Affinage

ARNT

Aryl hydrocarbon receptor nuclear translocator · UniProt P27540

Length
789 aa
Mass
86.6 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARNT (HIF-1β) is a constitutively expressed bHLH-PAS transcription factor that serves as the obligate heterodimerization partner for multiple class I bHLH-PAS proteins — including AhR, HIF-1α, HIF-2α, NPAS1, NPAS3, NPAS4, and AhRR — and is therefore a central node integrating xenobiotic, hypoxic, and neuronal transcriptional responses. Heterodimerization occurs through cooperative bHLH and PAS-A/PAS-B domain contacts, with ARNT inducing an allosteric conformational change in its partner that is required for high-affinity DNA binding; crystal structures of AhR–ARNT, NPAS1/3/4–ARNT, and AhRR–ARNT complexes reveal partner-specific domain arrangements and multiple ligand-binding pockets per heterodimer (PMID:8384309, PMID:9159130, PMID:27782878, PMID:39900897, PMID:36343253). The ARNT PAS-B domain simultaneously engages its dimerization partner on one face and recruits coactivators (TACC3, TRIP230, CoCoA) on the opposite face to drive target gene transcription, while ARNT also independently coactivates estrogen receptor-dependent transcription via its C-terminal domain and can form homodimers that bind E-box elements and activate targets such as ALK3 (PMID:19324882, PMID:21512126, PMID:12754377, PMID:29664738). Conditional deletion of Arnt in mice causes embryonic lethality from failed placental vascularization, suppresses VHL-driven hemangiomas, and produces tissue-specific metabolic defects in heart, adipose, and endothelium, establishing ARNT as essential for VEGF-dependent vasculogenesis, glucose homeostasis, and lipid metabolism in vivo (PMID:9398442, PMID:15798202, PMID:21982709, PMID:25329697).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1993 High

    Establishing that ARNT is the obligate ligand-dependent dimerization partner for the dioxin receptor resolved how AhR acquires DNA-binding competence — ARNT heterodimerizes only with ligand-activated AhR (not the hsp90-bound form) and is required for dioxin response element recognition.

    Evidence In vitro reconstitution of DNA binding, coimmunoprecipitation, and complementation of dioxin-resistant cells

    PMID:8384309

    Open questions at the time
    • Structural basis of ligand-dependent selectivity unknown
    • Whether ARNT has partners beyond AhR not yet tested
  2. 1994 High

    Systematic domain mapping revealed that both HLH helices and PAS-A/PAS-B domains are required for ARNT dimerization, while the basic region mediates DNA binding, establishing the modular architecture of ARNT function.

    Evidence Deletion mutagenesis with in vivo rescue in ARNT-deficient c4 cells

    PMID:8065341

    Open questions at the time
    • Atomic-resolution structure not yet available
    • Distinct contributions of PAS-A vs PAS-B to dimerization not resolved
  3. 1995 High

    Demonstrating that ARNT can homodimerize and bind E-box elements expanded its functional repertoire beyond an AhR cofactor, revealing it as an independent transcription factor.

    Evidence Co-IP, gel-shift, and CAT reporter assays

    PMID:7892203

    Open questions at the time
    • Physiological targets of ARNT homodimers unknown
    • Relative abundance of homodimers vs heterodimers in cells not quantified
  4. 1997 High

    Showing that ARNT induces an allosteric conformational change in HIF-1α (detected by altered protease sensitivity) that is required for high-affinity DNA binding established that ARNT is not merely a passive scaffold but an active allosteric regulator of its partners.

    Evidence Limited proteolysis conformational assay and EMSA with truncated ARNT mutants

    PMID:9159130

    Open questions at the time
    • Structural basis of conformational change not resolved at atomic level
    • Whether allosteric mechanism applies to all ARNT partners untested
  5. 1997 High

    Identification of CBP/p300 as a coactivator interacting with ARNT's transactivation domain established that ARNT directly recruits chromatin-remodeling machinery to drive transcription.

    Evidence Yeast two-hybrid, mammalian two-hybrid, and GST pull-down

    PMID:9399571

    Open questions at the time
    • Binding interface not mapped at residue level
    • Contribution of CBP/p300 to different ARNT heterodimer complexes not compared
  6. 1997 High

    ARNT-null embryonic lethality due to failed placental vascularization established ARNT as essential for developmental angiogenesis in vivo, connecting its transcriptional role to a critical physiological outcome.

    Evidence Homologous recombination knockout mouse with histological analysis

    PMID:9398442

    Open questions at the time
    • Whether lethality is due to HIF-dependent or AhR-dependent or combined ARNT functions not resolved
    • Cell-type specificity of requirement unknown
  7. 1998 High

    Demonstrating that insulin/IGF-I activate the HIF-1α–ARNT complex and that ARNT-deficient cells fail to induce glycolytic enzymes and VEGF linked ARNT to growth factor-driven metabolic gene regulation beyond classical hypoxia signaling.

