Affinage

NR2C1

Nuclear receptor subfamily 2 group C member 1 · UniProt P13056

Length
603 aa
Mass
67.3 kDa
Annotated
2026-06-10
10 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR2C1 (TR2/TR2-11) is an orphan nuclear receptor that acts as a sequence-specific transcriptional repressor controlling cell fate decisions and the retinoid signaling axis (PMID:8530418, PMID:28551284). It binds AGGTCA half-site direct-repeat hormone response elements with a preference order of DR1 > DR2 > DR5 ≈ DR4 ≈ DR6 > DR3, as well as palindromic TREpal and NBRE elements, and it antagonizes RXRα and RARα/RXRα by outcompeting them for shared elements such as CRBPIIp (DR1) and RARβ (DR5) — a competition driven by NR2C1's ≥100-fold higher DNA affinity rather than by heterodimerization (PMID:8530418). Repression requires three separable activities: high-affinity DNA binding, receptor dimerization through a leucine-dependent dimer interface, and an active silencing domain within the C-terminal DEF (ligand-binding) region, whose terminal 49 residues confer trans-suppression in GAL4 chimeras (PMID:9660764). NR2C1 is itself embedded in a cross-regulatory loop with the retinoid pathway: its proximal promoter contains an IR0-type RARE bound by RARα/RXRβ heterodimers (Kd ~8 nM), rendering the gene retinoic-acid-inducible in a protein-synthesis-independent manner (PMID:10393558, PMID:10807954). Functionally, NR2C1 modulates the pluripotency regulators Oct4 and Nanog and influences embryonic stem cell self-renewal and lineage commitment (PMID:27075724), and it is required in vivo for early retinal cell patterning, binding chromatin at regulators of progenitor identity including Satb2 and thyroid/retinoic acid receptors, with its loss causing vision deficits and disrupted amacrine and cone cell organization (PMID:28551284).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1995 Medium

    Established that NR2C1 is a DNA-binding orphan receptor that represses retinoid target genes not by heterodimerizing with RXR/RAR but by directly outcompeting them at shared response elements.

    Evidence Gel mobility shift and CAT reporter competition assays with affinity measurements on CRBPIIp and RARβ elements

    PMID:8530418

    Open questions at the time
    • Repression mechanism downstream of DNA occupancy not defined
    • No cofactor or chromatin-modifying partner identified
    • Endogenous target genes not yet mapped
  2. 1998 High

    Dissected the repression machinery into separable modules, showing dimerization can be uncoupled from suppression and localizing an active silencing domain to the C-terminal DEF region.

    Evidence Point mutagenesis of dimer-interface leucines and LBD glutamates, deletion analysis, and GAL4-chimera assays

    PMID:9660764

    Open questions at the time
    • Corepressor proteins recruited by the silencing domain not identified
    • No structural model of the dimer interface or LBD
    • Ligand, if any, for the orphan LBD unknown
  3. 1999 High

    Defined a feedback loop placing NR2C1 downstream of retinoid signaling via an IR0-type RARE in its own promoter bound by RARα/RXRβ.

    Evidence Gel retardation with Kd determination and reporter assays in COS-1 and P19 cells

    PMID:10393558

    Open questions at the time
    • Physiological significance of the autoregulatory loop in vivo not tested
    • Other promoter inputs not characterized
  4. 2000 Medium

    Refined the minimal promoter and showed RA induction is protein-synthesis-independent, while implicating NR2C1 in cell survival when overexpressed.

    Evidence Promoter-deletion reporter assays, cycloheximide experiments, and overexpression with apoptosis readout in P19 cells

    PMID:10807954

    Open questions at the time
    • Mechanism linking NR2C1 overexpression to apoptosis unresolved
    • Requirement for intron 1 splicing mechanistically unexplained
  5. 2016 Medium

    Linked NR2C1 to control of pluripotency and lineage commitment, and showed hominid sequence changes altered its regulatory output.

    Evidence Luciferase reporter assays on Oct4, Nanog, and Pepck promoters and ES cell colony assays comparing human, chimpanzee, and ancestral variants

    PMID:27075724

    Open questions at the time
    • Direct chromatin binding at Oct4/Nanog loci not demonstrated
    • In vivo developmental consequence of variant differences untested
  6. 2017 High

    Demonstrated an in vivo developmental requirement, with NR2C1 directly binding regulators of retinal progenitor identity to control early cell-fate patterning.

    Evidence Nr2c1 knockout mouse with histological cell-type analysis and ChIP at Satb2 and thyroid/retinoic acid receptor loci

    PMID:28551284

    Open questions at the time
    • Whether NR2C1 activates or represses each retinal target not resolved
    • Cofactors mediating retinal target regulation unknown
    • Genome-wide binding landscape not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether NR2C1 has an endogenous ligand and which corepressor complexes execute its DEF-domain silencing remain unresolved.
  • No ligand identified for the orphan LBD
  • Corepressor/chromatin-modifier partners of the silencing domain not identified
  • No structural data on DNA-bound NR2C1

