Affinage

NR2C1

Nuclear receptor subfamily 2 group C member 1 · UniProt P13056

Length
603 aa
Mass
67.3 kDa
Annotated
2026-04-29
65 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR2C1 (TR2) is an orphan nuclear receptor that functions as a ligand-independent transcriptional regulator of globin gene switching, stem cell pluripotency, retinal development, and other developmental programs. TR2 binds AGGTCA direct repeat elements (DR1–DR5) as homodimers or as TR2/TR4 heterodimers, recruiting epigenetic corepressor complexes (DNMT1, NuRD, LSD1/CoREST, HDAC3, HDAC4, RIP140, TIF1β) to silence embryonic and fetal β-type globin genes in definitive erythroid cells, while conditional loss of both TR2 and TR4 reactivates embryonic globin expression and impairs terminal erythroid maturation (PMID:12093744, PMID:25561507, PMID:21670149). Post-translational modifications act as a molecular switch controlling TR2 output: PKC-mediated phosphorylation at Ser-185 promotes DNA binding and PCAF coactivator recruitment for target gene activation, whereas ERK2-mediated phosphorylation at Thr-210 drives TR2 into PML nuclear bodies where SUMOylation at Lys-238 triggers coactivator-to-corepressor exchange (PCAF→RIP140), converting TR2 from an activator to a repressor of Oct4 (PMID:16317770, PMID:18682553, PMID:17187077). Nr2c1 loss-of-function in mice causes severe visual deficits with disrupted early retinal cell patterning, establishing a non-redundant role in retinal development (PMID:28551284).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1989 High

    The molecular identity of TR2 as an orphan nuclear receptor was established, revealing a steroid receptor superfamily member with no known ligand, thereby opening the question of what biological functions it serves.

    Evidence cDNA cloning from human testis libraries with sequence analysis and in vitro translation

    PMID:2597158

    Open questions at the time
    • No endogenous ligand identified
    • No target genes or biological function known
    • Expression pattern beyond testis not characterized
  2. 1997 High

    The DNA-binding specificity and dual transcriptional activity of TR2 were defined: it binds AGGTCA direct repeats (DR1–DR5) as homodimers via its ligand-binding domain, functioning as either a repressor (competing with RAR/RXR at DR5) or an activator (at DR4 sites), with the full-length LBD required for DNA binding and opposing activities of truncated isoforms.

    Evidence EMSA with Kd measurements, CAT/luciferase reporter assays, isoform comparison, domain mutagenesis across multiple target elements (CRBPII, RARβ, CRABP-I, aldolase A)

    PMID:7890658 PMID:8530418 PMID:9071982 PMID:9369481

    Open questions at the time
    • Endogenous target genes in vivo not yet identified
    • Mechanism of context-dependent activation vs. repression unclear
    • In vivo relevance of homodimer binding not established
  3. 1998 High

    The corepressor and dimerization architecture of TR2 was resolved: RIP140 was identified as the first corepressor binding TR2 via LXXLL motifs at the AF-2 domain; TR2/TR4 heterodimers were shown to form preferentially and repress more strongly than homodimers; and a transferable silencing domain (DEF segment) with critical leucine residues on the dimer interface was mapped.

    Evidence Yeast two-hybrid, co-IP, GFP localization, pull-down assays, mammalian two-hybrid, EMSA, domain mutagenesis, reporter assays

    PMID:9660764 PMID:9737983 PMID:9774688

    Open questions at the time
    • How TR2 chooses between repression and activation at different promoters unknown
    • No chromatin-level evidence for corepressor action
    • Physiological significance of TR2/TR4 heterodimer not established in vivo
  4. 1998 High

    The nuclear localization mechanism of TR2 was mapped to a 20-amino-acid constitutive NLS within the second zinc finger of the DNA-binding domain, and upstream regulation by p53 (repression upon ionizing radiation) and CNTF signaling was established.

    Evidence GFP fusion imaging with deletion mapping; radiation treatment with Northern blot and p53 epistasis; RT-PCR and reporter assays for CNTF pathway

    PMID:8663350 PMID:9694834 PMID:9795341

    Open questions at the time
    • Physiological consequence of p53-mediated TR2 repression unclear
    • CNTF pathway connection not validated in vivo
  5. 2001 High

    TR2-mediated repression was linked to histone deacetylation: HDAC3 (class I) and HDAC4 (class II) directly interact with TR2 through its DNA-binding domain, and HDAC inhibitor TSA relieves TR2 repression, establishing an epigenetic mechanism for TR2 silencing activity.