    Evidence EMSA, ARNT-deficient cell rescue, and reporter assays for HRE activity

    PMID:9724644

    Open questions at the time
    • Direct vs indirect mechanism of insulin-induced HIF activation through ARNT not fully dissected
  8. 1999 High

    Showing that ligand maintains a specific AhR–ARNT conformation required for transcription (distinct from mere DNA-binding competence) revealed that ligand has roles beyond nuclear import, including sustaining an active heterodimer conformation.

    Evidence Geldanamycin vs dioxin comparison, limited proteolysis, and reporter assays in constitutively nuclear AhR cells

    PMID:10409767

    Open questions at the time
    • Structural identity of transcriptionally active vs inactive conformations unknown
  9. 1999 High

    ARNT-null embryoid bodies failed hypoxia-induced hematopoietic expansion, and VEGF rescue restored the defect, placing ARNT upstream of VEGF in a pathway required for hypoxia-driven hematopoiesis.

    Evidence Arnt knockout embryoid bodies, VEGF rescue, hematopoietic colony assays

    PMID:10521392

    Open questions at the time
    • Whether additional ARNT targets beyond VEGF contribute to hematopoietic defect not excluded
  10. 2003 High

    Discovery that ARNT coactivates estrogen receptor-dependent transcription via its C-terminal domain — independent of bHLH/PAS — expanded ARNT function beyond bHLH-PAS partnerships to nuclear receptor signaling.

    Evidence Co-IP, GST pull-down, reporter assays, and ChIP at endogenous ER target promoter

    PMID:12754377

    Open questions at the time
    • Whether ER coactivation competes with bHLH-PAS heterodimerization for ARNT pools not tested
    • Structural basis of ER–ARNT interaction unresolved
  11. 2003 High

    Quantitative reconstitution showed PAS-A domains are required for high-affinity DNA binding by AhR–ARNT and HIF-1α–ARNT heterodimers, and PAS-A identity is partner-specific, explaining how ARNT discriminates among partners.

    Evidence Quantitative EMSA with recombinant proteins and PAS-A domain chimeras

    PMID:14638687

    Open questions at the time
    • Atomic structure of PAS-A–PAS-A interface not yet determined
  12. 2005 High

    NMR structure of the ARNT PAS-B domain identified the solvent-exposed β-sheet surface as the dimerization interface for both homo- and heterodimerization, providing the first atomic-resolution view of the ARNT interaction surface.

    Evidence NMR structure determination with HADDOCK docking and site-directed spin labeling

    PMID:16181639

    Open questions at the time
    • Full heterodimer structures with complete domain architecture not yet available
  13. 2005 High

    Conditional Arnt deletion completely suppressed VHL-associated hemangiomas while Hif-1α deletion alone did not, demonstrating that multiple HIF-α subunits converge on ARNT and that ARNT is the critical bottleneck in VHL disease pathogenesis.

    Evidence Cre-loxP conditional knockouts in VHL mouse model

    PMID:15798202

    Open questions at the time
    • Relative contributions of HIF-1α vs HIF-2α through ARNT not individually quantified
  14. 2009 High

    NMR mapping showed ARNT PAS-B uses opposite faces for partner dimerization and coactivator (TRIP230/CoCoA) recruitment via an LXXLL motif, establishing a bifunctional architecture that couples partner selection to transcriptional output.

    Evidence NMR interface mapping, LXXLL mutagenesis, pull-down and reporter assays

    PMID:19324882

    Open questions at the time
    • Whether all ARNT partners use the same coactivator-recruitment surface not tested
  15. 2011 High

    ARNT PAS-B recruits TACC3 as a coactivator required for hypoxic transcriptional responses, and PAS-B mutations selectively modulate coactivator choice and target gene profiles, revealing ARNT as a specificity determinant for gene-selective output.

    Evidence NMR, mutagenesis, and in vivo reporter assays

    PMID:21512126

    Open questions at the time
    • How coactivator selectivity translates to genome-wide target gene specificity not profiled
  16. 2011 High

    Identification of partner-selective PAS-A residues (E163 and S190 for AhR; D217 shared with HIF-1α) mapped the structural determinants of ARNT's ability to serve as a hub for multiple bHLH-PAS partners.

    Evidence Bacterial two-hybrid loss-of-interaction screen and site-directed mutagenesis

    PMID:21245039

    Open questions at the time
    • Full PAS-A crystal structure of ARNT alone not available at this time
  17. 2011 High

    NF-κB was shown to directly regulate ARNT mRNA and protein levels, with downstream effects on HIF-2α stability — revealing that ARNT abundance is transcriptionally controlled and can be limiting for HIF signaling.

