCC, and AML cell lines\",\n      \"pmids\": [\"32280303\", \"32170966\", \"32338183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NR3C2 transcriptional targets in these non-epithelial contexts not identified\", \"miR-454 targeting lacks luciferase validation\", \"ceRNA stoichiometry not assessed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying AKT/ERK pathway inhibition as a downstream effector: NR3C2 overexpression in colon cancer suppressed AKT and ERK phosphorylation and VEGF expression, linking NR3C2 to inhibition of angiogenesis.\",\n      \"evidence\": \"CCK-8, colony formation, Transwell, tube formation assay, Western blot in colon cancer cell lines\",\n      \"pmids\": [\"35191517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NR3C2 acts via direct transcriptional repression of pathway components or indirectly not resolved\", \"In vivo confirmation absent\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing a metabolic tumor-suppressive mechanism: NR3C2 was shown to inhibit colorectal cancer proliferation by suppressing glycolytic enzymes HK2 and LDHA, reducing glucose consumption and lactate production, and decreasing AMPK phosphorylation.\",\n      \"evidence\": \"Lentiviral overexpression/knockdown in CRC cell lines, glucose metabolism assays, Western blot for metabolic enzymes and AMPK\",\n      \"pmids\": [\"36950803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AMPK reduction is direct or secondary to metabolic changes unclear\", \"No ChIP evidence for NR3C2 binding at glycolytic gene promoters\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Elucidating the mechanistic basis of glycolytic reprogramming: NR3C2 was found to interact with AP-1 to suppress HK1/HK2/LDHA, while the opposing MIF–MAPK-ERK axis upregulates these enzymes, establishing an interactive MIF/NR3C2 metabolic control circuit in pancreatic cancer.\",\n      \"evidence\": \"In vitro and mouse PDAC models, metabolomics (pyruvate/lactate), AP-1 interaction analysis, MAPK-ERK pathway analysis, patient tumor data\",\n      \"pmids\": [\"38629149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nature of NR3C2–AP-1 interaction (direct binding vs. tethering) not structurally resolved\", \"Whether ligand (aldosterone/cortisol) modulates the tumor-suppressive AP-1 interaction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open question: whether the tumor-suppressive functions of NR3C2 require classical ligand (aldosterone/cortisol) binding or represent ligand-independent activities, and what the direct chromatin targets of NR3C2 are in non-renal tissues, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ChIP-seq or CUT&RUN for NR3C2 in cancer contexts\", \"Ligand dependence of tumor-suppressive function untested\", \"Structural basis of NR3C2–AP-1 interaction unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [1, 3, 8]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"AP-1\",\n      \"MIF\",\n      \"ENaC\",\n      \"HK2\",\n      \"LDHA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NR3C2 encodes the mineralocorticoid receptor (MR), a ligand-activated nuclear receptor that binds aldosterone and glucocorticoids with high affinity and translocates to the nucleus to regulate target gene transcription, functioning in renal sodium homeostasis, cardiovascular physiology, HPA-axis feedback, and tumor suppression [PMID:3037703, PMID:9662404, PMID:15939817]. Receptor activation depends on a ligand-mediated hydrogen bond network involving Asn770 and Thr945 in the ligand-binding domain and is gated by inhibitory phosphorylation at Ser843, which prevents ligand binding and is dynamically regulated by angiotensin II and WNK4 signaling to produce context-dependent responses in renal intercalated cells [PMID:15967794, PMID:24206662]. In the collecting duct, MR cell-autonomously controls ENaC abundance and apical targeting for sodium reabsorption; in vascular endothelial and smooth muscle cells, MR mediates aldosterone-dependent ICAM1 upregulation and proinflammatory gene programs [PMID:26898302, PMID:18467630, PMID:15718497]. Heterozygous loss-of-function NR3C2 mutations cause autosomal dominant pseudohypoaldosteronism type I, whereas the gain-of-function S810L mutation converts progesterone into an MR agonist and causes pregnancy-exacerbated hypertension [PMID:9662404, PMID:10884226].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Cloning of NR3C2 established the mineralocorticoid receptor as a member of the nuclear receptor superfamily that binds both aldosterone and glucocorticoids with high affinity and activates transcription, resolving the molecular identity of the aldosterone effector.