    Evidence Co-IP, GST pull-down, far Western, deacetylase activity assay, reporter assays with TSA

    PMID:11463856 PMID:14521922

    Open questions at the time
    • Which endogenous target genes are repressed via HDAC recruitment unknown
    • Relative contribution of HDAC3 vs. HDAC4 not resolved
    • No in vivo chromatin-level evidence at this stage
  6. 2002 High

    The physiological target of TR2/TR4 was identified: the DRED complex (~540 kDa TR2/TR4 heterodimer) binds DR1 sites in embryonic ε-globin and fetal γ-globin promoters, and an HPFH mutation disrupts this binding, directly implicating TR2/TR4 in developmental globin gene silencing. Separately, TR2 was shown to suppress estrogen receptor signaling through direct heterodimerization.

    Evidence Biochemical purification with mass spectrometry, EMSA with HPFH mutant DR1, transgenic mouse overexpression; GST pull-down and two-hybrid for ER interaction

    PMID:12093744 PMID:12093804

    Open questions at the time
    • How TR2/TR4 distinguish embryonic from adult globin promoters not explained
    • Corepressor complexes on globin promoters not yet identified
    • ER interaction not validated in primary tissues
  7. 2006 High

    Post-translational modifications were shown to act as a molecular switch controlling TR2 output: PKC phosphorylation at Ser-185 (DBD) enhances DNA binding and PCAF coactivator recruitment, while SUMOylation at Lys-238 triggers release from PML nuclear bodies and coactivator-to-corepressor (PCAF→RIP140) exchange, converting TR2 from an Oct4 activator to a repressor.

    Evidence LC-ESI-MS/MS phosphosite identification, site-directed mutagenesis, EMSA, co-IP, GFP live imaging at PML bodies, ChIP, SUMOylation assays

    PMID:16130175 PMID:16317770 PMID:17187077

    Open questions at the time
    • How SUMOylation physically displaces TR2 from PML bodies not resolved
    • Whether the PKC and SUMO modifications are coordinated or independent unclear
    • In vivo relevance for stem cell differentiation not yet demonstrated genetically
  8. 2008 High

    A complete atRA-triggered signaling cascade was delineated: atRA activates MEK/ERK2, which phosphorylates TR2 at Thr-210; phospho-TR2 is chaperoned to PML bodies by HDAC3 (independent of its deacetylase activity), undergoes SUMOylation, and switches from Oct4 activator to repressor, providing an integrated mechanism for retinoic acid-induced loss of pluripotency.

    Evidence Phosphorylation assays with Thr-210 mutagenesis, MEK/ERK inhibitors, co-IP, confocal microscopy, deacetylase-dead HDAC3 mutant rescue

    PMID:18682553 PMID:19204783

    Open questions at the time
    • Whether this cascade operates in embryonic stem cells in vivo not shown
    • Structural basis for HDAC3 chaperone function unknown
    • Fate of TR2 after PML body targeting (degradation vs. stable repression) unclear
  9. 2011 High

    The full corepressor landscape at globin promoters was defined: TR2/TR4 recruit DNMT1, NuRD, LSD1/CoREST, HDAC3, and TIF1β specifically to embryonic β-globin promoters in adult erythroid cells; during terminal differentiation these corepressors remain at silenced embryonic promoters but dissociate from adult promoters, explaining developmental stage-specific silencing.

    Evidence Biotin-tagged purification with mass spectrometry, co-IP, ChIP comparing differentiated vs. undifferentiated erythroid cells

    PMID:21670149

    Open questions at the time
    • How promoter-specific retention of corepressors is achieved unknown
    • Which corepressor is rate-limiting for silencing not determined
    • No evidence for direct DNA methylation by DNMT1 at these loci shown
  10. 2015 High

    Genetic proof that TR2/TR4 are required for embryonic globin silencing in adult erythropoiesis was obtained: compound conditional knockout of Tr2 and Tr4 in adult bone marrow reactivated embryonic εy and βh1 globins, abolished TR2/TR4 and corepressor occupancy at those promoters, and impaired terminal erythroid maturation.

    Evidence Conditional double knockout mouse, ChIP, RT-PCR, flow cytometry, in vitro bone marrow differentiation

    PMID:25561507

    Open questions at the time
    • Whether TR2/TR4 loss can reactivate human fetal γ-globin therapeutically not tested
    • Mechanism of erythroid maturation defect beyond globin regulation not explored
    • Redundancy between TR2 and TR4 at individual promoters not fully parsed
  11. 2017 High

    A non-redundant role for NR2C1 in retinal development was established: Nr2c1 knockout mice exhibit severe vision deficits with disrupted early retinal progenitor patterning, including altered amacrine cell displacement and cone photoreceptor topography, with ChIP showing TR2 directly regulates early retinal transcription factors including Satb2.

