Affinage

NR2C2

Nuclear receptor subfamily 2 group C member 2 · UniProt P49116

Length
596 aa
Mass
65.4 kDa
Annotated
2026-06-10
100 papers in source corpus 49 papers cited in narrative 49 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR2C2 (TR4) is a nuclear orphan receptor that binds direct-repeat hormone response elements as a homodimer or as a heterodimer with the related receptor TR2, exerting element-dependent bidirectional transcriptional control—repressing DR1/DR3/DR5 targets while activating DR4 targets (PMID:9115296, PMID:9737983, PMID:10347174). Heterodimerization with TR2 is mediated by the ligand-binding domain, requiring three leucines on helix 10 of TR2, and TR2/TR4 complexes show enhanced repressive activity on shared elements (PMID:9737983). Crystallography of the LBD reveals an autorepressed conformation in which helix 10 and the AF-2 helix occupy the ligand pocket and cofactor surface; retinol and retinoic acid bind this pocket to drive coactivator recruitment and activation (PMID:21068381), and TR4 is responsive to additional lipophilic ligands including polyunsaturated fatty acid metabolites and a mycobacterial keto-mycolic acid (PMID:19666541, PMID:24907344). In erythroid cells, TR2/TR4 function as the DNA-binding core of the DRED corepressor complex that occupies DR1 sites in embryonic ε- and fetal γ-globin promoters and recruits epigenetic silencing machinery (DNMT1, NuRD, LSD1/CoREST, HDAC3, TIF1β) to stage-selectively repress these genes; loss of TR2/TR4 delays embryonic globin silencing while forced expression can paradoxically induce γ-globin and elevate fetal hemoglobin in adult cells (PMID:12093744, PMID:17431400, PMID:21670149, PMID:22042865). TR4 additionally represses GATA1 through a conserved enhancer DR element and is independently required for erythroid maturation and heme biosynthesis gene expression (PMID:17974920, PMID:29018082). Beyond erythropoiesis, TR4 directly transactivates metabolic and stress-response targets identified through knockout-mouse and promoter studies—PEPCK in gluconeogenesis, CD36 and apolipoprotein genes in lipid handling, NDUFAF1 in mitochondrial complex I assembly, and GADD45A/ATM in DNA-damage responses (PMID:12954636, PMID:17827404, PMID:19666541, PMID:21622535, PMID:22396141). TR4 activity is tuned by post-translational modification and selective cofactors: ARA55-promoted acetylation of DBD lysines K175/K176 reduces DNA binding, SIRT7-driven DDB1 deacetylation protects TR4 from CUL4B/DDB1/DCAF1-mediated degradation, and the selective repressors TIP27 and TRA16 bind the LBD/DBD to block transactivation (PMID:21515881, PMID:28623141, PMID:15302918, PMID:12486131).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1994 High

    Establishing that TR4 is a distinct nuclear receptor defined the molecular class of factor under study and predicted a DNA-binding, ligand-regulated transcriptional role.

    Evidence cDNA cloning and sequence analysis from human and rat tissues

    PMID:8016112

    Open questions at the time
    • No ligand or target gene identified at this stage
    • No functional or structural characterization
  2. 1997 Medium

    Quantitative binding and reporter assays answered whether TR4 acts as activator or repressor, revealing element-dependent bidirectional regulation—repressing DR1 targets but activating DR4 promoters.

    Evidence EMSA, Scatchard analysis, and CAT reporter assays on DR1 and DR4 elements

    PMID:9006963 PMID:9115296

    Open questions at the time
    • Cofactors mediating the opposite outcomes not identified
    • Single-lab reporter data without endogenous target validation
  3. 1998 High

    Demonstrating that TR4 forms TR2/TR4 heterodimers via LBD helix 10 leucines, competes with PPARα for DNA and coactivators, and feeds back on retinoic acid signaling established its mode of intersecting with other receptor pathways.

    Evidence Yeast/mammalian two-hybrid, pull-down, EMSA, GFP imaging, and reporter assays with mutagenesis

    PMID:9556573 PMID:9593676 PMID:9737983

    Open questions at the time
    • Physiological context of receptor crosstalk untested in vivo
    • Cell-type specificity of competition not defined
  4. 1999 Medium

    Conformational analyses on DR3 versus DR4 elements answered how a single receptor produces opposite transcriptional outputs, showing element-induced TR4 conformations select distinct coregulators.

    Evidence EMSA, antibody supershift, proteolytic footprinting, and reporter assays

    PMID:10347174

    Open questions at the time
    • Specific coregulators recruited to each conformation not identified
    • Structural basis inferred indirectly
  5. 2002 High

    Purifying the endogenous DRED complex and showing TR2/TR4 occupy embryonic globin DR1 sites identified the receptor's central role in developmental hemoglobin switching.

    Evidence Biochemical purification with mass spectrometry, EMSA, and transgenic mice

    PMID:12093744

    Open questions at the time
    • Full corepressor composition not yet defined
    • Mechanism of stage-selectivity unresolved
  6. 2002 Medium

    Selective cofactors and direct receptor inhibition were defined: TRA16 and (later) TIP27 repress TR4 via its LBD/DBD, and TR4 directly inhibits ER dimerization, mapping protein-level control of TR4 output.

    Evidence Two-hybrid, Co-IP, GST pull-down, EMSA, and proliferation assays

    PMID:11844790 PMID:12486131 PMID:15302918

    Open questions at the time
    • Physiological relevance of TRA16/TIP27 repression in vivo unestablished
    • Tissue distribution of these cofactors unclear
  7. 2003 High

    Identification of apoE/apoC and HBV core promoter targets showed TR4 directly regulates lipoprotein metabolism and can repress viral transcription through receptor crosstalk, with knockout mice confirming the apoE link in vivo.

    Evidence Gel shift, reporter assays, Co-IP, and TR4 knockout mice

    PMID:12522137 PMID:12954636

    Open questions at the time
    • Quantitative contribution of TR4 to systemic lipid homeostasis not isolated
    • HNF4α interaction interface not mapped
  8. 2007 High

    Genetic mouse models resolved the in vivo developmental function of TR2/TR4 as stage-selective repressors of embryonic globins and direct repressors of GATA1, anchoring the in vitro DRED model in physiology.

    Evidence Null and transgenic mice, dominant-negative TR4, ChIP, EMSA, and CD34+ knockdown

    PMID:17431400 PMID:17974920

    Open questions at the time
    • Paradoxical γ-globin induction by forced expression mechanistically unexplained
    • Relative contributions of TR2 vs TR4 not separated
  9. 2007 High

    Knockout phenotypes established TR4 as a direct transcriptional driver of gluconeogenesis via PEPCK, extending its role into systemic glucose metabolism.

