id: P27540 gene_symbol: ARNT product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ARNT encodes aryl hydrocarbon receptor nuclear translocator, also known as HIF-1 beta, a broadly expressed nuclear bHLH-PAS transcription factor subunit. ARNT dimerizes with AHR, HIF-alpha proteins, and other bHLH-PAS partners through PAS-domain interfaces, and the resulting complexes bind cis-regulatory DNA elements such as xenobiotic/dioxin response elements and hypoxia response elements to regulate RNA polymerase II transcription. Through these heterodimeric complexes, ARNT participates in xenobiotic response, hypoxia adaptation, angiogenic and metabolic gene regulation, and selected immune and developmental transcriptional programs. The primary molecular roles are sequence-specific regulatory DNA binding and partner-specific transcription factor dimerization in the nucleus. alternative_products: - name: 1 (Long) id: P27540-1 - name: 2 (Short) id: P27540-2 sequence_note: VSP_002092 - name: '3' id: P27540-3 sequence_note: VSP_036532, VSP_036533 - name: '4' id: P27540-4 sequence_note: VSP_055030 existing_annotations: - term: id: GO:0006357 label: regulation of transcription by RNA polymerase II evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: >- regulation of transcription by RNA polymerase II is supported by ARNT-containing AHR and HIF transcriptional regulatory complexes. action: ACCEPT reason: >- ARNT-containing heterodimers activate and regulate RNA polymerase II target genes in hypoxia and xenobiotic-response pathways. This is a central biological role of the protein. supported_by: - &id003 reference_id: PMID:7539918 supporting_text: >- HIF-1 beta is a series of ARNT gene products, which can thus heterodimerize with either HIF-1 alpha or AHR. - &id004 reference_id: PMID:8756616 supporting_text: >- VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. - &id005 reference_id: PMID:30429208 supporting_text: >- In contrast, HIF‐β is constitutively expressed 11. In hypoxia, HIF‐α polypeptides escape destruction and are able to associate with HIF‐β to drive transcriptional responses 4. - &id001 reference_id: PMID:1317062 supporting_text: >- The ligand-bound receptor activates Cyp 1a1 gene transcription through interaction with specific DNA sequences, termed xenobiotic responsive elements (XREs). - &id002 reference_id: PMID:28396409 supporting_text: >- We determined the crystal structure of the mammalian AHR-ARNT heterodimer in complex with the DRE. - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: >- nucleus is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0034751 label: aryl hydrocarbon receptor complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: >- aryl hydrocarbon receptor complex is directly supported for ARNT-containing AHR complexes. action: ACCEPT reason: >- ARNT is the required nuclear translocator/dimerization partner of AHR and is a structural component of the DNA-binding AHR complex. supported_by: &id010 - *id001 - *id002 - &id015 reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors including hypoxia-inducible factors (HIF)18, single-minded proteins (SIM)19 or the estrogen receptor (ER)20. - term: id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: >- RNA polymerase II cis-regulatory region sequence-specific DNA binding is consistent with ARNT-containing AHR and HIF transcription factor complexes binding regulatory DNA. action: ACCEPT reason: >- ARNT is a bHLH-PAS transcription factor subunit. Primary AHR and HIF studies show ARNT-containing heterodimers binding DRE/XRE or HRE-like regulatory DNA and activating transcription. supported_by: - &id006 reference_id: PMID:1317062 supporting_text: >- Arnt is now shown to be a structural component of the XRE binding form of the Ah receptor. - &id007 reference_id: PMID:7539918 supporting_text: >- HIF-1 beta is a series of ARNT gene products, which can thus heterodimerize with either HIF-1 alpha or AHR. - &id008 reference_id: PMID:28396409 supporting_text: >- The AHR forms a transcriptionally active heterodimer with ARNT (AHR nuclear translocator), which recognizes the dioxin response element (DRE) in the promoter of downstream genes. - *id003 - term: id: GO:0001666 label: response to hypoxia evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: >- response to hypoxia is supported through ARNT/HIF transcriptional response to low oxygen. action: ACCEPT reason: >- ARNT is HIF-1 beta, the constitutive dimerization partner for HIF-alpha proteins. Loss of ARNT/HIF-1 beta disrupts hypoxia-inducible VEGF expression, and HIF-alpha:ARNT complexes drive hypoxia transcriptional programs. supported_by: &id014 - *id003 - *id004 - *id005 - term: id: GO:0003700 label: DNA-binding transcription factor activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: >- The broad DNA-binding transcription factor annotation is directionally correct but should be represented by RNA polymerase II-specific DNA-binding transcription factor terms. action: MODIFY reason: >- ARNT is not a generic transcription factor; its curated role is as a bHLH-PAS subunit of RNA polymerase II regulatory complexes that bind defined cis-regulatory DNA