    Evidence Nr2c1 knockout mouse, electroretinography, histology, immunofluorescence, ChIP

    PMID:28551284

    Open questions at the time
    • Whether TR2 functions as activator or repressor of retinal target genes not fully resolved
    • Retinal phenotype relationship to TR2/TR4 heterodimer function not tested
    • Human retinal disease association not established
  12. 2025 Medium

    TR2 was implicated in alternative lengthening of telomeres (ALT) through recruitment of TRIM28/TIF1β to telomeric chromatin, promoting H3K9me3 heterochromatin formation; a TRIM28 variant unable to interact with orphan nuclear receptors failed to localize to telomeres or promote ALT phenotypes.

    Evidence Co-IP, ChIP, C-circle and APB assays, TRIM28 interaction-defective mutant in ALT cancer cell lines (preprint)

    PMID:bio_10.1101_2025.06.16.658187

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Relative contribution of TR2 vs. other orphan NRs (COUP-TFs, TR4) at telomeres not parsed
    • Whether TR2 is required for ALT in vivo not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: whether TR2 has an endogenous ligand, the structural basis for context-dependent switching between activation and repression, whether TR2/TR4-targeted therapies can reactivate fetal hemoglobin for sickle cell disease treatment, and how TR2's roles in retinal development, pluripotency, and telomere biology are integrated at the organismal level.
  • No endogenous ligand identified despite >35 years of study
  • No crystal structure of full-length TR2 or TR2/TR4 heterodimer available
  • Therapeutic targeting of TR2/TR4 for hemoglobin disorders not validated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 8 GO:0140110 transcription regulator activity 8 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 3
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-392499 Metabolism of proteins 4 R-HSA-4839726 Chromatin organization 3 R-HSA-1266738 Developmental Biology 2
Partners
DNMT1HDAC3HDAC4NR2C2PCAFPMLRIP140TRIM28
Complex memberships
DRED (TR2/TR4 heterodimer)LSD1/CoRESTNuRD