    Evidence Knockout mice, EMSA, ChIP, reporter, RNAi, and glucose production assays

    PMID:17827404

    Open questions at the time
    • Upstream signals controlling hepatic TR4 activity unclear
    • Coregulators at the PEPCK promoter unidentified
  10. 2009 High

    Showing TR4 transactivates CD36 in response to fatty acid metabolites and TZDs defined TR4 as a lipid/fatty-acid sensor controlling foam-cell formation.

    Evidence Knockout mice, EMSA, ChIP, siRNA/rescue, and foam-cell and reporter assays

    PMID:19666541

    Open questions at the time
    • Endogenous high-affinity ligand not definitively established
    • Direct ligand binding not measured in this study
  11. 2010 High

    The LBD crystal structure answered why TR4 is an 'orphan' with low basal activity, revealing an autorepressed pocket that retinoids relieve to enable coactivator recruitment.

    Evidence X-ray crystallography, coactivator recruitment, reporter assays, and mutagenesis

    PMID:21068381

    Open questions at the time
    • Physiological endogenous ligand not crystallized
    • Conformational dynamics in solution not captured
  12. 2010 High

    Comprehensive metabolic knockout studies established that TR4 loss confers resistance to metabolic syndrome, integrating TR4 into whole-body lipid and energy homeostasis.

    Evidence Knockout mice, expression profiling, and metabolic and hepatocyte rescue studies

    PMID:20864514

    Open questions at the time
    • Tissue-specific contributions not dissected
    • Direct vs indirect target regulation not fully separated
  13. 2010 Medium

    Genome-wide ChIP-seq tested whether the in vitro DR1 model captures TR4 chromatin occupancy, revealing most sites lack DR1 and many are co-bound with ELK4, indicating recruitment via protein-protein interactions.

    Evidence TR4 and ELK4 ChIP-seq with motif and co-occupancy analysis in four cell types

    PMID:21126370

    Open questions at the time
    • Direct TR4-ELK4 interaction not biochemically demonstrated
    • Functional output at DR1-less sites untested
  14. 2011 High

    Defining the epigenetic corepressors recruited by TR2/TR4 at embryonic globin promoters explained the molecular silencing mechanism and showed multiple distinct corepressor complexes operate.

    Evidence ChIP, biotin-tag complex purification, mass spectrometry, Co-IP, and differentiation assays

    PMID:21670149

    Open questions at the time
    • Determinants of complex selection at specific promoters unclear
    • Order of corepressor assembly not defined
  15. 2011 High

    Knockout studies extended TR4 function into mitochondrial complex I assembly (via NDUFAF1), oxidative-stress/DNA-damage defense (GADD45A), and bone formation (osteocalcin), broadening its role as a stress- and differentiation-responsive activator.

    Evidence Knockout mice, ATP/complex I assays, ChIP, EMSA, reporter, and rescue experiments

    PMID:21521714 PMID:21622535 PMID:22396141 PMID:22676849

    Open questions at the time
    • Signals inducing TR4 in stress contexts incompletely defined
    • Direct vs indirect regulation of some targets uncertain
  16. 2011 Medium

    Discovery that ARA55 promotes acetylation of TR4 DBD lysines K175/K176 to reduce DNA binding established post-translational modification as a direct lever on TR4 activity.

    Evidence Site-directed mutagenesis, Co-IP, DNA-binding, and reporter assays

    PMID:21515881

    Open questions at the time
    • The responsible acetyltransferase not identified
    • In vivo relevance of acetylation untested
  17. 2011 High

    Forced TR2/TR4 expression in a sickle-cell mouse model demonstrated therapeutic-relevant induction of fetal hemoglobin, linking the repressor mechanism to hemoglobinopathy intervention.

    Evidence Humanized sickle-cell transgenic mice with hematological readouts

    PMID:22042865

    Open questions at the time
    • Mechanism of paradoxical γ-globin activation unresolved
    • Translation to human therapy untested
  18. 2013 High

    Demonstrating MAPK-phosphorylation-enhanced TR4 activation of POMC in corticotroph tumors revealed a phosphorylation-regulated oncogenic transactivation function.

    Evidence Overexpression/knockdown, reporter assays with MAPK inhibitors, and xenograft model

    PMID:23653479

    Open questions at the time
    • MAPK phosphorylation site(s) not mapped
    • Upstream activating signals in tumors unclear
  19. 2014 Medium

    ITC and structural identification of a mycobacterial keto-mycolic acid as a TR4 ligand established that TR4 senses pathogen-derived lipids to drive foamy macrophage and granuloma formation.

    Evidence Transactivation, ITC, TLC/NMR, and granuloma models

    PMID:24907344

    Open questions at the time
    • Structural basis of the keto-MA-LBD interaction not solved
    • Generality across mycolic acid species untested
  20. 2014 Medium

    Multiple cancer studies dissected context-dependent TR4 roles—tumor suppressor via ATM in prostate cancer initiation versus pro-metastatic via CCL2 and stemness/chemoresistance axes—revealing dual oncogenic and suppressive functions.

    Evidence Knockout and xenograft mouse models, ChIP, reporter, and rescue/neutralization experiments

    PMID:23609451 PMID:24583925 PMID:24975468

    Open questions at the time
    • What dictates suppressor vs promoter context unresolved
    • Most downstream axes shown in single labs
  21. 2014 Medium

    Identification of pyruvate carboxylase as a direct TR4 target connected TR4 transcriptional activity to de novo fatty acid synthesis in adipocytes.

    Evidence Reporter, ChIP, siRNA epistasis, and radiolabeled carbon incorporation assays

    PMID:25240193

    Open questions at the time
    • In vivo contribution to lipogenesis not isolated
    • Coregulators at PC promoter unidentified
  22. 2015 High

    Conditional adult-bone-marrow knockout confirmed that loss of TR2/TR4 occupancy de-represses embryonic globins and is required for terminal erythroid maturation, separating developmental silencing from cell viability.

    Evidence Conditional knockout mice, in vitro differentiation, and ChIP

    PMID:25561507

    Open questions at the time
    • Mechanism of maturation requirement not fully defined
    • Redundancy between TR2 and TR4 not resolved here
  23. 2017 High

    Two findings defined TR4 protein-level regulation and a non-redundant erythroid role: SIRT7/DDB1 deacetylation protects TR4 from CUL4B-mediated degradation, and TR4-specific knockout causes embryonic lethality with heme-biosynthesis defects.