elements. A more specific Pol II DNA-binding transcription factor term is preferable. proposed_replacement_terms: &id017 - id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding - id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific supported_by: &id009 - *id006 - *id007 - *id008 - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: >- nucleus is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0005667 label: transcription regulator complex evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: part_of review: summary: >- Transcription regulator complex is true but too broad. action: MODIFY reason: >- ARNT is part of RNA polymerase II transcription regulatory complexes, including AHR-ARNT and HIF-alpha:ARNT complexes. The Pol II-specific complex term is more informative. proposed_replacement_terms: - id: GO:0090575 label: RNA polymerase II transcription regulator complex supported_by: *id009 - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: >- Cytoplasm is not supported as a stable ARNT localization in the reviewed evidence. action: REMOVE reason: >- ARNT is principally nuclear and functions in nuclear transcription factor complexes. Cytoplasmic AHR trafficking should not be transferred to ARNT as a cytoplasmic localization without direct evidence. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: >- The annotation is directionally correct but too broad. action: MODIFY reason: >- ARNT regulates RNA polymerase II transcription as part of AHR/HIF-family complexes, so the Pol II-specific transcription regulation term already present in GOA is preferable. proposed_replacement_terms: - id: GO:0006357 label: regulation of transcription by RNA polymerase II supported_by: *id009 - term: id: GO:0030522 label: intracellular receptor signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000108 qualifier: involved_in review: summary: >- Intracellular receptor signaling pathway is plausible but broad for ARNT. action: KEEP_AS_NON_CORE reason: >- ARNT contributes to ligand-activated AHR signaling, but ARNT itself is not the ligand-binding receptor. More specific AHR complex, AHR binding, and transcription regulation annotations better capture the function. supported_by: *id010 - term: id: GO:0046983 label: protein dimerization activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- Generic protein dimerization is supported but should be replaced by the more informative heterodimerization activity. action: MODIFY reason: >- ARNT primarily functions by heterodimerizing with AHR, HIF1A/EPAS1, and other bHLH-PAS partners. The broad dimerization term loses the biologically important partner-specific heterodimer context. proposed_replacement_terms: &id011 - id: GO:0046982 label: protein heterodimerization activity supported_by: - &id012 reference_id: PMID:16181639 supporting_text: >- ARNT is a promiscuous bHLH-PAS (Per-ARNT-Sim) protein that forms heterodimeric transcriptional regulator complexes with several other bHLH-PAS subunits. - &id013 reference_id: PMID:16181639 supporting_text: >- we have solved the solution structure of the corresponding PAS domain of ARNT and show that it utilizes a very similar interface for the interaction with the HIF-2alpha PAS domain. - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:10395741 qualifier: enables review: summary: >- The generic protein binding annotation is not informative as a gene-function statement. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction may be experimentally detected, but protein binding alone does not describe ARNT molecular function and several cited records come from large-scale or pathway-context interaction studies. ARNT function is better captured by specific transcription factor dimerization, AHR binding, DNA binding, and transcription regulatory complex terms. supported_by: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:11018023 qualifier: enables review: summary: >- The interaction evidence is real, but the GO term protein binding is uninformative for ARNT. action: MODIFY reason: >- For ARNT, these interaction papers support bHLH-PAS transcription factor heterodimerization or AHR binding rather than a generic protein-binding molecular function. Replace with an informative dimerization or AHR-binding term where appropriate. proposed_replacement_terms: *id011 supported_by: - *id012 - *id013 - *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14668441 qualifier: enables review: summary: >- The interaction evidence is real, but the GO term protein binding is uninformative for ARNT. action: MODIFY reason: >- For ARNT, these interaction papers support bHLH-PAS transcription factor heterodimerization or AHR binding rather than a generic protein-binding molecular function. Replace with an informative dimerization or AHR-binding term where appropriate. proposed_replacement_terms: *id011 supported_by: - *id012 - *id013 - *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19129502 qualifier: enables review: summary: >- The interaction evidence is real, but the GO term protein binding is uninformative for ARNT. action: MODIFY reason: >- For ARNT, these interaction papers support bHLH-PAS transcription factor heterodimerization or AHR binding rather than a generic protein-binding molecular function. Replace with an informative dimerization or AHR-binding term where appropriate. proposed_replacement_terms: *id011 supported_by: - *id012 - *id013 - *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20562859 qualifier: enables review: summary: >- The generic protein binding annotation is not informative as a gene-function statement. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction may be experimentally detected, but protein binding alone does not describe ARNT molecular function and several cited records come from large-scale or pathway-context interaction studies. ARNT function is better captured by specific transcription factor dimerization, AHR binding, DNA binding, and transcription regulatory complex terms. supported_by: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20603618 qualifier: enables review: summary: >- The generic protein binding annotation is not informative as a gene-function statement. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction may be experimentally detected, but protein binding alone does not describe ARNT molecular function and several cited records come from large-scale or pathway-context interaction studies. ARNT function is better captured by specific transcription factor dimerization, AHR binding, DNA binding, and transcription regulatory complex terms. supported_by: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20932347 qualifier: enables review: summary: >- The generic protein binding annotation is not informative as a gene-function statement. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction may be experimentally detected, but protein binding alone does not describe ARNT molecular function and several cited records come from large-scale or pathway-context interaction studies. ARNT function is better captured by specific transcription factor dimerization, AHR binding, DNA binding, and transcription regulatory complex terms. supported_by: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21620138 qualifier: enables review: summary: >- The generic protein binding annotation is not informative as a gene-function statement. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction may be experimentally detected, but protein binding alone does not describe ARNT molecular function and several cited records come from large-scale or pathway-context interaction studies. ARNT function is better captured by specific transcription factor dimerization, AHR binding, DNA binding, and transcription regulatory complex terms. supported_by: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23434853 qualifier: enables review: summary: >- The interaction evidence is real, but the GO term protein binding is uninformative for ARNT. action: MODIFY reason: >- For ARNT, these interaction papers support bHLH-PAS transcription factor heterodimerization or AHR binding rather than a generic protein-binding molecular function. Replace with an informative dimerization or AHR-binding term where appropriate. proposed_replacement_terms: *id011 supported_by: - *id012 - *id013 - *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24434214 qualifier: enables review: summary: >- The generic protein binding annotation is not informative as a gene-function statement. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction may be experimentally detected, but protein binding alone does not describe ARNT molecular function and several cited records come from large-scale or pathway-context interaction studies. ARNT function is better captured by specific transcription factor dimerization, AHR binding, DNA binding, and transcription regulatory complex terms. supported_by: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24981860 qualifier: enables review: summary: >- The generic protein binding annotation is not informative as a gene-function statement. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction may be experimentally detected, but protein binding alone does not describe ARNT molecular function and several cited records come from large-scale or pathway-context interaction studies. ARNT function is better captured by specific transcription factor dimerization, AHR binding, DNA binding, and transcription regulatory complex terms. supported_by: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: >- The generic protein binding annotation is not informative as a gene-function statement. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction may be experimentally detected, but protein binding alone does not describe ARNT molecular function and several cited records come from large-scale or pathway-context interaction studies. ARNT function is better captured by specific transcription factor dimerization, AHR binding, DNA binding, and transcription regulatory complex terms. supported_by: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: >- The generic protein binding annotation is not informative as a gene-function statement. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction may be experimentally detected, but protein binding alone does not describe ARNT molecular function and several cited records come from large-scale or pathway-context interaction studies. ARNT function is better captured by specific transcription factor dimerization, AHR binding, DNA binding, and transcription regulatory complex terms. supported_by: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:9704006 qualifier: enables review: summary: >- The interaction evidence is real, but the GO term protein binding is uninformative for ARNT. action: MODIFY reason: >- For ARNT, these interaction papers support bHLH-PAS transcription factor heterodimerization or AHR binding rather than a generic protein-binding molecular function. Replace with an informative dimerization or AHR-binding term where appropriate. proposed_replacement_terms: *id011 supported_by: - *id012 - *id013 - *id006 - term: id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: >- RNA polymerase II cis-regulatory region sequence-specific DNA binding is consistent with ARNT-containing AHR and HIF transcription factor complexes binding regulatory DNA. action: ACCEPT reason: >- ARNT is a bHLH-PAS transcription factor subunit. Primary AHR and HIF studies show ARNT-containing heterodimers binding DRE/XRE or HRE-like regulatory DNA and activating transcription. supported_by: - *id006 - *id007 - *id008 - *id003 - term: id: GO:0004879 label: nuclear receptor activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: contributes_to review: summary: >- Nuclear receptor activity is not an ideal term for ARNT. action: MODIFY reason: >- ARNT does not itself bind ligand as a receptor. The evidence supports ARNT contribution to AHR-containing transcription factor complexes, so AHR binding and RNA polymerase II DNA-binding transcription factor activity are better replacements. proposed_replacement_terms: - id: GO:0017162 label: aryl hydrocarbon receptor binding - id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific supported_by: *id010 - term: id: GO:0033235 label: positive regulation of protein sumoylation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- Positive regulation of protein sumoylation is not supported as a core ARNT function in this review. action: MARK_AS_OVER_ANNOTATED reason: >- ARNT can be present in HIF/AHR regulatory contexts where partner proteins are post-translationally modified, but the reviewed primary ARNT function is transcription-factor dimerization and DNA binding. This electronic transfer should not be promoted in the PN review without direct ARNT-specific evidence. supported_by: - &id016 reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- Required for activity of the AHR. Upon ligand binding, AHR translocates into the nucleus, where it heterodimerizes with ARNT and induces transcription by binding to xenobiotic response elements (XRE). - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- The heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters and functions as a transcriptional regulator of the adaptive response to hypoxia. - *id006 - *id007 - *id008 - term: id: GO:0043565 label: sequence-specific DNA binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: >- sequence-specific DNA binding is true but less specific than the supported Pol II cis-regulatory DNA-binding role. action: MODIFY reason: >- The primary evidence concerns ARNT-containing AHR/HIF transcription factor complexes binding DRE/XRE or HRE cis-regulatory elements. The annotation should use the Pol II cis-regulatory DNA-binding term rather than a generic sequence-specific DNA-binding term. proposed_replacement_terms: - id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding supported_by: *id009 - term: id: GO:0046982 label: protein heterodimerization activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: >- ARNT heterodimerization is a core molecular function. action: ACCEPT reason: >- Multiple structural and functional studies show ARNT forming heterodimers with AHR and HIF-alpha proteins through bHLH-PAS/PAS-B interfaces; these heterodimers are the active transcriptional regulatory complexes. supported_by: - *id012 - *id013 - *id001 - *id002 - term: id: GO:1990837 label: sequence-specific double-stranded DNA binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: >- sequence-specific double-stranded DNA binding is consistent with ARNT-containing AHR and HIF transcription factor complexes binding regulatory DNA. action: ACCEPT reason: >- ARNT is a bHLH-PAS transcription factor subunit. Primary AHR and HIF studies show ARNT-containing heterodimers binding DRE/XRE or HRE-like regulatory DNA and activating transcription. supported_by: - *id006 - *id007 - *id008 - *id003 - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:10085255 qualifier: located_in review: summary: >- nucleus is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0006357 label: regulation of transcription by RNA polymerase II evidence_type: NAS original_reference_id: PMID:23033253 qualifier: involved_in review: summary: >- regulation of transcription by RNA polymerase II is supported by ARNT-containing AHR and HIF transcriptional regulatory complexes. action: ACCEPT reason: >- ARNT-containing