    Evidence siRNA knockdown of NF-κB subunits, ARNT rescue, conserved in Drosophila

    PMID:21298084

    Open questions at the time
    • Whether NF-κB-ARNT axis operates in all tissues or is context-specific not defined
  18. 2014 High

    Cardiac-specific ARNT deletion caused cardiomyopathy with lipid accumulation via derepression of PPARα, and double knockout of Arnt and Ppara fully rescued the phenotype — positioning ARNT as a direct transcriptional regulator of PPARα in the heart.

    Evidence Cardiac Cre-loxP Arnt deletion, ChIP at Ppara promoter, double-KO epistasis rescue

    PMID:25329697

    Open questions at the time
    • Which ARNT partner (HIF-2α or other) mediates Ppara regulation not fully dissected
  19. 2016 High

    Crystal structures of NPAS1–ARNT and NPAS3–ARNT–DNA complexes revealed four putative ligand-binding pockets per heterodimer, establishing that the bHLH-PAS family uses multi-ligand architecture.

    Evidence X-ray crystallography of multi-domain complexes

    PMID:27782878

    Open questions at the time
    • Endogenous ligands for ARNT PAS-B pocket not identified
    • Functional significance of all four pockets not tested
  20. 2018 High

    Discovery that FKBP12/YY1 represses ARNT transcription and that FK506 derepresses ARNT to drive homodimer-dependent ALK3 induction and BMP signaling revealed a pharmacologically targetable pathway through which ARNT protects against kidney fibrosis.

    Evidence Morpholino knockdown, FK506 treatment, ChIP, reporter assays, and chronic kidney disease mouse models

    PMID:29664738

    Open questions at the time
    • Whether ARNT homodimer–ALK3 axis operates outside kidney not tested
    • Direct ARNT binding to ALK3 promoter element not mapped at base-pair resolution
  21. 2022 High

    Crystal structures of NPAS4–ARNT complexes revealed uniquely interconnected domain conformations with ARNT PAS-A contacting both PAS-A and PAS-B of NPAS4, extending the known repertoire of ARNT dimerization modes beyond those seen in AhR and HIF complexes.

    Evidence X-ray crystallography, biochemical and cell-based assays

    PMID:36343253

    Open questions at the time
    • Physiological significance of distinct ARNT–NPAS4 conformation not established in vivo
  22. 2025 High

    Crystal structures of AhR–ARNT–DNA complexes with six different ligands revealed a conserved activation mechanism: a segment of AhR transitions from hsp90 engagement to ARNT PAS-B stabilization upon ligand binding, generating the transcriptionally competent assembly through intimate PAS-B–PAS-B association.

    Evidence X-ray crystallography of full AhR–ARNT–DNA complexes with six ligands

    PMID:39900897

    Open questions at the time
    • Dynamics of hsp90-to-ARNT transition not captured in crystal structures
    • Whether all ligand classes induce identical conformational endpoints not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether ARNT PAS-B binds an endogenous ligand, how ARNT pools are partitioned among competing partners in vivo, and whether coactivator selectivity at ARNT PAS-B dictates genome-wide target gene specificity.
  • No endogenous ARNT PAS-B ligand identified
  • Quantitative in vivo measurement of ARNT partner competition lacking
  • Genome-wide mapping of coactivator-specific ARNT target genes not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-74160 Gene expression (Transcription) 9 R-HSA-8953897 Cellular responses to stimuli 5 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
AHRAHRREPAS1HIF1ANPAS1NPAS3NPAS4TACC3
Complex memberships
AhR-ARNTAhRR-ARNTHIF-1 (HIF-1α–ARNT)NPAS4-ARNT