    Evidence Co-IP, K1121R mutagenesis, qPCR, and congenic conditional knockout mice

    PMID:28623141 PMID:29018082

    Open questions at the time
    • E3 ligase regulation of TR4 in physiological contexts incompletely mapped
    • TR4-specific vs TR2/TR4-shared targets only partly resolved
  24. 2018 Medium

    ccRCC studies established TR4-centered miRNA/oncogene axes (miR-32-5p/HGF/Met and miR-490-3p/vimentin) driving metastasis and vasculogenic mimicry, expanding TR4's regulatory reach to non-coding RNA networks.

    Evidence 3'UTR targeting, ChIP/reporter at TR4REs, invasion assays, and xenograft models

    PMID:29396852 PMID:29973687

    Open questions at the time
    • Single-lab pathway dissections
    • Clinical generalizability untested
  25. 2020 Medium

    Bexarotene was shown to directly bind the TR4 LBD, induce a conformational change and nuclear-to-cytoplasmic relocalization, providing a pharmacological strategy to inhibit TR4-driven POMC/ACTH output.

    Evidence Virtual screening, conformational and fractionation assays, ChIP/reporter, and xenograft model

    PMID:33491272

    Open questions at the time
    • Binding pose not solved by crystallography
    • Specificity over related receptors not fully tested
  26. 2023 Medium

    Identification of NR2C2-driven NF-κB activation in macrophages linked the receptor to inflammatory cytokine production and testicular inflammation, defining an immune-regulatory function.

    Evidence RNAi in primary macrophages, DR-element binding, cytokine assays, and LPS-orchitis mouse model

    PMID:37427695

    Open questions at the time
    • Direct ChIP occupancy at the Nfkb promoter only implied
    • Generality beyond testicular macrophages untested
  27. 2024 High

    Resolving the long-standing question of how TR4 represses γ-globin, this work showed TR4 and BCL11A compete at the -117 γ-globin promoter region but TR4 acts independently of BCL11A and binds the locus control region genome-wide.

    Evidence In vitro binding competition, in vivo functional epistasis, and ChIP-seq

    PMID:39393056

    Open questions at the time
    • Precise in vivo TR4 binding site at γ-globin promoter still ambiguous
    • Mechanistic interplay with BCL11A at LCR not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the physiological endogenous ligand(s) that relieve TR4 autorepression in vivo, and the rules determining whether TR4 activates or represses a given locus, remain unresolved.
  • No endogenous high-affinity ligand defined despite retinoid/fatty-acid binding
  • Determinants of element-dependent activation vs repression not mechanistically settled
  • Rules governing tissue-specific corepressor recruitment unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6 GO:0008289 lipid binding 3
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 1
Partners
BCL11AELK4ERHNF4ASP1TIP27TR2TRA16
Complex memberships
DRED (TR2/TR4) repressor complex