heterodimers activate and regulate RNA polymerase II target genes in hypoxia and xenobiotic-response pathways. This is a central biological role of the protein. supported_by: - *id003 - *id004 - *id005 - *id001 - *id002 - term: id: GO:0090575 label: RNA polymerase II transcription regulator complex evidence_type: IPI original_reference_id: PMID:23033253 qualifier: part_of review: summary: >- ARNT is part of RNA polymerase II transcription regulator complexes. action: ACCEPT reason: >- HIF and AHR transcription complexes contain ARNT and regulate Pol II target genes through HRE/DRE regulatory elements. supported_by: - *id006 - *id007 - *id008 - *id003 - term: id: GO:0006357 label: regulation of transcription by RNA polymerase II evidence_type: NAS original_reference_id: PMID:23434853 qualifier: involved_in review: summary: >- regulation of transcription by RNA polymerase II is supported by ARNT-containing AHR and HIF transcriptional regulatory complexes. action: ACCEPT reason: >- ARNT-containing heterodimers activate and regulate RNA polymerase II target genes in hypoxia and xenobiotic-response pathways. This is a central biological role of the protein. supported_by: - *id003 - *id004 - *id005 - *id001 - *id002 - term: id: GO:0071456 label: cellular response to hypoxia evidence_type: NAS original_reference_id: PMID:30429208 qualifier: involved_in review: summary: >- cellular response to hypoxia is supported through ARNT/HIF transcriptional response to low oxygen. action: ACCEPT reason: >- ARNT is HIF-1 beta, the constitutive dimerization partner for HIF-alpha proteins. Loss of ARNT/HIF-1 beta disrupts hypoxia-inducible VEGF expression, and HIF-alpha:ARNT complexes drive hypoxia transcriptional programs. supported_by: *id014 - term: id: GO:0090575 label: RNA polymerase II transcription regulator complex evidence_type: IPI original_reference_id: PMID:23434853 qualifier: part_of review: summary: >- ARNT is part of RNA polymerase II transcription regulator complexes. action: ACCEPT reason: >- HIF and AHR transcription complexes contain ARNT and regulate Pol II target genes through HRE/DRE regulatory elements. supported_by: - *id006 - *id007 - *id008 - *id003 - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: >- nucleoplasm is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0006805 label: xenobiotic metabolic process evidence_type: TAS original_reference_id: Reactome:R-HSA-8937144 qualifier: involved_in review: summary: >- Xenobiotic metabolic process is supported through the AHR-ARNT transcriptional response. action: ACCEPT reason: >- ARNT is required for ligand-activated AHR transcriptional complexes that bind xenobiotic response elements and induce detoxification/metabolic genes. This is a core AHR-ARNT biological role. supported_by: - *id001 - *id002 - *id015 - *id016 - term: id: GO:0016604 label: nuclear body evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: >- Nuclear body localization is HPA-supported but peripheral to ARNT function. action: KEEP_AS_NON_CORE reason: >- The localization may describe an observed nuclear subcompartment signal, but ARNT core function is in transcription factor complexes and regulatory DNA binding rather than nuclear-body biology. supported_by: - reference_id: GO_REF:0000052 supporting_text: >- [HPA immunofluorescence-derived GO cellular-component annotation] - term: id: GO:0001228 label: DNA-binding transcription activator activity, RNA polymerase II-specific evidence_type: TAS original_reference_id: Reactome:R-HSA-8937177 qualifier: enables review: summary: >- DNA-binding transcription activator activity, RNA polymerase II-specific captures the transcription-factor activity of ARNT-containing RNA polymerase II regulatory complexes. action: ACCEPT reason: >- The activity is best interpreted as the activity of ARNT-containing heterodimers. ARNT contributes DNA-binding and PAS-dimerization surfaces to AHR/HIF complexes that regulate Pol II target genes. supported_by: - *id006 - *id007 - *id008 - *id012 - term: id: GO:0045821 label: positive regulation of glycolytic process evidence_type: IDA original_reference_id: PMID:8089148 qualifier: acts_upstream_of review: summary: >- Positive regulation of glycolysis is a supported downstream HIF pathway output, but not ARNT molecular core function. action: KEEP_AS_NON_CORE reason: >- The cited study shows HIF-1-mediated induction of glycolytic enzyme genes under hypoxia. Because ARNT is HIF-1 beta, this is biologically plausible, but it is a downstream transcriptional program rather than a direct proteostasis or adaptor role. supported_by: - reference_id: PMID:8089148 supporting_text: >- RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 - reference_id: PMID:8089148 supporting_text: >- These results support the role of HIF-1 as a mediator of adaptive responses to hypoxia - term: id: GO:0034599 label: cellular response to oxidative stress evidence_type: IDA original_reference_id: PMID:8089148 qualifier: involved_in review: summary: >- Cellular response to oxidative stress is too indirect for the cited ARNT/HIF glycolysis paper. action: MARK_AS_OVER_ANNOTATED reason: >- PMID:8089148 supports