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 ARNT (Arnt) functions as a ligand-dependent coregulator of the dioxin receptor: Arnt physically interacts in solution with the ligand-activated dioxin receptor (via the bHLH motif of Arnt) but fails to heterodimerize with the ligand-free, hsp90-associated receptor form, and Arnt is required to reconstitute DNA binding activity of the AhR at dioxin response elements in vitro. In vitro reconstitution of DNA binding, coimmunoprecipitation, cytosolic complementation assay with mutant dioxin-resistant cell line Molecular and cellular biology High 8384309
1994 Functional domain mapping of ARNT showed that: (1) both helix 1 and helix 2 of the bHLH region are required for dimerization with AhR; (2) the basic region is required for XRE DNA binding but not dimerization; (3) deletion of the complete PAS region severely impairs dimerization; (4) PAS-A and PAS-B each contribute additional functions beyond dimerization that are required for biological activity. Deletion mutagenesis, in vivo complementation of ARNT-deficient c4 cell line, DNA binding assays Molecular and cellular biology High 8065341
1995 ARNT forms a homodimer with itself as well as heterodimers with AhR, Drosophila Per, and Sim via cooperative PAS and HLH domains; the ARNT homodimer binds the E-box core sequence CACGTG of the adenovirus major late promoter and activates transcription from this element. Coimmunoprecipitation, gel-shift DNA binding assay, cotransfection reporter assay (CAT) Proceedings of the National Academy of Sciences of the United States of America High 7892203
1997 Upon dimerization with Arnt, HIF-1alpha protein acquires a new conformational state (increased resistance to limited proteolysis in vitro); only truncated Arnt forms capable of inducing this allosteric change generate high-affinity DNA-binding HIF-1alpha–Arnt complexes, demonstrating that allosteric change by Arnt recruitment is mechanistically required for HIF-1 activation. Immunoblot, limited proteolysis conformational assay, EMSA with truncated Arnt mutants Proceedings of the National Academy of Sciences of the United States of America High 9159130
1997 CBP/p300 functions as a transcriptional coactivator of ARNT: CBP/p300 interacts with the transactivation domain of ARNT (but not AhR) via the CREB-binding domain, as demonstrated by yeast two-hybrid, mammalian two-hybrid, and GST pull-down assays. Yeast two-hybrid, mammalian two-hybrid, GST pull-down assay Journal of biochemistry High 9399571
1997 ARNT-deficient (Arnt−/−) mice die in utero between E9.5–10.5 due to failure of the embryonic placenta to vascularize and form the labyrinthine spongiotrophoblast, establishing a required in vivo role for ARNT in placental vasculogenesis. Homologous recombination knockout mouse, histological analysis Developmental biology High 9398442
1998 Insulin and IGF-I induce the HIF-1alpha/ARNT transcription complex in multiple cell types, and basal and insulin-induced expression of Glut1, Glut3, aldolase A, phosphoglycerate kinase, and VEGF are reduced in ARNT-deficient cells; reintroduction of ARNT rescues insulin-induced HRE reporter activation. EMSA with HRE, specific antisera neutralization, ARNT-deficient cell rescue experiments, reporter assays The EMBO journal High 9724644
1999 Ligand (dioxin) has multiple mechanistic roles in AhR activation beyond nuclear import: it drives Arnt dimerization in the nucleus and maintains a structural conformation in the DR–Arnt complex required for transcriptional activation; geldanamycin-mediated release of hsp90 from the nuclear AhR generates a DR–Arnt complex competent for DNA binding but not transcription, and limited proteolysis reveals different DR–Arnt conformations for dioxin- versus geldanamycin-transformed receptors. Constitutively nuclear DR cell line, proteasome inhibitor experiments, geldanamycin treatment, limited proteolysis conformational assay, reporter assays Molecular and cellular biology High 10409767
1999 Arnt−/− embryoid bodies fail to exhibit hypoxia-mediated proliferation of multilineage hematopoietic progenitors; Arnt−/− embryos have decreased yolk sac hematopoietic progenitors in a cell-extrinsic manner dependent on ARNT-regulated VEGF expression, and exogenous VEGF rescues the defect. Arnt knockout embryoid bodies and embryos, VEGF rescue, hematopoietic progenitor colony assays Genes & development High 10521392