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
RARARXRARXRB

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 NR2C1 (TR2 orphan receptor) binds hormone response elements (HREs) consisting of AGGTCA half-site direct repeats with binding affinity in the order DR1 > DR2 > DR5 ≈ DR4 ≈ DR6 > DR3, and also binds palindromic TREpal and NBRE elements. It competes with RXRα and RARα/RXRα heterodimers for binding to CRBPIIp (DR1) and RARΕβ (DR5) response elements, suppressing their transcriptional activation. This suppression is not mediated by heterodimer formation with RXRα or RARα, but rather by higher affinity (≥100-fold) of NR2C1 for CRBPIIp compared to RXRα. Gel mobility shift assays for HRE binding; CAT reporter assays for transcriptional competition; binding affinity measurements The Journal of biological chemistry Medium 8530418
1998 Mouse NR2C1 (TR2-11) functions as a transcriptional repressor via mechanisms requiring: (1) high-affinity DNA binding, (2) receptor dimerization, and (3) an active silencing domain encoded within the DEF (ligand-binding) segment. Point mutations at three conserved leucine residues on the predicted dimer interface abolish suppressive activity, dimerization, and DNA binding. Mutation of two consecutive glutamate residues in the hinge between helices 10–11 of the LBD abolishes suppressive activity and DNA binding without affecting dimerization, demonstrating that dimerization can be uncoupled from suppressive activity. The C-terminal 49 amino acids are required for trans-suppressive activity as shown by GAL4 chimera assays. CAT reporter assays, point mutagenesis of dimer interface and LBD residues, GAL4-chimera transcriptional assays, deletion analysis The Journal of biological chemistry High 9660764
1999 The mouse NR2C1 (TR2-11) gene promoter contains a functional IR0-type retinoic acid response element (5'-GGGTCA CGAACT-3') in its proximal promoter. RARα/RXRβ heterodimers bind specifically to this IR0 element (Kd ~8 nM) in gel retardation assays; neither receptor alone binds efficiently. This element drives RA-inducible reporter expression in COS-1 cells with exogenous RARα/RXRβ, and in P19 cells with endogenous receptors, establishing a cross-regulatory loop between NR2C1 and the RAR/RXR pathway. Gel mobility shift assays, Kd determination, CAT/reporter assays in COS-1 and P19 cells, nuclear extract binding assays Biochemistry High 10393558
2000 The mouse NR2C1 (TR2-11) gene promoter minimal activity is defined within 212 nucleotides upstream of the translation start site, and efficient promoter activity requires splicing of intron 1. RARα/RXRβ binding to this minimal promoter region was demonstrated by gel retardation assays. In P19 cells, the endogenous NR2C1 gene is induced by retinoic acid in a protein synthesis-independent manner. Overexpression of NR2C1 protein in P19 cells results in cellular apoptosis in the absence of RA. Reporter/promoter-deletion assays, gel retardation assays, protein synthesis inhibition (cycloheximide) experiments, overexpression in P19 cells with apoptosis readout Biochemical pharmacology Medium 10807954
2016 NR2C1 modulates transcriptional activity of pluripotency regulators Oct4 and Nanog, and affects promoter activity of Pepck (a differentiation proxy) and embryonic stem cell colony size (self-renewal proxy). Human, chimpanzee, and ancestral NR2C1 variants show functional differences in these assays, indicating that amino acid changes in NR2C1 during hominid evolution altered its ability to regulate pluripotency and cell lineage commitment. Luciferase reporter assays for Oct4, Nanog, and Pepck promoters; embryonic stem cell colony size assays; comparison of human, chimpanzee, and ancestral NR2C1 variants Genetics Medium 27075724
2017 Nr2c1 (Tr2) is required for early retinal cell patterning; loss of Nr2c1 causes severe vision deficit and disrupts early (but not late) retinal cell types, with increased displaced amacrine cells and disrupted cone cell topography. ChIP experiments reveal NR2C1 directly binds regulatory regions of transcription factors controlling retinal progenitor cells, including Satb2 (amacrine regulator) and thyroid and retinoic acid receptors (cone photoreceptor regulators). Nr2c1 knockout mouse (loss-of-function), histological and cell-type analysis, chromatin immunoprecipitation (ChIP) assays Developmental biology High 28551284

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Multiple functions of the TR2-11 orphan receptor in modulating activation of two key cis-acting elements involved in the retinoic acid signal transduction system. The Journal of biological chemistry 57 8530418
1998 Mechanisms of the mouse orphan nuclear receptor TR2-11-mediated gene suppression. The Journal of biological chemistry 23 9660764
2023 NamiRNA-enhancer network of miR-492 activates the NR2C1-TGF-β/Smad3 pathway to promote epithelial-mesenchymal transition of pancreatic cancer. Carcinogenesis 22 36591938
1999 Characterization of an inverted repeat with a zero spacer (IR0)-type retinoic acid response element from the mouse nuclear orphan receptor TR2-11 gene. Biochemistry 22 10393558
2016 Functional Divergence of the Nuclear Receptor NR2C1 as a Modulator of Pluripotentiality During Hominid Evolution. Genetics 21 27075724
2017 The nuclear hormone receptor gene Nr2c1 (Tr2) is a critical regulator of early retina cell patterning. Developmental biology 9 28551284
2000 Characterization of the mouse nuclear orphan receptor TR2-11 gene promoter and its potential role in retinoic acid-induced P19 apoptosis. Biochemical pharmacology 9 10807954
2015 Testicular receptor 2, Nr2c1, is associated with stem cells in the developing olfactory epithelium and other cranial sensory and skeletal structures. Gene expression patterns : GEP 7 26712358
1997 Molecular cloning from neurulating Ambystoma mexicanum embryos of the cDNA encoding an orphan nuclear receptor (aDOR1) closely related to TR2-11. Differentiation; research in biological diversity 7 9503600
1998 Polymorphism in the murine Tr2-11 gene encoding an orphan receptor, and its exclusion as a candidate gene for the cataract mutation Cat3. Biological chemistry 3 9504722

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