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 TR4 (NR2C2) was identified as a member of the steroid receptor superfamily, cloned from human and rat hypothalamus/prostate/testis, encoding a 615 (human) or 596 (rat) amino acid protein with high homology to TR2, establishing TR2 and TR4 as a unique subfamily within the nuclear receptor superfamily. cDNA cloning, sequence analysis Proceedings of the National Academy of Sciences of the United States of America High 8016112
1997 TR4 binds with high affinity (Kd = 0.066 nM) to a conserved DR1 hormone response element (CNTFR-DR1) in the 5th intron of the CNTFRα gene and induces its enhancer activity in a dose-dependent manner, identifying CNTFRα as the first neural-specific gene transactivated by TR4. EMSA, reporter gene (CAT) assay, in situ hybridization The Journal of biological chemistry Medium 9006963
1997 TR4 binds DR4-HRE with strong affinity (Kd = 2 nM) and induces transcription from DR4-containing promoters (including rat α-myosin heavy chain and S14), in contrast to its repressive activity on DR1-HRE targets, demonstrating element-dependent bidirectional transcriptional regulation. EMSA, Scatchard analysis, CAT reporter assay The Journal of biological chemistry Medium 9115296
1998 TR4 represses RA-induced transactivation via a negative feedback mechanism by binding DR1 and DR5 elements (RAR and RXR response elements) with higher affinity than RAR/RXR, and RA treatment increases TR4 mRNA and protein levels in F9 cells, establishing a negative feedback loop. EMSA, CAT reporter assay, Western blot, Northern blot The Journal of biological chemistry Medium 9593676
1998 TAK1/TR4 binds DR1 response elements as a homodimer with greatest affinity for AGGTCAAAGGTCA, represses PPARα-mediated transactivation by competing with PPARα/RXR for PPRE binding, and also competes with PPARα for the co-activator RIP-140 (shown by two-hybrid analysis); TR4 does not heterodimerize with PPARα or RXRα. Site selection analysis, gel shift assay, cell transfection/reporter assay, two-hybrid analysis The Journal of biological chemistry Medium 9556573
1998 TR2 and TR4 preferentially form heterodimers in solution and on DR5-containing DNA elements; the dimerization is mediated by the ligand-binding domains with three leucine residues on helix 10 of TR2 being critical; coexpression of TR2 and TR4 exerts stronger repressive activity on DR5-reporter than either receptor alone. Yeast two-hybrid, mammalian two-hybrid, pull-down assay, EMSA, GFP intracellular localization tracking, reporter assay The Journal of biological chemistry High 9737983
1998 TR4 crosstalks with COUP-TF1 and thyroid hormone receptor (TRα1) to potentiate HIV-LTR transcriptional activity, while TR4 alone has no effect on HIV-LTR; TR2 does not show this crosstalk activity, demonstrating TR4-specific functional interaction with other nuclear receptors. Gel retardation assay (EMSA), CAT reporter assay, transient transfection Endocrine Low 9704574
1998 TR4 suppresses estrogen receptor-mediated transactivation in bone cells (osteosarcoma cell lines) but not in kidney or breast cancer cells, establishing a bone cell-specific repressor activity of TR4 on ER signaling. Transient transfection assay, Northern blot Endocrinology Low 9421416
1998 CNTF increases TR4 expression and enhances TR4 DNA-binding capacity; TR2 expression is also induced by CNTF and TR2 induces CNTFRα transcriptional activity via CNTFR-I5 DR element, establishing bidirectional regulation between TR2/TR4 and the CNTF signaling pathway. EMSA, reporter assay, in situ hybridization, Western blot The Journal of biological chemistry Medium 9694834
1999 TR4 binds DR3VDRE with high affinity (Kd = 1.32 nM) and represses vitamin D3 target gene (25-hydroxyvitamin D3 24-hydroxylase) expression, in contrast to its induction of DR4T3RE target genes; distinct TR4 conformations when bound to DR3VDRE vs. DR4T3RE (shown by antibody supershift and proteolytic analysis) allow recruitment of different coregulators. EMSA, cell transfection/reporter assay, antibody supershift, proteolytic analysis The Journal of biological chemistry Medium 10347174
2002 TR4 directly interacts with estrogen receptor (ER) via protein-protein interaction, inhibits ER homodimerization, and prevents ER binding to estrogen response elements, resulting in suppression of ER target genes (cyclin D1, pS2) and inhibition of ER-mediated cell proliferation in MCF-7 cells. EMSA, GST pull-down assay, reporter assay, stable transfection, cell proliferation assay The Journal of biological chemistry Medium 11844790
2002 The DRED (direct repeat erythroid-definitive) repressor complex contains TR2 and TR4 as a heterodimer that binds DR1 sites in human embryonic ε-globin and fetal γ-globin gene promoters; DRED is a ~540 kDa complex; TR2/TR4 binding is reduced by an HPFH mutation in the DR1 site; forced transgenic TR2/TR4 expression reduces embryonic εy-globin transcription. Biochemical purification, mass spectrometry/sequence determination, EMSA, transgenic mouse model The EMBO journal High 12093744
2002 A novel TR4-associated protein TRA16 (16 kDa, 139 amino acids, nuclear localization) selectively represses TR4-mediated transactivation by interacting with TR4 DNA-binding and ligand-binding domains; TRA16 reduces TR4 binding to TR4RE without inhibiting TR4 homodimerization; TRA16 blocks TR4-LBD interaction; the repression is TR4-selective (minimal effect on AR, GR, PR). Mammalian two-hybrid, Co-IP, EMSA, reporter assay, confocal microscopy The Journal of biological chemistry Medium 12486131
2003 TR4 binds to a DR1 element (TR4RE-HBV) in the HBV core promoter and suppresses pre-core and core mRNA transcription; TR4 suppresses HBV core promoter by repressing HNF4α-mediated transactivation through protein-protein interaction (TR4 N- and C-terminal regions required), without inhibiting HNF4α DNA binding. EMSA, luciferase reporter assay, primer extension, co-immunoprecipitation, deletion/domain analysis The Journal of biological chemistry Medium 12522137
2003 TR4 induces apoE gene expression via a TR4 response element in the hepatic control region 15 kb downstream of the apoE gene, and also regulates apoC-I and apoC-II expression via the same hepatic control region TR4RE; TR4 forms a complex with Sp1 for synergistic apoE induction via a proximal promoter DR0 element; TR4 knockout mice show significantly reduced serum apoE protein and liver apoE mRNA. Gel shift assay, luciferase reporter, TR4 knockout mice, quantitative analysis of serum/mRNA levels The Journal of biological chemistry High 12954636
2004 TIP27, a novel 27 kDa zinc finger protein, interacts specifically with the TR4 ligand-binding domain (helix 3 to C-terminus) via its TAK1-interaction domain (residues Asp39–Lys79) and functions as a selective repressor of TR4/DR1-dependent transactivation without inhibiting TR4 homodimerization or DNA binding, suggesting repression via interference with co-activator recruitment. Yeast two-hybrid, mammalian two-hybrid, pull-down assay, confocal microscopy, reporter assay Nucleic acids research Medium 15302918
2005 TR4 induces apoE expression in multiple cell lines via binding to a DR0 element (TR4RE-DR0-apoE at -303 to -292 bp) in the apoE 5' proximal promoter, and forms a complex with Sp1 to synergistically induce apoE expression. Gel shift assay, luciferase reporter assay, RT-PCR, Western blot Biochemical and biophysical research communications Low 15670754