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 NR2C1 (TR2) was molecularly cloned from human testis cDNA libraries as a new member of the steroid receptor superfamily containing conserved zinc-finger DNA-binding domains; multiple isoforms with distinct ligand-binding domain lengths were identified, and no binding activity with known steroid hormones was found, classifying it as an orphan receptor. cDNA cloning, in vitro translation, sequence analysis Biochemical and biophysical research communications High 2597158
1995 TR2 orphan receptor binds hormone response elements containing AGGTCA direct repeat sequences with preference order DR1 > DR2 > DR5 ≥ DR4 > DR6 > DR3, and competes with RXRα and RARα/RXRα heterodimers at CRBPIIp (DR1) and RARβ (DR5) response elements to suppress retinoic acid-stimulated transcription without forming heterodimers with RXRα or RARα. CAT reporter assays, gel mobility shift assays (EMSA), competition binding The Journal of biological chemistry High 8530418
1995 A natural TR2 response element (TR2RE-SV40) was identified in the SV40 +55 region with high affinity binding (Kd = 9 nM); TR2 binding to this element represses both SV40 early and late promoter transcriptional activities. EMSA with in vitro translated TR2, CAT reporter assays, DNA-swap experiments The Journal of biological chemistry High 7890658
1997 The TR2 orphan receptor (TR2-11-f) binds as homodimers to a DR4 hormone response element in the mouse CRABP-I gene promoter (Kd = 2.6 nM) through its ligand-binding domain, and suppresses CRABP-I reporter gene expression. Gel retardation assay, yeast two-hybrid, CAT reporter assays Biochemistry High 9369481
1997 TR2 binds the M1 site in the human aldolase A muscle-specific promoter (Kd = 4.6 nM), induces localized DNA bending (~73°), and functions as a transcriptional inducer of aldolase A expression in muscle cells. EMSA, circular permutation assay, dual-luciferase reporter assay Biochemical and biophysical research communications Medium 9196064
1997 Two TR2 isoforms (TR2-11 and truncated TR2-11-t lacking the ligand-binding domain) have opposing biological activities: TR2-11 represses RA induction via a DR5-type RARE and binds DNA as dimers, whereas TR2-11-t enhances RA induction and cannot bind DNA; the full-length LBD is required for DNA binding and repression. CAT reporter assays, gel-shift assays, prokaryotic expression, isoform characterization The Journal of endocrinology High 9071982
1998 Mouse RIP140 was identified as a corepressor for TR2; RIP140 interacts with TR2 through LXXLL motifs binding to the C-terminal AF-2 region of TR2's LBD; in the presence of RIP140, cytosolic GFP-tagged TR2 LBD translocates to the nucleus; RIP140 represses TR2-mediated and RA receptor-mediated transcription in reporter assays. Yeast two-hybrid, coimmunoprecipitation, GFP localization, GAL4 reporter assays, domain mapping Molecular and cellular biology High 9774688
1998 TR2 and TR4 preferentially form heterodimers in solution and on DR5 DNA elements; heterodimerization is mediated by the ligand-binding domains, with three leucine residues on helix 10 of TR2 critical for interaction; TR2/TR4 coexpression exerts stronger repression on a DR5 reporter than either receptor alone. Yeast two-hybrid, mammalian two-hybrid, pull-down assay, EMSA, GFP colocalization, reporter assays, domain mutagenesis The Journal of biological chemistry High 9737983
1998 TR2 repressor activity requires high-affinity DNA binding, receptor dimerization, and an active silencing domain (DEF segment); a transferable trans-repressive activity resides in the DEF segment including C-terminal 49 amino acids; point mutations at three conserved leucines on the predicted dimer interface abolish suppressive activity, dimerization, and DNA binding. GAL4 reporter assays, deletion and point mutagenesis, functional domain mapping The Journal of biological chemistry High 9660764
1998 TR2 bidirectionally interacts with the CNTF signaling pathway: CNTF induces TR2 expression, and TR2 in turn activates CNTFRα transcription through a direct repeat response element (AGGTCA) in the CNTFRα intron 5; TR2 and CNTFRα show overlapping expression in developing neural structures. Reporter assays (CAT), RT-PCR, in situ hybridization, DNA binding assays The Journal of biological chemistry Medium 9694834
1998 TR2 is exclusively localized to the nucleus via a constitutive nuclear localization signal comprising 20 amino acids (KDCVINKHHRNRCQYCRLQR) within the second zinc-finger of the DNA-binding domain; no NLS activity was found in the N-terminus or LBD; nuclear-localized GFP-TR2 retains repressive activity on DR5 reporters. GFP fusion live-cell imaging, HA-antibody detection, deletion analysis, EMSA The Journal of endocrinology High 9795341
1998 TR2 shows transactivation via a DR4-TRE element and competes with unliganded TRα1/RXRα heterodimer; TR2 cancels the suppressive effect of unliganded TRα1 on CAT reporter activity in a dose-dependent, DNA-binding–dependent manner. EMSA, CAT reporter assays, competition binding Molecular and cellular biochemistry Medium 9879671