HIF-dependent hypoxia-responsive glycolytic gene transcription, not a direct ARNT role in oxidative-stress response. Hypoxia-response annotations already capture the supported biology. supported_by: - reference_id: PMID:8089148 supporting_text: >- These results support the role of HIF-1 as a mediator of adaptive responses to hypoxia - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IDA original_reference_id: PMID:8089148 qualifier: involved_in review: summary: >- positive regulation of transcription by RNA polymerase II is supported by ARNT-containing AHR and HIF transcriptional regulatory complexes. action: ACCEPT reason: >- ARNT-containing heterodimers activate and regulate RNA polymerase II target genes in hypoxia and xenobiotic-response pathways. This is a central biological role of the protein. supported_by: - *id003 - *id004 - *id005 - *id001 - *id002 - term: id: GO:0050728 label: negative regulation of inflammatory response evidence_type: IDA original_reference_id: PMID:29454749 qualifier: involved_in review: summary: >- Negative regulation of inflammatory response is plausible through AHR-ARNT epithelial signaling, but it is not a core ARNT molecular function. action: KEEP_AS_NON_CORE reason: >- The cited study supports microbiota-derived indole metabolites activating AHR-dependent IL-10 receptor regulation and anti-inflammatory pathways. ARNT is the AHR transcriptional partner, but the anti-inflammatory phenotype is pathway-level and context-specific. supported_by: - reference_id: PMID:29454749 supporting_text: >- Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor. - reference_id: PMID:29454749 supporting_text: >- This work defines a novel role of indole metabolites in anti-inflammatory pathways mediated by epithelial IL-10 signaling - term: id: GO:0004879 label: nuclear receptor activity evidence_type: IDA original_reference_id: PMID:34521881 qualifier: contributes_to review: summary: >- Nuclear receptor activity is not an ideal term for ARNT. action: MODIFY reason: >- ARNT does not itself bind ligand as a receptor. The evidence supports ARNT contribution to AHR-containing transcription factor complexes, so AHR binding and RNA polymerase II DNA-binding transcription factor activity are better replacements. proposed_replacement_terms: - id: GO:0017162 label: aryl hydrocarbon receptor binding - id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific supported_by: *id010 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:34521881 qualifier: enables review: summary: >- The interaction evidence is real, but the GO term protein binding is uninformative for ARNT. action: MODIFY reason: >- For ARNT, these interaction papers support bHLH-PAS transcription factor heterodimerization or AHR binding rather than a generic protein-binding molecular function. Replace with an informative dimerization or AHR-binding term where appropriate. proposed_replacement_terms: &id018 - id: GO:0017162 label: aryl hydrocarbon receptor binding - id: GO:0046982 label: protein heterodimerization activity supported_by: - *id012 - *id013 - *id006 - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:34521881 qualifier: located_in review: summary: >- nucleus is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0034753 label: nuclear aryl hydrocarbon receptor complex evidence_type: IDA original_reference_id: PMID:34521881 qualifier: is_active_in review: summary: >- nuclear aryl hydrocarbon receptor complex is directly supported for ARNT-containing AHR complexes. action: ACCEPT reason: >- ARNT is the required nuclear translocator/dimerization partner of AHR and is a structural component of the DNA-binding AHR complex. supported_by: *id010 - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IDA original_reference_id: PMID:34521881 qualifier: involved_in review: summary: >- positive regulation of transcription by RNA polymerase II is supported by ARNT-containing AHR and HIF transcriptional regulatory complexes. action: ACCEPT reason: >- ARNT-containing heterodimers activate and regulate RNA polymerase II target genes in hypoxia and xenobiotic-response pathways. This is a central biological role of the protein. supported_by: - *id003 - *id004 - *id005 - *id001 - *id002 - term: id: GO:0046982 label: protein heterodimerization activity evidence_type: IDA original_reference_id: PMID:34521881 qualifier: enables review: summary: >- ARNT heterodimerization is a core molecular function. action: ACCEPT reason: >- Multiple structural and functional studies show ARNT forming heterodimers with AHR and HIF-alpha proteins through bHLH-PAS/PAS-B interfaces; these heterodimers are the active transcriptional regulatory complexes. supported_by: - *id012 - *id013 - *id001 - *id002 - term: id: GO:1990837 label: sequence-specific double-stranded DNA binding evidence_type: IDA original_reference_id: PMID:34521881 qualifier: enables review: summary: >- sequence-specific double-stranded DNA binding is consistent with ARNT-containing AHR and HIF transcription factor complexes binding regulatory DNA. action: ACCEPT reason: >- ARNT is a bHLH-PAS transcription factor subunit. Primary AHR and HIF studies show ARNT-containing