2007 TR2 and TR4 are stage-selective repressors of embryonic β-type globin genes in vivo: Tr2 and Tr4 null mutant mice show delayed silencing of εy and βh1 globins in definitive erythroid cells; dominant-negative TR4 activates human ε-globin in both primitive and definitive erythroid cells but activates γ-globin only in definitive cells; forced TR2/TR4 expression causes precocious ε-globin repression but paradoxically induces γ-globin in definitive erythroid cells. Knockout and transgenic mouse models, gene expression analysis The EMBO journal High 17431400
2007 TR2 and TR4 directly repress Gata1/GATA1 transcription in murine and human erythroid progenitor cells through an evolutionarily conserved DR element in the GATA1 hematopoietic enhancer; TR2/TR4 binds this site in vitro and in vivo; mutation of the DR element elevates Gata1 promoter activity and reduces responsiveness to cotransfected TR2/TR4. Knockout and transgenic mouse models, ChIP, EMSA, reporter assay, shRNA knockdown in human CD34+ cells Genes & development High 17974920
2007 TR4 knockout mice show significantly reduced PEPCK expression and impaired gluconeogenesis; TR4 transactivates the PEPCK promoter by direct binding to a TR4RE at -451 to -439 bp; TR4 knockdown in hepatocytes reduces glucose production; ectopic TR4 expression increases PEPCK expression and hepatic glucose production. Knockout mice, EMSA, ChIP, luciferase reporter assay, siRNA/RNAi in hepatocytes, glucose production assay Diabetes High 17827404
2009 TR4 induces CD36 expression transcriptionally by binding to a TR4 response element in the CD36 5' promoter; this transactivation is enhanced by polyunsaturated fatty acids (omega-3/-6) and their metabolites (15-HETE, 13-HODE) and by rosiglitazone (TZD); TR4 knockout mice show reduced CD36 expression and foam cell formation; TR4 acts as a fatty acid sensor. TR4 knockout mice, EMSA, ChIP, siRNA knockdown, cDNA rescue, foam cell formation assay, reporter assay Proceedings of the National Academy of Sciences of the United States of America High 19666541
2010 Crystal structure of the TR4 ligand-binding domain reveals an autorepressed conformation: the LBP is filled by the C-terminal half of helix 10 and the AF-2 helix occupies the cofactor binding site; retinol and retinoic acid promote TR4 to recruit coactivators and activate TR4-regulated reporters; mutations disrupting cofactor binding, dimerization, or ligand binding substantially reduce TR4 transcriptional activity. X-ray crystallography, coactivator recruitment assay, reporter assay, site-directed mutagenesis The Journal of biological chemistry High 21068381
2010 TAK1/TR4 knockout mice are resistant to age- and high-fat-diet-induced metabolic syndrome; TR4 deficiency reduces hepatic triglyceride levels, lipid accumulation in adipose tissue, adipose inflammation, and insulin resistance; TR4 regulates lipogenic genes (Cidea, Cidec, Mogat1, CD36) in liver; TR4 knockout mice show increased energy expenditure. TR4 knockout mice, gene expression profiling, histochemical/biochemical analysis, metabolic studies, primary hepatocyte rescue experiments Diabetes High 20864514
2010 Genome-wide ChIP-seq of TR4 in 4 human cell types shows that less than 30% of TR4 binding sites contain a DR1 motif (derived from in vitro studies), and ~30% of TR4 sites are co-occupied by the ETS factor ELK4 at sites lacking DR1, suggesting TR4 can be recruited to chromatin via protein-protein interaction with ETS factors. ChIP-seq, bioinformatics/motif analysis, ELK4 ChIP-seq BMC genomics Medium 21126370
2011 TR2 and TR4 recruit multiple epigenetic corepressor complexes (DNMT1, NuRD, LSD1/CoREST, HDAC3, TIF1β) specifically to embryonic β-globin promoters but not the adult β-globin promoter in adult erythroid cells; at least four distinct TR2/TR4 molecular complexes exist; upon terminal erythroid differentiation, corepressors dissociate from adult but not embryonic globin promoters. ChIP, biotin-tag purification of TR2/TR4 complexes, mass spectrometry, co-immunoprecipitation, erythroid differentiation assays Molecular and cellular biology High 21670149
2011 TR4 knockout mice develop mitochondrial myopathy with reduced complex I activity, decreased mitochondrial ATP production, and increased serum lactate; TR4 transcriptionally regulates the complex I assembly factor NDUFAF1; restoration of TR4 or NDUFAF1 in TR4-/- myoblasts rescues mitochondrial ATP generation and complex I activity. TR4 knockout mice, histology, ATP production assay, complex I activity assay, qPCR, promoter study, rescue experiments Molecular endocrinology (Baltimore, Md.) High 21622535
2011 TR4 knockout mice show premature aging with increased genome instability and defective oxidative stress defense; TR4-/- MEFs show rapid growth arrest and reduced resistance to oxidative stress and DNA damage; restoring TR4 or adding antioxidant NAC reduces DNA damage in TR4-/- MEFs; TR4 loss alters genes in DNA damage response and anti-ROS pathways. TR4 knockout mice, MEF culture, DNA damage assays, qPCR array, NAC rescue, oxidative stress assays American journal of physiology. Endocrinology and metabolism Medium 21521714
2011 ARA55 functions as a corepressor of TR4 by enhancing acetylation of TR4 at conserved lysine residues K175 and K176 in the DNA-binding domain via recruiting histone acetyltransferase activity, thereby significantly reducing TR4 DNA-binding activity and suppressing TR4 transactivation. Mutation analysis, co-IP, reporter assay, DNA binding assay The Journal of biological chemistry Medium 21515881
2011 Forced TR2/TR4 expression in sickle cell disease model mice increases fetal hemoglobin (HbF) from 7.6% to 18.6% of total hemoglobin, increases hematocrit, reduces reticulocytes, and reduces hepatosplenomegaly, demonstrating that TR2/TR4 can paradoxically induce γ-globin in adult definitive erythroid cells. Transgenic mouse model (humanized sickle cell model), hemoglobin analysis, hematological measurements, histology Proceedings of the National Academy of Sciences of the United States of America High 22042865
2011 TR4 transcriptionally regulates GADD45A through TR4 response elements located in intron 3 of the GADD45A gene; TR4 deficiency abrogates Gadd45a expression and increases IR-induced cell death; IR increases TR4 expression in normal but not TR4 knockdown cells. ChIP, luciferase reporter assay, qPCR, shRNA knockdown, TR4 knockout MEFs, irradiation assay Cellular & molecular biology letters Medium 22396141
2012 TR4 knockout mice develop osteoporosis with reduced osteoblast activity; TR4 directly binds the promoter region of osteocalcin and induces its transcription; osteoblast progenitor cells from TR4 knockout mice show reduced differentiation and calcification with decreased expression of ALP, type I collagen α1, osteocalcin, PTH, and PTHR. TR4 knockout mice, bone analysis, primary osteoblast culture, alkaline phosphatase/alizarin red staining, luciferase reporter, ChIP, EMSA Reproductive biology and endocrinology : RB&E High 22676849
2013 TR4 is overexpressed in human corticotroph tumors and transcriptionally activates proopiomelanocortin (POMC) via binding a DR1 response element in the POMC promoter; this activation is enhanced by MAPK-mediated TR4 phosphorylation; forced TR4 overexpression increases ACTH secretion, cellular proliferation, and tumor invasion in vitro and promotes corticotroph tumor growth in vivo. Overexpression/knockdown in cell lines, reporter assay, luciferase assay with MAPK inhibitors, xenograft mouse model, ACTH/corticosterone measurement Proceedings of the National Academy of Sciences of the United States of America High 23653479