1996 Ionizing radiation represses TR2 expression at both transcriptional and translational levels; p53 (endogenously induced or exogenously transfected) represses TR2 gene expression, and this repression is reversed by SV40 large T antigen co-transfection, placing p53 upstream of TR2 in the radiation response. Transient transfection, CAT reporter assays, Northern blot, radiation treatment The Journal of biological chemistry Medium 8663350
1999 An IR0-type retinoic acid response element in the TR2-11 gene proximal promoter is bound specifically by RARα/RXRβ heterodimers (Kd ~8 nM) but not by either receptor alone; this element mediates RA-induced transcription of the TR2-11 gene. EMSA, reporter assays, gel mobility shift with nuclear extracts Biochemistry Medium 10393558
2000 TR2 constitutively activates endogenous RARβ2 gene expression in P19 cells via the DR5 element in the RARβ2 promoter; cAMP enhances this activation via the CRE; the constitutive activation function (AF-1) maps to residues 10–30 in the N-terminal A segment; TR2 and CREMτ directly interact (co-IP) via the TR2 N-terminal AB segment. Reporter assays, EMSA competition, coimmunoprecipitation, domain mapping, Northern blot The Journal of biological chemistry High 10766818
2001 TR2 directly interacts with class I (HDAC3) and class II (HDAC4) histone deacetylases; the DNA-binding domain of TR2 mediates the interaction with both HDACs (not the LBD); TR2-HDAC complexes exhibit deacetylase activity in vitro; HDAC inhibitor trichostatin A relieves TR2-mediated transcriptional repression. Co-IP with FLAG-tagged HDACs, GST pull-down, far Western blot, deacetylase activity assay, reporter assays with TSA Molecular endocrinology High 11463856
2002 TR2 forms a heterodimer with the estrogen receptor (ER) that disrupts ER homodimerization and ER DNA binding, thereby suppressing ER-mediated transcription; an interaction-blocking peptide (ER-6, aa 312–340) reverses this suppression; antisense TR2 in MCF7 cells enhances ER transcriptional activity; TR2-mediated ER suppression inhibits estrogen-induced cell growth and G1/S transition. GST pull-down, mammalian two-hybrid, CAT reporter assays, antisense knockdown, cell proliferation assays The Journal of biological chemistry High 12093804
2002 TR2 and TR4 form a heterodimer (DRED complex, ~540 kDa) that binds DR1 sites in the human embryonic ε-globin and fetal γ-globin gene promoters with high affinity; an HPFH mutation in the DR1 site reduces TR2/TR4 binding in vitro; transgenic forced expression of TR2/TR4 reduces endogenous embryonic εy-globin transcription in mice. Biochemical purification, mass spectrometry, EMSA, EMSA competition with mutant DR1, transgenic mouse expression The EMBO journal High 12093744
2003 HDAC3 interacts with TR2 through two domains: N-terminal residues 1–135 (specifically 1–70) and C-terminal residues 210–428 (specifically 270–320); these two binding sites compete for TR2; the TR2-HDAC3 complex formed on TR2 DNA target sequences exhibits histone deacetylase activity in vivo. GST pull-down, coimmunoprecipitation, ChIP, histone deacetylase activity assay, domain mapping Biochemical and biophysical research communications High 14521922
2003 TR2 suppresses androgen receptor (AR)-mediated transactivation and PSA expression in prostate cancer PC-3 cells through direct protein-protein interaction with AR (demonstrated by GST pulldown and mammalian two-hybrid), not by competing for common coregulators. CAT reporter assays, Northern blot, GST pull-down, mammalian two-hybrid The Prostate Medium 12949936
2005 PKC phosphorylates TR2 at Ser-568 and Ser-461 in the LBD; Ser-568 phosphorylation is required for PKC-mediated enhancement of TR2 protein stability (protection from proteasome-mediated degradation) and transcriptional activation of its target gene RARβ. In vivo metabolic labeling, kinase/phosphatase inhibitor treatment, LC-ESI-MS/MS, site-directed mutagenesis, reporter assays, proteasome inhibitor experiments Proteomics High 16130175
2006 PKC phosphorylates TR2 at Ser-185 in the DNA-binding domain (confirmed by MS); DBD phosphorylation facilitates TR2 DNA binding and recruitment of coactivator PCAF; Ser-185 is required for DNA binding, and both Ser-170 and Ser-185 are necessary for PCAF interaction; double mutant significantly reduces RARβ2 activation. LC-ESI-MS/MS, site-directed mutagenesis, EMSA, co-IP, reporter assays Proteomics High 16317770
2006 TR2 can be SUMOylated at Lys-238; unSUMOylated TR2 localizes to PML nuclear bodies and activates Oct4 (recruiting coactivator PCAF), whereas elevated TR2 abundance triggers SUMOylation, release from PML bodies, and coregulator exchange: PCAF is replaced by corepressor RIP140, converting TR2 from an activator to a repressor of Oct4. SUMOylation assays, coimmunoprecipitation, GFP live imaging, ChIP, reporter assays, knockdown experiments Nature structural & molecular biology High 17187077
2007 TR2 is a preadipocyte proliferator that activates c-Myc via an IR0-type RA response element; in preadipocytes RA induces GRIP1/PCAF coactivator complex recruitment to the TR2 promoter (promoting TR2 expression), while in differentiated adipocytes RA induces GRIP1/RIP140 corepressor complex recruitment (repressing TR2); GRIP1 directly interacts with both PCAF and RIP140 and serves as a platform molecule. siRNA knockdown, reporter assays, ChIP, co-IP, domain mapping, 3T3-L1 cell model Nucleic acids research High 17389641