1999 The dioxin receptor undergoes proteasomal degradation specifically upon nuclear entry; nuclear localization initiates rapid destruction (half-life ≤1 h) dependent on ubiquitination (blocked by UbK48R mutant ubiquitin and proteasome inhibitor MG132), and a nuclear kinase (triggered by phosphorylation detected with calyculin) is required to initiate receptor proteolysis, with ARNT association occurring concomitantly. Constitutively nuclear DR cell line, ubiquitin mutant co-expression, MG132 proteasome inhibition, phosphatase inhibitor calyculin, immunoprecipitation for ubiquitin The Journal of biological chemistry High 10593927
1999 A fibroblast-specific factor associates with Arnt and forms a complex capable of binding the dioxin response element, functioning as a repressor of dioxin-induced target gene expression; repression is abolished by HDAC inhibitor trichostatin A, implicating histone deacetylase activity in this cell-type-specific Arnt-associated repression. EMSA showing Arnt-repressor complex on DRE, TSA HDAC inhibition, Arnt-GAL4 fusion transactivation assay The Journal of biological chemistry Medium 10224119
2000 AINT (ARNT Interacting protein) interacts with the PAS domain of ARNT in yeast two-hybrid and in vitro pull-down assays; AINT localizes to the cytoplasm and its overexpression causes non-nuclear localization of ARNT, indicating AINT can sequester ARNT outside the nucleus. Yeast two-hybrid, in vitro interaction assay, subcellular localization by overexpression imaging Mechanisms of development Medium 11025203
2003 ARNT functions as a potent coactivator of ERalpha- and ERbeta-dependent transcription through direct physical interaction; the coactivating effect requires the C-terminal domain of ARNT (not the bHLH/PAS motifs), depends on E2-activated ligand binding domain of ER, and ARNT is recruited to a natural ER target gene promoter in an estrogen-dependent manner. Cotransfection reporter assays, GST pull-down and co-IP for physical interaction, chromatin immunoprecipitation (ChIP) Proceedings of the National Academy of Sciences of the United States of America High 12754377
2003 PAS-A domains are required for formation of stable, high-affinity DNA-binding complexes by DR/Arnt (Kd ~0.4 nM) and HIF-1alpha/Arnt (~50 nM) heterodimers; PAS domains of Arnt have little effect on Arnt homodimer DNA binding (Kd ~45 nM). PAS domain identity is critical: substitution of DR PAS-A with Arnt PAS-A destabilizes the complex and impairs DNA binding. In vitro reconstitution with bacterially expressed proteins, quantitative EMSA with Kd determination, PAS domain chimeras The Journal of biological chemistry High 14638687
2004 The AHR-Arnt heterodimer functions as a transcriptional coactivator through an indirect mechanism at the CYP1A2 enhancer that lacks a canonical XRE: bacterially expressed AhR-Arnt heterodimer does not directly bind the enhancer but interacts with an enhancer-specific factor, and a dominant-negative AhR mutant (unable to bind XRE) activates the enhancer, establishing a novel non-XRE induction pathway. Deletion and mutational analysis of enhancer, EMSA with bacterially expressed proteins, dominant-negative AhR, complementation with ARNT/AhR-deficient cell lines Biochemical and biophysical research communications Medium 15144902
2005 Conditional Arnt deletion completely suppresses VHL-associated liver hemangiomas and polycythemia in a mouse model, demonstrating that ARNT (and HIF signaling through ARNT) is genetically required for VHL-associated vascular tumor development; Hif-1alpha deletion alone did not suppress tumors, revealing functional redundancy among HIF-alpha subunits that converges on ARNT. Cre-loxP conditional Arnt and Hif-1alpha knockout in VHL mouse model, histology, gene expression analysis Molecular and cellular biology High 15798202
2005 The ARNT PAS-B domain structure (solved by NMR) reveals that it uses a solvent-exposed beta-sheet surface for both heterodimerization with HIF-2alpha PAS-B and homodimerization, as confirmed by HADDOCK docking using NMR restraints and site-directed spin labeling for long-range distance validation. NMR structure determination, HADDOCK computational docking with experimental NMR restraints, site-directed spin labeling Journal of molecular biology High 16181639
2005 AhR hypomorphs and Arnt hypomorphs both develop a patent ductus venosus; gestational dioxin exposure (as early as E12.5) rescues ductus venosus closure in both AHR and ARNT hypomorphic mice, demonstrating that AhR–ARNT heterodimerization and receptor activation are required for normal hepatic vascular development. Hypomorphic allele generation, gestational dioxin rescue, vascular anatomy assessment Proceedings of the National Academy of Sciences of the United States of America High 15545609