2013 TR4 promotes prostate cancer CD133+ stem/progenitor cell chemoresistance via a TR4→Oct4→IL1Ra axis; TR4 knockdown reduces Oct4 expression which reduces IL1Ra expression; restoring Oct4 or IL1Ra in TR4-knockdown cells reverses chemosensitivity. siRNA/lentiviral knockdown, drug sensitivity (IC50) assay, apoptosis assay, neutralization experiments The Journal of biological chemistry Medium 23609451
2014 Mycobacterium tuberculosis keto-mycolic acid acts as a heterologous ligand for TR4, binding with energetically favorable thermodynamics (isothermal titration calorimetry); this keto-MA–TR4 interaction induces foamy macrophage formation and granuloma development in vitro and in vivo. Transactivation assay, promoter reporter assay, TLC, NMR, isothermal titration calorimetry, in vitro and in vivo granuloma models Journal of immunology (Baltimore, Md. : 1950) Medium 24907344
2014 TR4 promotes prostate cancer metastasis by transcriptionally upregulating CCL2; ChIP and luciferase assays confirmed TR4 binding to the CCL2 promoter; CCR2 antagonist reverses TR4-enhanced PCa cell migration/invasion in vitro and PCa metastasis in orthotopic mouse model. siRNA/cDNA overexpression, migration/invasion assay, ChIP, luciferase assay, orthotopic xenograft mouse model International journal of cancer Medium 24975468
2014 TR4 functions as a tumor suppressor during PCa initiation by transcriptionally regulating ATM expression; TR4 knockdown increases DNA damage and reduces ATM levels; ATM restoration partially reverses TR4-siRNA-induced tumorigenesis; three mouse models support TR4's suppressor role. TR4 knockout mouse models, siRNA knockdown, cell transformation assay, ATM rescue experiment, IHC, qPCR Carcinogenesis Medium 24583925
2014 TR4 directly binds the pyruvate carboxylase (PC) promoter via a TR4 responsive element and increases PC gene expression and activity in 3T3-L1 adipocytes; TR4-mediated fatty acid synthesis requires PC activity, as siRNA knockdown of PC or PC inhibition abolishes TR4-enhanced fatty acid synthesis. Luciferase reporter assay, ChIP (implied by direct binding), siRNA, PC activity assay, radiolabeled carbon incorporation assay FEBS letters Medium 25240193
2015 Compound conditional knockout of Tr2 and Tr4 in adult bone marrow cells leads to induced expression of embryonic εy and βh1 globins, confirms loss of TR2/TR4 occupancy at embryonic globin promoters and impairs co-occupancy by interacting corepressors; TR2/TR4 function is also required for terminal erythroid cell maturation. Conditional knockout mouse model, in vitro bone marrow differentiation, globin expression analysis, ChIP Blood High 25561507
2015 TR4 increases prostate cancer invasion by decreasing miR-373-3p expression, which activates TGFβR2/p-Smad3 signaling; in vivo orthotopic mouse model confirmed TR4-increased PCa metastasis is mediated through decreased miR-373-3p. Overexpression/knockdown, invasion assay, miRNA expression analysis, orthotopic xenograft mouse model Oncotarget Low 25980442
2015 TR4 transcriptionally regulates TIMP-1 and MMP2; knockdown of TR4 in PCa cells suppresses macrophage infiltration via increasing TIMP-1 with decreased MMP2; TIMP-1 neutralizing antibody reverses the effect, establishing TR4→MMP2/TIMP-1 axis in macrophage-mediated PCa invasion. siRNA knockdown, macrophage migration assay, invasion assay, TIMP-1 neutralization, IHC of patient samples Molecular cancer Low 25623427
2017 SIRT7 deacetylates DDB1 at Lys1121, reducing its binding to DCAF1, thereby attenuating CUL4B/DDB1/DCAF1 E3 ubiquitin ligase activity and increasing TR4 protein levels; K1121R-DDB1 (deacetylation mimic) shows reduced DCAF1 binding and elevated TR4 and TR4 target gene expression (Cd36, Cidea, Cidec, Pparg1). Co-IP (SIRT7-DDB1 interaction), site-directed mutagenesis (K1121R), overexpression, Western blot, qPCR Biochemical and biophysical research communications Medium 28623141
2017 TR4 plays a distinct individual role in erythroid development beyond TR2/TR4 redundancy: Tr4 null mutation in congenic C57BL/6 background causes early embryonic lethality (~E7.0); conditional Tr4 erythroid cells show failure to fully differentiate, diminished proliferation, decreased Alad and Alas2 (heme biosynthesis genes), and increased Cdkn1c expression. Conditional knockout mouse model, erythroid differentiation analysis, gene expression analysis Blood High 29018082
2018 TR4 promotes ccRCC metastasis via the miR-32-5p/TR4/HGF/Met/MMP2-MMP9 axis; miR-32-5p suppresses TR4 protein by binding to the 3'UTR of TR4 mRNA; TR4 transcriptionally regulates HGF via direct binding to TR4RE on the HGF promoter; in vivo mouse model confirmed pathway. miR target binding assay (3'UTR), ChIP/reporter for TR4-HGF, invasion/migration assay, xenograft mouse model International journal of cancer Medium 29396852
2018 TR4 promotes ccRCC vasculogenic mimicry (VM) and metastasis via miR490-3p/vimentin (VIM) signaling; TR4 decreases miR-490-3p by binding TR4-REs on its promoter, leading to increased VIM expression; preclinical mouse sub-renal capsule model confirmed the pathway. ChIP/reporter for TR4 on miR-490-3p promoter, 3'UTR targeting assay, VM assay, xenograft mouse model Oncogene Medium 29973687
2019 TR4 modulates lncTASR (ENST00000600671.1) expression via transcriptional regulation; lncTASR increases AXL protein expression by enhancing AXL mRNA stability, conferring sunitinib resistance in RCC; bexarotene (a retinoid) antagonizes TR4, increasing sunitinib sensitivity. TR4 knockdown/overexpression, reporter assay, RNA stability assay, drug sensitivity assay, xenograft mouse model Oncogene Medium 31501521
2020 Bexarotene directly interacts with TR4 ligand-binding domain, induces a conformational change in TR4-LBD secondary structure, and promotes TR4 translocation from nucleus to cytoplasm, thereby reducing TR4 binding to TR4RE on the POMC promoter and suppressing POMC expression and ACTH secretion; validated in vivo in mouse corticotroph tumor model. In silico virtual screening, structural modeling, TR4-LBD conformational assay, nuclear/cytoplasmic fractionation, ChIP/reporter assay, xenograft mouse model Journal of cellular and molecular medicine Medium 33491272
2020 TR4 transcriptionally increases RNA-binding protein QKI expression; increased QKI elevates circZEB1, which sponges miR-141-3p to increase ZEB1 expression, conferring prostate cancer radioresistance; metformin combined with radiation suppresses PCa via this pathway. siRNA knockdown, reporter assay, RT-PCR, xenograft mouse model Cancer letters Low 32768524
2023 NR2C2 activates NF-κB signaling in macrophages by binding DR elements in the promoter of the Nfκb gene, promoting expression of IL-1β and IL-6, and thereby inducing testicular inflammation (orchitis) and inhibiting spermatogonial proliferation. RNA interference in primary macrophages and RAW264.7, ChIP (implied by DR binding assay), inflammatory cytokine measurement, spermatogonia proliferation assay, LPS-induced orchitis mouse model Reproduction (Cambridge, England) Medium 37427695
2024 TR4 and BCL11A competitively bind in vitro to distinct but overlapping sequences at the -117 position of the γ-globin promoter; TR4 represses γ-globin transcription and fetal hemoglobin in vivo independently of BCL11A; genome-wide ChIP shows BCL11A but not TR4 binds γ-globin promoters at statistically significant frequency in vivo, while both bind the locus control region. In vitro binding competition assay, in vivo functional studies, ChIP-seq Blood High 39393056