2007 TR2/TR4 directly represses GATA1/Gata1 transcription in murine and human erythroid progenitor cells through binding to an evolutionarily conserved DR element within the GATA1 hematopoietic enhancer (G1HE); TR2/TR4 binding was shown by EMSA and ChIP, and mutation of the DR element elevated Gata1 promoter activity and reduced TR2/TR4 responsiveness. EMSA, ChIP, reporter assays with DR site mutagenesis, transgenic mice, null mutant mice, shRNA knockdown in CD34+ cells Genes & development High 17974920
2007 TR2/TR4 play critical roles in developmental silencing of embryonic β-type globin genes (εy and γ); TR2 and TR4 null mutant mice show delayed silencing of embryonic and fetal β-globin genes; dominant-negative TR4 activates human ε-globin in both primitive and definitive erythroid cells, but activates γ-globin only in definitive erythroid cells; forced expression of TR2/TR4 causes precocious ε-globin repression. Knockout mice, transgenic mice (dominant-negative and forced expression), RT-PCR, Southern blot, in situ hybridization The EMBO journal High 17431400
2008 All-trans retinoic acid (atRA) triggers a nongenomic signaling cascade: atRA → MEK/ERK2 complex formation → ERK2 phosphorylates TR2 at Thr-210 → phospho-TR2 associates increasingly with PML nuclear bodies and undergoes SUMOylation → corepressor RIP140 replaces coactivator PCAF → TR2 switches from activator to repressor of Oct4; unphosphorylated TR2 recruits PCAF and activates Oct4. Phosphorylation assays, site-directed mutagenesis (Thr-210), co-IP, ChIP, confocal microscopy, reporter assays, inhibitor studies (MEK/ERK inhibitors) Proceedings of the National Academy of Sciences of the United States of America High 18682553
2009 HDAC3 acts as a molecular chaperone to shuttle phosphorylated TR2 (phospho-Thr-210) to PML nuclear bodies; this chaperone function is independent of HDAC3 deacetylase activity; atRA also stimulates nuclear enrichment of HDAC3 and its complex formation with PML in an ERK2-independent manner. Co-IP, in vitro binding assays, confocal microscopy, deacetylase-dead HDAC3 mutants, PML recruitment assays PloS one High 19204783
2011 TR2 and TR4 recruit multiple epigenetic corepressor complexes (DNMT1, NuRD, LSD1/CoREST, HDAC3, TIF1β) to embryonic β-type globin promoters in differentiated adult erythroid cells; ChIP shows TR2/TR4 bind embryonic but not adult β-globin promoters; upon terminal differentiation, corepressors dissociate selectively from the adult promoter but remain at silenced embryonic promoters. Biotin-tagged protein complex purification, mass spectrometry, co-IP, ChIP in differentiated vs. undifferentiated erythroid cells Molecular and cellular biology High 21670149
2015 Compound conditional knockout of both Tr2 and Tr4 in adult bone marrow cells induces expression of embryonic εy and βh1 globins; loss of TR2/TR4 abolishes their occupancy on εy and βh1 promoters and impairs co-occupancy by interacting corepressors; TR2/TR4 function is also required for terminal erythroid cell maturation. Conditional knockout mouse genetics, in vitro bone marrow differentiation, ChIP, RT-PCR, flow cytometry Blood High 25561507
2017 Nr2c1 (Tr2) loss-of-function in mice causes severe vision deficits, disrupts early retinal cell patterning (increased displaced amacrine cells, altered cone photoreceptor topography), and affects early but not late retinal cell types; ChIP experiments show NR2C1 regulates early retinal progenitor transcription factors including Satb2 (amacrine) and cone photoreceptor regulators (thyroid and retinoic acid receptors). Nr2c1 knockout mouse, electroretinography, histology, ChIP, immunofluorescence Developmental biology High 28551284
2016 Evolutionary analysis and functional assays of human, chimpanzee, and ancestral NR2C1 proteins showed that hominid-specific changes in NR2C1 alter its ability to modulate Oct4 and Nanog transcription (pluripotency regulators), Pepck promoter activity (a differentiation proxy), and embryonic stem cell colony size, indicating NR2C1 underwent adaptive evolution affecting stem cell pluripotency regulation. Codon evolution analysis, reporter assays, stem cell colony assays, ancestral sequence reconstruction Genetics Medium 27075724
2023 In pancreatic cancer, miR-492 acts as an enhancer trigger that activates NR2C1 expression; NR2C1 promotes epithelial-mesenchymal transition (EMT) through the TGF-β/Smad3 signaling pathway; CRISPR-Cas9 and ChIP assays confirmed miR-492 enhancer regulation of NR2C1, and antagomiR-492 suppressed tumorigenesis by downregulating NR2C1. CRISPR-Cas9, ChIP, in vitro migration/invasion assays, in vivo xenograft, Western blot, knockdown/overexpression Carcinogenesis Medium 36591938
2025 TR2 (along with COUP-TF1, COUP-TF2, and TR4) promotes telomeric H3K9me3 and alternative lengthening of telomeres (ALT) by recruiting TRIM28 to telomeres; physical interaction between TR2 and TRIM28 is required for TRIM28 telomeric localization; a TRIM28 variant defective in orphan NR interaction fails to localize to telomeres and cannot promote H3K9me3 or ALT phenotypes. Co-IP, ChIP, telomere-specific assays (C-circles, APBs), TRIM28 interaction-defective mutant, human fibroblast and ALT cancer cell lines bioRxivpreprint Medium bio_10.1101_2025.06.16.658187