\",\n      \"evidence\": \"cDNA cloning by low-stringency hybridization with GR probe; radioligand binding and reporter gene assays in expression systems\",\n      \"pmids\": [\"3037703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous target genes uncharacterized\", \"Tissue-specific cofactor requirements unknown\", \"Post-translational regulation not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of heterozygous loss-of-function NR3C2 mutations in pseudohypoaldosteronism type I kindreds proved that MR haploinsufficiency is sufficient to disrupt renal sodium balance, linking the receptor directly to human disease.\",\n      \"evidence\": \"Genetic linkage and mutation screening in multiple PHA1 kindreds; frameshift, nonsense, and splice-site mutations segregating with phenotype\",\n      \"pmids\": [\"9662404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype–phenotype severity correlation not systematically assessed\", \"Compensatory mechanisms in heterozygous tissue undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Structural and biochemical characterization of the S810L mutation revealed how a single residue change converts MR antagonists (progesterone) into agonists, explaining pregnancy-exacerbated hypertension and establishing the helix 3–helix 5 interface as a critical determinant of ligand selectivity.\",\n      \"evidence\": \"X-ray crystallography of MR LBD, site-directed mutagenesis, transactivation and binding assays in a hypertensive kindred\",\n      \"pmids\": [\"10884226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length MR structure not resolved\", \"Cofactor interactions with mutant receptor unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Crystal structures of the wild-type MR LBD with agonists and antagonists defined the Asn770–Thr945 hydrogen bond network as the activation switch, while parallel in vivo studies in cardiac-specific MR-overexpressing mice and vascular cells established critical roles for MR in arrhythmogenesis and vascular inflammation.\",\n      \"evidence\": \"X-ray crystallography with mutagenesis; cardiac-specific MR transgenic mice with electrophysiology and spironolactone rescue; RT-PCR, reporter assays, and microarray in human vascular smooth muscle cells\",\n      \"pmids\": [\"15967794\", \"15939817\", \"15718497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cardiac MR target ion channel genes not individually characterized\", \"Vascular MR cofactors not identified\", \"Structural basis of antagonist-bound state in full receptor context unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Functional characterization of additional PHA1-causing NR3C2 mutations mapped distinct mechanisms of receptor inactivation—loss of ligand binding, failure of nuclear translocation, and conformational disruption—building a structure–function map of critical MR residues.\",\n      \"evidence\": \"Aldosterone binding assays, reporter transactivation, fluorescence microscopy for nuclear translocation, limited proteolysis on six disease mutations\",\n      \"pmids\": [\"16954160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structures for these individual mutants\", \"Dominant-negative effects versus haploinsufficiency not distinguished for all mutants\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The I180V polymorphism demonstrated that MR can have ligand-selective functional variation (reduced cortisol but not aldosterone sensitivity), establishing MR as a physiological mediator of cortisol-dependent HPA-axis feedback in humans.\",\n      \"evidence\": \"In vitro transactivation with cortisol versus aldosterone; Trier Social Stress Test with salivary/plasma cortisol in genotyped human subjects\",\n      \"pmids\": [\"17018659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Brain-specific MR targets mediating stress feedback undefined\", \"Sex-specific mechanisms not fully dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that endothelial MR directly upregulates ICAM1 and promotes leukocyte adhesion provided a molecular mechanism for aldosterone-driven vascular inflammation, explaining clinical benefits of MR antagonism in cardiovascular disease.\",\n      \"evidence\": \"siRNA knockdown of MR in human coronary/aortic endothelial cells; ICAM1 expression and functional leukocyte adhesion assay with spironolactone blockade\",\n      \"pmids\": [\"18467630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Broader endothelial MR transcriptome not defined\", \"In vivo endothelial-specific MR knockout not performed in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of Ser843 phosphorylation as an inhibitory gate on MR ligand binding revealed how the same receptor produces distinct physiological outputs in different cell types: dephosphorylation by angiotensin II/WNK4 selectively activates MR in intercalated cells during volume depletion.