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2012 Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPARγ and TR4 for survival. Journal of immunology (Baltimore, Md. : 1950) 161 22544925
1994 Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily. Proceedings of the National Academy of Sciences of the United States of America 147 8016112
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 107 21670149
2002 An embryonic/fetal beta-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer. The EMBO journal 98 12093744
2010 Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance. Diabetes 92 20864514
2009 TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation. Proceedings of the National Academy of Sciences of the United States of America 90 19666541
2007 Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4. The EMBO journal 86 17431400
2004 TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4. Nucleic acids research 85 15302918
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
2019 Fusaric acid instigates the invasion of banana by Fusarium oxysporum f. sp. cubense TR4. The New phytologist 67 31513293
2010 The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor. The Journal of biological chemistry 63 21068381
2007 Loss of TR4 orphan nuclear receptor reduces phosphoenolpyruvate carboxykinase-mediated gluconeogenesis. Diabetes 63 17827404
1998 Regulation of peroxisome proliferator-activated receptor alpha-induced transactivation by the nuclear orphan receptor TAK1/TR4. The Journal of biological chemistry 59 9556573
2014 Mycobacterium tuberculosis keto-mycolic acid and macrophage nuclear receptor TR4 modulate foamy biogenesis in granulomas: a case of a heterologous and noncanonical ligand-receptor pair. Journal of immunology (Baltimore, Md. : 1950) 56 24907344
2013 Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease. Proceedings of the National Academy of Sciences of the United States of America 56 23653479
1998 Negative feedback control of the retinoid-retinoic acid/retinoid X receptor pathway by the human TR4 orphan receptor, a member of the steroid receptor superfamily. The Journal of biological chemistry 53 9593676
1997 Induction of the intronic enhancer of the human ciliary neurotrophic factor receptor (CNTFRalpha) gene by the TR4 orphan receptor. A member of steroid receptor superfamily. The Journal of biological chemistry 52 9006963
1997 Identification of direct repeat 4 as a positive regulatory element for the human TR4 orphan receptor. A modulator for the thyroid hormone target genes. The Journal of biological chemistry 52 9115296
2013 Increased chemosensitivity via targeting testicular nuclear receptor 4 (TR4)-Oct4-interleukin 1 receptor antagonist (IL1Ra) axis in prostate cancer CD133+ stem/progenitor cells to battle prostate cancer. The Journal of biological chemistry 50 23609451
2007 The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription. Genes & development 45 17974920
2002 Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells. The Journal of biological chemistry 43 11844790
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
1999 Differential regulation of direct repeat 3 vitamin D3 and direct repeat 4 thyroid hormone signaling pathways by the human TR4 orphan receptor. The Journal of biological chemistry 41 10347174
1998 A novel nuclear receptor heterodimerization pathway mediated by orphan receptors TR2 and TR4. The Journal of biological chemistry 39 9737983
2018 Preclinical studies using miR-32-5p to suppress clear cell renal cell carcinoma metastasis via altering the miR-32-5p/TR4/HGF/Met signaling. International journal of cancer 38 29396852
2014 TR4 nuclear receptor promotes prostate cancer metastasis via upregulation of CCL2/CCR2 signaling. International journal of cancer 38 24975468
2003 Disruption of TR4 orphan nuclear receptor reduces the expression of liver apolipoprotein E/C-I/C-II gene cluster. The Journal of biological chemistry 36 12954636
2018 TR4 nuclear receptor promotes clear cell renal cell carcinoma (ccRCC) vasculogenic mimicry (VM) formation and metastasis via altering the miR490-3p/vimentin signals. Oncogene 35 29973687
2017 TR2 and TR4 Orphan Nuclear Receptors: An Overview. Current topics in developmental biology 35 28527578
2020 Targeting the radiation-induced TR4 nuclear receptor-mediated QKI/circZEB1/miR-141-3p/ZEB1 signaling increases prostate cancer radiosensitivity. Cancer letters 34 32768524
2015 Targeting TR4 nuclear receptor suppresses prostate cancer invasion via reduction of infiltrating macrophages with alteration of the TIMP-1/MMP2/MMP9 signals. Molecular cancer 34 25623427
2011 Premature aging with impaired oxidative stress defense in mice lacking TR4. American journal of physiology. Endocrinology and metabolism 33 21521714
2015 TR4 nuclear receptor increases prostate cancer invasion via decreasing the miR-373-3p expression to alter TGFβR2/p-Smad3 signals. Oncotarget 32 25980442
2018 NR2C2-uORF targeting UCA1-miR-627-5p-NR2C2 feedback loop to regulate the malignant behaviors of glioma cells. Cell death & disease 29 30518750
2014 TR4 nuclear receptor functions as a tumor suppressor for prostate tumorigenesis via modulation of DNA damage/repair system. Carcinogenesis 29 24583925
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
2016 miRNA-133a attenuates lipid accumulation via TR4-CD36 pathway in macrophages. Biochimie 28 27109382
2014 Minireview: Pathophysiological roles of the TR4 nuclear receptor: lessons learned from mice lacking TR4. Molecular endocrinology (Baltimore, Md.) 28 24702179
2010 Genome-wide binding of the orphan nuclear receptor TR4 suggests its general role in fundamental biological processes. BMC genomics 28 21126370
2010 Altered cerebellar development in nuclear receptor TAK1/ TR4 null mice is associated with deficits in GLAST(+) glia, alterations in social behavior, motor learning, startle reactivity, and microglia. Cerebellum (London, England) 27 20393820
2017 Sirtuin 7-dependent deacetylation of DDB1 regulates the expression of nuclear receptor TR4. Biochemical and biophysical research communications 25 28623141
2012 Reduced osteoblast activity in the mice lacking TR4 nuclear receptor leads to osteoporosis. Reproductive biology and endocrinology : RB&E 25 22676849
2019 Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression. Oncogene 24 31501521
2003 Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4. The Journal of biological chemistry 23 12522137
2019 Identification of Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) responsive miRNAs in banana root. Scientific reports 22 31548557
2018 Role and mechanism of miR-4778-3p and its targets NR2C2 and Med19 in cervical cancer radioresistance. Biochemical and biophysical research communications 22 30473219
2015 Compound loss of function of nuclear receptors Tr2 and Tr4 leads to induction of murine embryonic β-type globin genes. Blood 22 25561507
2020 Long Noncoding RNA CDKN2B-AS1 Facilitates Lung Cancer Development Through Regulating miR-378b/NR2C2. OncoTargets and therapy 21 33116641
2018 TR4 nuclear receptor suppresses HCC cell invasion via downregulating the EphA2 expression. Cell death & disease 21 29449527
2008 The roles of testicular orphan nuclear receptor 4 (TR4) in cerebellar development. Cerebellum (London, England) 21 18418664
2009 Activation of TR4 orphan nuclear receptor gene promoter by cAMP/PKA and C/EBP signaling. Endocrine 20 19618297