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. The Journal of clinical investigation 211 9739048
1998 Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. The Journal of biological chemistry 192 9765287
2005 Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proceedings of the National Academy of Sciences of the United States of America 189 16319225
1998 Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2. Molecular and cellular biology 113 9774688
2011 Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic β-type globin promoters in differentiated adult erythroid cells. Molecular and cellular biology 106 21670149
2002 An embryonic/fetal beta-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer. The EMBO journal 98 12093744
1998 Antibodies to TR2 (herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines. Journal of immunology (Baltimore, Md. : 1950) 96 9712045
1989 Molecular cloning of new human TR2 receptors: a class of steroid receptor with multiple ligand-binding domains. Biochemical and biophysical research communications 94 2597158
2003 Induction of caspase 8 by interferon gamma renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB. Cancer research 87 12615731
2007 Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4. The EMBO journal 86 17431400
2002 Recent advances in the TR2 and TR4 orphan receptors of the nuclear receptor superfamily. The Journal of steroid biochemistry and molecular biology 79 12361719
2008 Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor TR2 to suppress Oct4 expression. Proceedings of the National Academy of Sciences of the United States of America 65 18682553
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
2021 Isolation and Characterization of a Novel Salmonella Phage vB_SalP_TR2. Frontiers in microbiology 55 34234757
1995 Identification of human TR2 orphan receptor response element in the transcriptional initiation site of the simian virus 40 major late promoter. The Journal of biological chemistry 54 7890658
2006 SUMOylation of Tr2 orphan receptor involves Pml and fine-tunes Oct4 expression in stem cells. Nature structural & molecular biology 46 17187077
2007 The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription. Genes & development 45 17974920
1996 p53 is a mediator for radiation-repressed human TR2 orphan receptor expression in MCF-7 cells, a new pathway from tumor suppressor to member of the steroid receptor superfamily. The Journal of biological chemistry 43 8663350
2011 Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes. Proceedings of the National Academy of Sciences of the United States of America 42 22042865
1998 A novel nuclear receptor heterodimerization pathway mediated by orphan receptors TR2 and TR4. The Journal of biological chemistry 39 9737983
2002 Suppression of estrogen receptor-mediated transcription and cell growth by interaction with TR2 orphan receptor. The Journal of biological chemistry 38 12093804
2017 TR2 and TR4 Orphan Nuclear Receptors: An Overview. Current topics in developmental biology 35 28527578
1998 A bidirectional regulation between the TR2/TR4 orphan receptors (TR2/TR4) and the ciliary neurotrophic factor (CNTF) signaling pathway. The Journal of biological chemistry 29 9694834
2001 The orphan nuclear receptor TR2 interacts directly with both class I and class II histone deacetylases. Molecular endocrinology (Baltimore, Md.) 27 11463856
2007 Orphan nuclear receptor TR2, a mediator of preadipocyte proliferation, is differentially regulated by RA through exchange of coactivator PCAF with corepressor RIP140 on a platform molecule GRIP1. Nucleic acids research 25 17389641
1986 Initiation of swimming activity by trigger neurons in the leech subesophageal ganglion. III. Sensory inputs to Tr1 and Tr2. Journal of comparative physiology. A, Sensory, neural, and behavioral physiology 25 3023604
2003 TR2 orphan receptor functions as negative modulator for androgen receptor in prostate cancer cells PC-3. The Prostate 24 12949936
1997 Distinct expression patterns and biological activities of two isoforms of the mouse orphan receptor TR2. The Journal of endocrinology 24 9071982
1998 Mechanisms of the mouse orphan nuclear receptor TR2-11-mediated gene suppression. The Journal of biological chemistry 23 9660764
2015 Compound loss of function of nuclear receptors Tr2 and Tr4 leads to induction of murine embryonic β-type globin genes. Blood 22 25561507
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
1997 The orphan nuclear receptor TR2 suppresses a DR4 hormone response element of the mouse CRABP-I gene promoter. Biochemistry 22 9369481
2023 NamiRNA-enhancer network of miR-492 activates the NR2C1-TGF-β/Smad3 pathway to promote epithelial-mesenchymal transition of pancreatic cancer. Carcinogenesis 21 36591938