\",\n      \"evidence\": \"Phosphospecific antibodies, phosphomimetic/phospho-null mutant binding assays, mouse genetic models, immunofluorescence in kidney\",\n      \"pmids\": [\"24206662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Ser843 phosphorylation not identified\", \"Whether Ser843 phosphorylation operates in non-renal tissues unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mosaic MR-knockout mice proved that MR cell-autonomously controls ENaC expression and apical targeting in collecting duct cells but regulates NCC indirectly, resolving a long-standing question about direct versus systemic aldosterone signaling in the distal nephron.\",\n      \"evidence\": \"Mosaic MR-knockout mouse model with side-by-side comparison of MR+ and MR− cells; immunofluorescence and Western blot for ENaC, NCC, Na-K-ATPase under Na+ restriction\",\n      \"pmids\": [\"26898302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream MR transcriptional targets controlling ENaC trafficking not identified\", \"Systemic mediator linking MR to NCC regulation uncharacterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of NR3C2 as a miR-301b target suppressed by MIF in PDAC, with genetic validation in mouse models, established MR as a tumor suppressor that inhibits EMT when expressed—extending MR biology beyond classical epithelial electrolyte transport.\",\n      \"evidence\": \"miRNA target validation, NR3C2 overexpression/knockdown, EMT marker analysis, MIF-knockout genetically engineered mouse PDAC model\",\n      \"pmids\": [\"27197190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MR transcriptional targets mediating EMT suppression in PDAC not defined\", \"Whether MR ligands are required for tumor suppressor activity unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"NR3C2 overexpression in colorectal and colon cancer models suppressed proliferation, glycolysis, and angiogenesis by downregulating HK2/LDHA and inhibiting AKT/ERK signaling, revealing specific metabolic and signaling pathways through which MR exerts tumor suppression.\",\n      \"evidence\": \"Lentiviral NR3C2 overexpression/knockdown in CRC cell lines; metabolic assays (glucose, lactate, ATP); Western blot for AMPK, AKT, ERK phosphorylation; VEGF ELISA and tube formation; pathway activator rescue\",\n      \"pmids\": [\"36950803\", \"35191517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MR requires aldosterone/ligand binding to suppress glycolysis is untested\", \"In vivo tumor models not included in all studies\", \"AP-1 interaction mechanism from PDAC studies not confirmed in CRC\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"NR3C2 was shown to interact with the AP-1 complex to transcriptionally repress HK1/HK2/LDHA in PDAC, providing a direct transcriptional mechanism for MR-mediated glycolysis suppression and linking the MIF/MAPK-ERK and NR3C2/AP-1 pathways as opposing regulators of tumor glucose metabolism.\",\n      \"evidence\": \"AP-1 co-immunoprecipitation/interaction studies, NR3C2 overexpression/knockdown with metabolic assays, MAPK-ERK inhibition, mouse PDAC models\",\n      \"pmids\": [\"38629149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of MR–AP-1 interaction unknown\", \"Whether this mechanism operates in non-pancreatic cancers untested\", \"Ligand dependence of MR–AP-1 interaction not assessed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the kinase that phosphorylates MR at Ser843, the full-length MR structure in complex with cofactors, whether MR tumor-suppressive functions require ligand activation, and the tissue-specific MR interactome that dictates divergent physiological outputs across kidney, heart, vasculature, and tumors.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ser843 kinase identity unknown\", \"Full-length MR structure unresolved\", \"Ligand dependence of tumor suppressor activity untested\", \"Tissue-specific cofactor complexes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3, 4, 6, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2, 3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 4, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9, 10, 17]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 10, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 11, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"AP-1\",\n      \"ICAM1\",\n      \"ENaC\",\n      \"WNK4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}