2002 Identification of a novel testicular orphan receptor-4 (TR4)-associated protein as repressor for the selective suppression of TR4-mediated transactivation. The Journal of biological chemistry 20 12486131
2011 Mice lacking TR4 nuclear receptor develop mitochondrial myopathy with deficiency in complex I. Molecular endocrinology (Baltimore, Md.) 19 21622535
2005 Induction of apolipoprotein E expression by TR4 orphan nuclear receptor via 5' proximal promoter region. Biochemical and biophysical research communications 18 15670754
2000 Expression of the orphan receptor TR4 during brain development of the rat. Brain research. Molecular brain research 18 10814836
2021 Testicular orphan receptor 4 (TR4) promotes papillary thyroid cancer invasion via activating circ-FNLA/miR-149-5p/MMP9 signaling. Molecular therapy. Nucleic acids 17 33996257
2019 Targeting TR4 nuclear receptor with antagonist bexarotene increases docetaxel sensitivity to better suppress the metastatic castration-resistant prostate cancer progression. Oncogene 17 31748715
2012 Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation. Cellular & molecular biology letters 16 22396141
2016 TR4 nuclear receptor enhances the cisplatin chemo-sensitivity via altering the ATF3 expression to better suppress HCC cell growth. Oncotarget 15 27050071
2011 Increased acetylation in the DNA-binding domain of TR4 nuclear receptor by the coregulator ARA55 leads to suppression of TR4 transactivation. The Journal of biological chemistry 15 21515881
2007 Abnormal cerebellar cytoarchitecture and impaired inhibitory signaling in adult mice lacking TR4 orphan nuclear receptor. Brain research 15 17706948
2015 TR4 Nuclear Receptor Different Roles in Prostate Cancer Progression. Frontiers in endocrinology 14 26074876
2006 SmTR2/4, a Schistosoma mansoni homologue of TR2/TR4 orphan nuclear receptor. International journal for parasitology 14 16839558
2001 The nuclear orphan receptor TR4 promotes proliferation of myeloid progenitor cells. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 14 11714637
1999 Induction of TR4 orphan receptor by retinoic acid in human HaCaT keratinocytes. The Journal of investigative dermatology 14 10201524
1996 New variants of the human and rat nuclear hormone receptor, TR4: expression and chromosomal localization of the human gene. Genomics 14 8661150
2021 miR-616-5p Promotes Invasion and Migration of Bladder Cancer via Downregulating NR2C2 Expression. Frontiers in oncology 13 34956884
2015 TR4 nuclear receptor enhances prostate cancer initiation via altering the stem cell population and EMT signals in the PPARG-deleted prostate cells. Oncoscience 13 25859557
2014 Differential roles of PPARγ vs TR4 in prostate cancer and metabolic diseases. Endocrine-related cancer 13 24623743
2004 Modulation of the retinoic acid-induced cell apoptosis and differentiation by the human TR4 orphan nuclear receptor. Biochemical and biophysical research communications 13 15381082
1998 Cloning of rabbit TR4 and its bone cell-specific activity to suppress estrogen receptor-mediated transactivation. Endocrinology 13 9421416
2023 Disentangling the resistant mechanism of Fusarium wilt TR4 interactions with different cultivars and its elicitor application. Frontiers in plant science 12 36938065
2023 NR2C2 of macrophages promotes inflammation via NF-κB in LPS-induced orchitis in mice. Reproduction (Cambridge, England) 12 37427695
2017 The orphan nuclear receptor TR4 regulates erythroid cell proliferation and maturation. Blood 12 29018082
2011 Testicular nuclear receptor 4 (TR4) regulates UV light-induced responses via Cockayne syndrome B protein-mediated transcription-coupled DNA repair. The Journal of biological chemistry 12 21918225
2006 Transactivation of the proximal promoter of human oxytocin gene by TR4 orphan receptor. Biochemical and biophysical research communications 12 17054912
1998 TR4 orphan receptor crosstalks to chicken ovalbumin upstream protein-transcription factor and thyroid hormone receptor to induce the transcriptional activity of the human immunodeficiency virus type 1 long-terminal repeat. Endocrine 12 9704574
2020 Secretome Analysis of the Banana Fusarium Wilt Fungi Foc R1 and Foc TR4 Reveals a New Effector OASTL Required for Full Pathogenicity of Foc TR4 in Banana. Biomolecules 11 33050283
2019 Di(2-ethylhexyl)phthalate induces reproductive toxicity via JAZF1/TR4 pathway and oxidative stress in pubertal male rats. Toxicology and industrial health 11 30755103
2016 Di-(2-ethylhexyl) phthalate induces apoptosis of GC-2spd cells via TR4/Bcl-2 pathway. Environmental toxicology and pharmacology 11 27084994
2006 Stage dependent and androgen inductive expression of orphan receptor TR4 in rat testis. Biochemical and biophysical research communications 10 16414012
1996 Splice variants of rat TR4 orphan receptor: differential expression of novel sequences in the 5'-untranslated region and C-terminal domain. Endocrinology 10 8612486
2014 Biased, non-equivalent gene-proximal and -distal binding motifs of orphan nuclear receptor TR4 in primary human erythroid cells. PLoS genetics 9 24811540
2024 Roles of Nuclear Orphan Receptors TR2 and TR4 during Hematopoiesis. Genes 8 38790192
2020 Beta-catenin inhibits TR4-mediated lipid accumulation in 3T3-L1 adipocytes via induction of Slug. Cell & bioscience 8 33072258
2011 The roles of testicular nuclear receptor 4 (TR4) in male fertility-priapism and sexual behavior defects in TR4 knockout mice. Reproductive biology and endocrinology : RB&E 8 21995792
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
2021 Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT-20 cells. Journal of cellular and molecular medicine 7 33491272
2021 Weed-Associated Fungal Endophytes as Biocontrol Agents of Fusarium oxysporum f. sp. cubense TR4 in Cavendish Banana. Journal of fungi (Basel, Switzerland) 7 33803818
2019 Immunohistochemical Study of NR2C2, BTG2, TBX19, and CDK2 Expression in 31 Paired Primary/Recurrent Nonfunctioning Pituitary Adenomas. International journal of endocrinology 7 31223310
2016 CREB/GSK-3β signaling pathway regulates the expression of TR4 orphan nuclear receptor gene. Molecular and cellular endocrinology 7 26762765
2015 The Differential Effects of Anti-Diabetic Thiazolidinedione on Prostate Cancer Progression Are Linked to the TR4 Nuclear Receptor Expression Status. Neoplasia (New York, N.Y.) 7 25925376
1994 Induction of membrane ruffling by growth factors in morphologically TPA-resistant Balb/c3T3 TR4 cells. Cell structure and function 7 7522976
1994 The ER-TR4 monoclonal antibody recognizes murine thymic epithelial cells (type 1) and inhibits their capacity to interact with immature thymocytes: immuno-electron microscopic and functional studies. Histochemistry 7 7928419
2023 Iron necessity for chlamydospore germination in Fusarium oxysporum f. sp. cubense TR4. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 4 37380939
2022 De novo synthesis of ferrichrome by Fusarium oxysporum f. sp. cubense TR4 in response to iron starvation. Fungal biology 4 35851144
2014 TR4 promotes fatty acid synthesis in 3T3-L1 adipocytes by activation of pyruvate carboxylase expression. FEBS letters 4 25240193
2024 TR4 and BCL11A repress γ-globin transcription via independent mechanisms. Blood 3 39393056

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