2016 Functional Divergence of the Nuclear Receptor NR2C1 as a Modulator of Pluripotentiality During Hominid Evolution. Genetics 21 27075724
1998 A constitutive nuclear localization signal from the second zinc-finger of orphan nuclear receptor TR2. The Journal of endocrinology 20 9795341
2000 Constitutive activation of retinoic acid receptor beta2 promoter by orphan nuclear receptor TR2. The Journal of biological chemistry 19 10766818
1998 Thyroid hormone direct repeat 4 response element is a positive regulatory element for the human TR2 orphan receptor, a member of steroid receptor superfamily. Molecular and cellular biochemistry 18 9879671
2009 HDAC3 as a molecular chaperone for shuttling phosphorylated TR2 to PML: a novel deacetylase activity-independent function of HDAC3. PloS one 15 19204783
2006 Ligand-independent orphan receptor TR2 activation by phosphorylation at the DNA-binding domain. Proteomics 15 16317770
2005 Protein kinase C-mediated phosphorylation of orphan nuclear receptor TR2: effects on receptor stability and activity. Proteomics 15 16130175
2006 SmTR2/4, a Schistosoma mansoni homologue of TR2/TR4 orphan nuclear receptor. International journal for parasitology 14 16839558
1999 Identification of the histamine H1 receptor gene as a differentially repressed target of the human TR2 orphan receptor. Molecular and cellular biochemistry 14 10391141
1998 The genomic structure and chromosomal location of the human TR2 orphan receptor, a member of the steroid receptor superfamily. Endocrine 12 9704569
2006 Transcriptional regulation of the human TR2 orphan receptor gene by nuclear factor 1-A. Biochemical and biophysical research communications 11 17010934
1998 Striking evolutionary conservation of a cis-element related to nuclear receptor target sites and present in TR2 orphan receptor genes. Biochemical and biophysical research communications 10 9535784
1997 Identification of the human aldolase A gene as the first induced target for the TR2 orphan receptor, a member of the steroid hormone receptor superfamily. Biochemical and biophysical research communications 10 9196064
1994 Molecular cloning of a novel member of the nuclear receptor superfamily related to the orphan receptor, TR2. Gene expression 10 7841789
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
1988 Cell-mediated immunity induced in mice after vaccination with a protease activation mutant, TR-2, of Sendai virus. Journal of virology 9 2836627
2024 Molecular classification of ovarian high-grade serous/endometrioid carcinomas through multi-omics analysis: JGOG3025-TR2 study. British journal of cancer 8 39215190
2007 Collective repression of the hepatitis B virus enhancer II by human TR4 and TR2 orphan receptors. Hepatology research : the official journal of the Japan Society of Hepatology 8 17645519
2006 Expression of orphan receptors TR2, TR3, TR4, and p53 in heat-treated testis of cynomolgus monkeys (Macaca fascicularis). Journal of andrology 8 16452526
2024 Roles of Nuclear Orphan Receptors TR2 and TR4 during Hematopoiesis. Genes 7 38790192
2017 Combination of novel DR5 targeting agonistic scFv antibody TR2-3 with cisplatin shows enhanced synergistic antitumor activity in vitro and in vivo. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 7 29272788
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
2003 Identification of histone deacetylase-3 domains that interact with the orphan nuclear receptor TR2. Biochemical and biophysical research communications 7 14521922
2001 Feedback regulation between orphan nuclear receptor TR2 and human papilloma virus type 16. The Journal of biological chemistry 7 11358973
2000 Identification of an essential cis-acting element (TR2-PACE) in the 5' promoter of human TR2 orphan receptor gene. Endocrine 7 10855696
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
2003 Differential and bi-directional regulation between TR2/TR4 orphan nuclear receptors and a specific ligand mediated-peroxisome proliferator-activated receptor alpha in human HaCaT keratinocytes. Journal of dermatological science 3 12615366
1998 Cloning of a cDNA for xDOR2, a novel TR2-related nuclear orphan receptor, expressed during neurulation in Xenopus laevis embryos. DNA sequence : the journal of DNA sequencing and mapping 3 10520740
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
2025 Orphan Nuclear Receptors TR2 and TR4 in Erythropoiesis: From Mechanisms to Therapies. Biomolecules 1 40563438
2009 Post-translational modifications of orphan nuclear receptor TR2 - new insights into drug targets for stem cell therapy and the effect of retinoic acid. Proteomics. Clinical applications 1 26238624