2008 The AhR PASA domain undergoes a ligand-dependent conformational change (increased PASA exposure) during transformation; the PASA-PASB fragment of AhR reproduces key transformation steps including Arnt dimerization; Hsp90 binding to PASB exerts an inhibitory effect on transformation, and ligand initiates Arnt dimerization and Hsp90 displacement in PASA/B domains. AhR PASA-PASB truncation variants, PASB modification analysis, in vitro transformation assays, Hsp90 interaction analysis The Journal of biological chemistry Medium 18806268
2009 ARNT PAS-B domain recruits the coactivators TRIP230 and CoCoA via a single interface on the opposite side from the HIF-2alpha PAS-B interaction face; the TRIP230-ARNT interaction involves an LXXLL-like nuclear receptor box motif in TRIP230, and mutations at this interface impair transcriptional responses. NMR spectroscopy mapping of binding interface, biochemical pull-down assays, site-directed mutagenesis of LXXLL motif, cotransfection reporter assays The Journal of biological chemistry High 19324882
2011 ARNT PAS-B domain recruits the coactivator TACC3, and this interaction is necessary for transcriptional responses to hypoxia; NMR spectroscopy shows ARNT PAS-B simultaneously mediates interaction with HIF-alpha and TACC3; ARNT PAS-B mutations modulate coactivator selectivity and target gene induction in vivo. NMR spectroscopy, biochemical pull-down, site-directed mutagenesis, reporter gene assays in cells Proceedings of the National Academy of Sciences of the United States of America High 21512126
2011 NF-κB directly regulates HIF-1β (ARNT) mRNA and protein levels; NF-κB-mediated changes in HIF-1β modulate HIF-2alpha protein, and HIF-1β overexpression rescues HIF-2alpha after NF-κB depletion; this regulatory axis is evolutionarily conserved in Drosophila (NF-κB regulates tango/HIF-1β). siRNA knockdown of NF-κB subunits, NF-κB overexpression, HIF-1β rescue experiments, Drosophila genetic experiments PLoS genetics High 21298084
2011 Residues in the N-terminal PAS (PASA) domain of Arnt required for heterodimerization with AhR were identified (22 amino acids); Arnt E163 and S190 are selective for the AhR/Arnt interaction; Arnt D217 affects dimerization with both AhR and HIF-1alpha but not SIM1/2 or NPAS4; Arnt uses the same PASA domain face for homo- and heterodimerization, and the equivalent region of AhR PASA is used reciprocally. Bacterial two-hybrid selection for loss of interaction, site-directed mutagenesis of identified residues Nucleic acids research High 21245039
2011 Fat-specific deletion of Hif1β/Arnt in mice results in lean phenotype with reduced adipocyte size, reduced Vegf and vascular permeability, and impaired glucose uptake due to decreased Glut1 and Glut4; Hif1β knockdown in 3T3-L1 adipocytes reduces cellular respiration and mitochondrial gene expression under hypoxia, demonstrating ARNT is required for adipose glucose uptake and hypoxic metabolic responses. Conditional Arnt knockout in fat (Cre-loxP), 3T3-L1 Hif1β siRNA knockdown, glucose uptake assays, metabolic cage measurements Cell metabolism High 21982709
2012 ARNT controls expression of amphiregulin (AREG) and the downstream EGFR-ERK signaling pathway in keratinocytes; ARNT deficiency decreases AREG, reduces EGFR and ERK1/2 phosphorylation, and increases HDAC1/2/3 protein levels; TSA (HDAC inhibitor) abolishes the effects of ARNT deficiency, implicating HDAC regulation in the ARNT-AREG-EGFR pathway. Lentiviral ARNT knockdown and overexpression, Western blot, 3D epidermal equivalents, HDAC activity assays Journal of cell science Medium 22505606
2014 Cardiac-specific deletion of Arnt in adult mice causes cardiomyopathy with lipid droplet accumulation and 2-fold increase in fatty acid oxidation; ARNT directly regulates Ppara expression by binding to its promoter and forming a complex with HIF2alpha; double knockout of Arnt and Ppara completely reverses the cardiomyopathy phenotype, establishing PPARalpha as the mediator of ARNT-loss effects in heart. Cardiac-specific Cre-loxP Arnt deletion, ex vivo heart metabolic analysis, ChIP for ARNT binding to Ppara promoter, Arnt/Ppara double knockout rescue The Journal of clinical investigation High 25329697
2015 ARNT knockdown in cancer cells promotes migration and invasion via activation of the fibronectin/integrin β1/FAK signaling axis; restoration of ARNT expression in knockdown cells blocks the enhanced migration/invasion, demonstrating a mechanistic link between ARNT loss and FAK pathway activation. siRNA knockdown, ARNT re-expression rescue, migration/invasion assays, Western blot for FAK phosphorylation, xenograft models Oncotarget Medium 25839165
2016 Crystal structures of NPAS1-ARNT and NPAS3-ARNT-DNA complexes reveal four putative ligand-binding pockets per heterodimer; the bHLH-PAS family uses multi-ligand binding architecture, with ARNT contributing structurally to the heterodimeric complex architecture. X-ray crystallography of multi-domain complexes eLife High 27782878
