NR3C2

NR3C2 encodes the mineralocorticoid receptor (MR), a ligand-activated nuclear receptor that binds aldosterone and cortisol to drive transcription, and it is central to renal electrolyte handling: in the collecting system MR is required for ENaC expression and apical targeting and for Na+-K+-ATPase expression, yet is dispensable for NCC phosphorylation in the distal convoluted tubule (PMID:26898302). Loss-of-function mutations (Y134X nonsense, 2125delA frameshift) that completely abolish aldosterone binding and transactivation cause pseudohypoaldosteronism type 1, while common haplotype variants modulate the magnitude of cortisol-induced transactivation without necessarily altering ligand binding (PMID:17287415, PMID:21095064). Beyond mineralocorticoid signaling, MR functions cooperatively with the glucocorticoid receptor, as glucocorticoid-target genes require a functional MR for correct transcription (PMID:35269817). In cancer, NR3C2 acts as a tumor suppressor: its overexpression suppresses glycolytic gene expression (HK1, HK2, LDHA) — in pancreatic cancer through interaction with AP-1 — inhibits glucose uptake and lactate efflux, induces G2/M arrest and apoptosis, and restrains AKT/ERK signaling, thereby blocking proliferation, invasion, EMT, and angiogenesis (PMID:36950803, PMID:35191517, PMID:38629149). NR3C2 is repressed in tumors by an upstream MIF axis that induces miR-301b (PMID:27197190, PMID:38629149) and by multiple 3'UTR-targeting microRNAs including miR-124, miR-135a, miR-766, miR-301b-3p, miR-454, and miR-1204 (PMID:19944075, PMID:30130435, PMID:33542733, PMID:32170966, PMID:32280303).

1. 2007 High

   Established that specific NR3C2 mutations cause disease by directly destroying receptor function, defining the molecular basis of pseudohypoaldosteronism type 1.

   Evidence Aldosterone-binding and reporter transactivation assays on Y134X and 2125delA mutant constructs

   PMID:17287415

   Open questions at the time

   • Does not address how partial-function variants behave in vivo
   • No structural explanation of how each lesion disrupts ligand binding
2. 2009 Medium

   Showed that NR3C2 is post-transcriptionally controlled, with miR-124 and miR-135a repressing it translationally via the 3'UTR without mRNA degradation.

   Evidence Luciferase reporter assay with NR3C2 3'UTR and mRNA-level quantification

   PMID:19944075

   Open questions at the time

   • Physiological context of this repression not defined
   • No endogenous target validation beyond reporter
3. 2010 Medium

   Demonstrated that common NR3C2 haplotypes tune receptor output, modulating cortisol-induced transcription independent of ligand binding.

   Evidence In vitro cortisol-induced transactivation and protein expression assays across haplotypes

   PMID:21095064

   Open questions at the time

   • In vivo physiological consequence of haplotype differences unresolved
   • Mechanism by which MRI180V alters transactivation without affecting binding unknown
4. 2016 High

   Genetically separated MR-dependent from MR-independent transport in the nephron, establishing MR as required for ENaC and Na+-K+-ATPase but not NCC.

   Evidence Conditional mosaic MR knockout mouse with cell-autonomous MR-positive vs MR-negative comparison

   PMID:26898302

   Open questions at the time

   • Transcriptional targets mediating ENaC induction not enumerated
   • Does not resolve why NCC escapes MR control
5. 2016 High

   Defined an inflammatory suppression axis in which MIF induces miR-301b to silence NR3C2, framing MR as a tumor suppressor restraining EMT and metastasis.

   Evidence PDAC cell assays, MIF-deletion mouse model, and patient cohort expression analysis

   PMID:27197190

   Open questions at the time

   • Direct transcriptional targets of MR in this EMT program not identified
   • Receptor ligand dependence of tumor-suppressor activity unclear
6. 2022 Medium

   Placed MR within glucocorticoid signaling by showing GR-target gene transcription depends on a functional MR ortholog.

   Evidence Zebrafish mr knockout lines with RNA-seq compared to gr mutants

   PMID:35269817

   Open questions at the time

   • Direct MR-GR physical interaction at target promoters not demonstrated
   • Human relevance of the shared gene set not established
7. 2024 Medium

   Mechanistically linked MR tumor suppression to metabolic control, showing NR3C2 represses glycolytic genes by interacting with AP-1, opposed by MIF-MAPK/ERK signaling.

   Evidence PDAC cell lines, mouse models, patient data, metabolic flux and pathway-inhibitor studies

   PMID:38629149

   Open questions at the time

   • Whether MR-AP-1 binding is direct vs cofactor-mediated not resolved
   • Structural basis of MR/AP-1 cooperation unknown
8. 2023 Medium

   Generalized MR's anti-glycolytic, growth-suppressive role to colorectal cancer via HK2/LDHA suppression, AMPK dephosphorylation, and cell-cycle arrest.

   Evidence Lentiviral overexpression/knockdown with metabolic, proliferation, and flow cytometry assays

   PMID:36950803

   Open questions at the time

   • Mechanism connecting MR to AMPK phosphorylation not defined
   • No in vivo confirmation

• How ligand-dependent MR transcriptional activity is mechanistically integrated with its non-canonical tumor-suppressor functions (AP-1 interaction, metabolic and AKT/ERK control) remains unresolved.
• No defined MR cistrome bridging electrolyte and metabolic gene programs
• Unknown whether tumor-suppressor activity requires aldosterone/cortisol ligand binding
• Direct MR genomic binding sites for glycolytic gene repression not mapped