2016 A HIF-1alpha-driven feed-forward loop upregulates ARNT expression in hypoxic Hep3B cells: forced HIF-1alpha expression increases ARNT mRNA and protein under normoxia, and forced ARNT overexpression increases HIF reporter activity, suggesting ARNT can be a limiting factor for HIF signaling in certain tumor cells. Gene silencing (siRNA), overexpression, qRT-PCR, Western blot, HIF reporter assays Cell death & disease Medium 27362802
2017 Crystal structure of the AhRR-ARNT heterodimer reveals that AhRR competitively represses AhR binding to ARNT and to target DNA; the PAS-B of ARNT in the AhRR-ARNT complex adopts a different domain arrangement compared to AhR-ARNT, providing structural basis for AhRR-mediated transcriptional repression. X-ray crystallography The Journal of biological chemistry High 28904176
2018 ARNT expression is controlled by the FKBP12/YY1 transcriptional repressor complex; disruption of FKBP12/YY1 complexes by picomolar FK506 increases ARNT expression; increased ARNT then drives homodimeric ARNT-induced ALK3 transcription, activating antifibrotic BMP-signaling to protect against chronic kidney injury. Morpholino knockdown of FKBP12/YY1, FK506 and GPI-1046 pharmacological treatment, ChIP and reporter assays, chronic kidney disease mouse models The Journal of clinical investigation High 29664738
2022 Crystal structures of NPAS4-ARNT and NPAS4-ARNT2-DNA complexes reveal uniquely interconnected domain conformation of NPAS4; ARNT and ARNT2 PAS-A domains exhibit variable conformations within these heterodimers; the ARNT PAS-A forms interfaces with both PAS-A and PAS-B of NPAS4 that are distinct from previously characterized ARNT heterodimers, extending the known repertoire of ARNT dimerization modes. X-ray crystallography, biochemical interaction assays, cell-based reporter assays Proceedings of the National Academy of Sciences of the United States of America High 36343253
2025 Crystal structures of AHR-ARNT-DNA complexes bound with six different ligands (Tapinarof, FICZ, BaP, BNF, Indigo, Indirubin) reveal intimate association between PAS-B domains of AHR and ARNT; eight conserved residues in AHR PAS-B account for broad ligand binding via hydrophobic and π-π interactions; a segment of AHR undergoes a structural transition from chaperone (hsp90) engagement to ARNT heterodimer stabilization upon ligand binding, generating the transcriptionally competent assembly. X-ray crystallography of full AHR-ARNT-DNA complexes with six ligands Nature communications High 39900897
2001 SHP (short heterodimer partner) orphan nuclear receptor directly interacts with ARNT (but not AhR) in GST pull-down assays and inhibits AHR/ARNT DNA binding in vitro and TCDD-stimulated reporter activity from CYP1A1 and UGT1A6 promoters in cells, identifying ARNT as a novel SHP regulatory target. GST pull-down assay, EMSA, cotransfection reporter assays Archives of biochemistry and biophysics Medium 11368516
2006 Endothelial cell-specific Arnt deletion in mice causes impaired hepatic vasculature, liver necrosis, and degenerative cardiac lesions leading to ~90% neonatal lethality, with downregulation of glucose transporter-1 and glucose-6-phosphatase mRNA; adult survivors show portal fibrosis and altered lipid metabolism, demonstrating a required role for endothelial ARNT in embryonic liver vascular development. Cre-loxP endothelial-specific Arnt conditional knockout, MRI, gene expression analysis, metabolic measurements Hepatology (Baltimore, Md.) High 16941684
2006 Blocking zfARNT1 (but not zfARNT2) expression in zebrafish larvae via morpholino oligonucleotides protects against TCDD-induced cardiac toxicity including altered heart morphology, reduced cardiac myocyte number, decreased cardiac output, and ventricular standstill, demonstrating that the TCDD-induced cardiac effects are specifically mediated by the AHR2/ARNT1 pathway. Morpholino knockdown of specific AHR/ARNT isoforms, cardiac morphology and function assessment Toxicological sciences : an official journal of the Society of Toxicology High 16936225
2003 Cyclin-dependent kinase inhibitor p27(Kip1) is transcriptionally upregulated by hypoxia via an ARNT-dependent pathway; ARNT-deficient c4 cells fail to upregulate p27(Kip1) under hypoxia and instead show reduced p27(Kip1), while stable re-introduction of ARNT rescues hypoxia-induced p27(Kip1) mRNA upregulation. Comparison of ARNT-proficient and ARNT-deficient cell lines, stable ARNT re-expression, RT-PCR and Western blot of p27(Kip1) Journal of cellular biochemistry Medium 14523989

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. The EMBO journal 471 9724644
2005 Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proceedings of the National Academy of Sciences of the United States of America 431 16093318
1997 Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proceedings of the National Academy of Sciences of the United States of America 333 9159130
1997 ARNT-deficient mice and placental differentiation. Developmental biology 254 9398442
1994 Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT). Molecular and cellular biology 229 8065341
2017 Aryl hydrocarbon receptor (AHR): "pioneer member" of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of "sensors" of foreign and endogenous signals. Progress in lipid research 222 28606467
1993 Ligand-dependent recruitment of the Arnt coregulator determines DNA recognition by the dioxin receptor. Molecular and cellular biology 197 8384309
1995 Possible function of Ah receptor nuclear translocator (Arnt) homodimer in transcriptional regulation. Proceedings of the National Academy of Sciences of the United States of America 163 7892203
1997 CBP/p300 functions as a possible transcriptional coactivator of Ah receptor nuclear translocator (Arnt). Journal of biochemistry 157 9399571
1999 Multilineage embryonic hematopoiesis requires hypoxic ARNT activity. Genes & development 145 10521392
2011 Evolutionary conserved regulation of HIF-1β by NF-κB. PLoS genetics 133 21298084
1999 Identification and functional characterization of two highly divergent aryl hydrocarbon receptors (AHR1 and AHR2) in the teleost Fundulus heteroclitus. Evidence for a novel subfamily of ligand-binding basic helix loop helix-Per-ARNT-Sim (bHLH-PAS) factors. The Journal of biological chemistry 130 10559277
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2005 Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization. Journal of molecular biology 119 16181639
2003 The basic helix-loop-helix-PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription. Proceedings of the National Academy of Sciences of the United States of America 112 12754377
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2012 High-resolution genome-wide mapping of AHR and ARNT binding sites by ChIP-Seq. Toxicological sciences : an official journal of the Society of Toxicology 107 22903824
1999 Degradation of the basic helix-loop-helix/Per-ARNT-Sim homology domain dioxin receptor via the ubiquitin/proteasome pathway. The Journal of biological chemistry 103 10593927
2006 Blocking expression of AHR2 and ARNT1 in zebrafish larvae protects against cardiac toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicological sciences : an official journal of the Society of Toxicology 97 16936225
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2004 Gestational exposure of Ahr and Arnt hypomorphs to dioxin rescues vascular development. Proceedings of the National Academy of Sciences of the United States of America 88 15545609
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2004 A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor-Arnt heterodimer. Biochemical and biophysical research communications 80 15144902
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2003 Contribution of the Per/Arnt/Sim (PAS) domains to DNA binding by the basic helix-loop-helix PAS transcriptional regulators. The Journal of biological chemistry 68 14638687
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2014 Resveratrol inhibition of human keratinocyte proliferation via SIRT1/ARNT/ERK dependent downregulation of aquaporin 3. Journal of dermatological science 64 24726500
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2000 Isolation and characterization of AINT: a novel ARNT interacting protein expressed during murine embryonic development. Mechanisms of development 61 11025203
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2011 Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B. Proceedings of the National Academy of Sciences of the United States of America 56 21512126
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2022 Melatonin Prevents against Ethanol-Induced Liver Injury by Mitigating Ferroptosis via Targeting Brain and Muscle ARNT-like 1 in Mice Liver and HepG2 Cells. Journal of agricultural and food chemistry 45 36166594
1999 Functional diversity of vertebrate ARNT proteins: identification of ARNT2 as the predominant form of ARNT in the marine teleost, Fundulus heteroclitus. Archives of biochemistry and biophysics 45 9882441
2008 Glucose and endoplasmic reticulum calcium channels regulate HIF-1beta via presenilin in pancreatic beta-cells. The Journal of biological chemistry 44 18174159
2012 ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways. Journal of cell science 43 22505606
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2006 Disruption of the Arnt gene in endothelial cells causes hepatic vascular defects and partial embryonic lethality in mice. Hepatology (Baltimore, Md.) 40 16941684
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2019 Transcription Factors AhR/ARNT Regulate the Expression of CYP6CY3 and CYP6CY4 Switch Conferring Nicotine Adaptation. International journal of molecular sciences 25 31547315
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2019 Berberine stimulates fibroblast growth factor 21 by modulating the molecular clock component brain and muscle Arnt-like 1 in brown adipose tissue. Biochemical pharmacology 23 30991048
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2015 Heat Shock Protein 90 Associates with the Per-Arnt-Sim Domain of Heme-free Soluble Guanylate Cyclase: IMplications for Enzyme Maturation. The Journal of biological chemistry 23 26134567
2003 Cyclin dependent kinase inhibitor p27(Kip1) is upregulated by hypoxia via an ARNT dependent pathway. Journal of cellular biochemistry 23 14523989
2002 The aryl hydrocarbon receptor (AhR) and its nuclear translocator (Arnt) are dispensable for normal mammary gland development but are required for fertility. Genesis (New York, N.Y. : 2000) 23 11892012
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2021 Functional characterization of the transcription factors AhR and ARNT in Nilaparvata lugens. Pesticide biochemistry and physiology 21 34119220
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2006 Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation. Oncogene 21 16547490
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2018 Pharmacological induction of hypoxia-inducible transcription factor ARNT attenuates chronic kidney failure. The Journal of clinical investigation 18 29664738
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2014 Coactivator recruitment of AhR/ARNT1. International journal of molecular sciences 18 24950180
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2004 Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT). American journal of medical genetics. Part A 18 15368494
2003 Identification of novel splice variants of ARNT and ARNT2 in the rat. Biochemical and biophysical research communications 18 12684048