heterodimers binding DRE/XRE or HRE-like regulatory DNA and activating transcription. supported_by: - *id006 - *id007 - *id008 - *id003 - term: id: GO:0003700 label: DNA-binding transcription factor activity evidence_type: IDA original_reference_id: PMID:29454749 qualifier: enables review: summary: >- The broad DNA-binding transcription factor annotation is directionally correct but should be represented by RNA polymerase II-specific DNA-binding transcription factor terms. action: MODIFY reason: >- ARNT is not a generic transcription factor; its curated role is as a bHLH-PAS subunit of RNA polymerase II regulatory complexes that bind defined cis-regulatory DNA elements. A more specific Pol II DNA-binding transcription factor term is preferable. proposed_replacement_terms: *id017 supported_by: *id009 - term: id: GO:0005634 label: nucleus evidence_type: IC original_reference_id: PMID:28602820 qualifier: is_active_in review: summary: >- nucleus is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-1234167 qualifier: located_in review: summary: >- nucleoplasm is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-1234171 qualifier: located_in review: summary: >- nucleoplasm is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8936851 qualifier: located_in review: summary: >- nucleoplasm is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8937177 qualifier: located_in review: summary: >- nucleoplasm is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-9634850 qualifier: located_in review: summary: >- nucleoplasm is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0061629 label: RNA polymerase II-specific DNA-binding transcription factor binding evidence_type: IPI original_reference_id: PMID:7539918 qualifier: enables review: summary: >- RNA polymerase II-specific DNA-binding transcription factor binding is a supported molecular interaction function for ARNT. action: ACCEPT reason: >- ARNT is the common dimerization partner for AHR/HIF-family DNA-binding transcription factors. Specific transcription-factor binding and AHR-binding terms are more informative than generic protein binding. supported_by: - *id001 - *id002 - *id015 - *id012 - term: id: GO:0061629 label: RNA polymerase II-specific DNA-binding transcription factor binding evidence_type: IPI original_reference_id: PMID:9079689 qualifier: enables review: summary: >- RNA polymerase II-specific DNA-binding transcription factor binding is a supported molecular interaction function for ARNT. action: ACCEPT reason: >- ARNT is the common dimerization partner for AHR/HIF-family DNA-binding transcription factors. Specific transcription-factor binding and AHR-binding terms are more informative than generic protein binding. supported_by: - *id001 - *id002 - *id015 - *id012 - term: id: GO:0061629 label: RNA polymerase II-specific DNA-binding transcription factor binding evidence_type: IPI original_reference_id: PMID:10692439 qualifier: enables review: summary: >- RNA polymerase II-specific DNA-binding transcription factor binding is a supported molecular interaction function for ARNT. action: ACCEPT reason: >- ARNT is the common dimerization partner for AHR/HIF-family DNA-binding transcription factors. Specific transcription-factor binding and AHR-binding terms are more informative than generic protein binding. supported_by: - *id001 - *id002 - *id015 - *id012 - term: id: GO:0000987 label: cis-regulatory region sequence-specific DNA binding evidence_type: IDA original_reference_id: PMID:23275542 qualifier: enables review: summary: >- cis-regulatory region sequence-specific DNA binding is true but less specific than the supported Pol II cis-regulatory DNA-binding role. action: MODIFY reason: >- The primary evidence concerns ARNT-containing AHR/HIF transcription factor complexes binding DRE/XRE or HRE cis-regulatory elements. The annotation should use the Pol II cis-regulatory DNA-binding term rather than a generic sequence-specific DNA-binding term. proposed_replacement_terms: - id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding supported_by: *id009 - term: id: GO:0043565 label: sequence-specific DNA binding evidence_type: IDA original_reference_id: PMID:7539918 qualifier: enables review: summary: >- sequence-specific DNA binding is true but less specific than the supported Pol II cis-regulatory DNA-binding role. action: MODIFY reason: >- The primary evidence concerns ARNT-containing AHR/HIF transcription factor complexes binding DRE/XRE or HRE cis-regulatory elements. The annotation should use the Pol II cis-regulatory DNA-binding term rather than a generic sequence-specific DNA-binding term. proposed_replacement_terms: - id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding supported_by: *id009 - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IDA original_reference_id: PMID:7539918 qualifier: involved_in review: summary: >- positive regulation of transcription by RNA polymerase II is supported by ARNT-containing AHR and HIF transcriptional regulatory complexes. action: ACCEPT reason: >- ARNT-containing heterodimers activate and regulate RNA polymerase II target genes in hypoxia and xenobiotic-response pathways. This is a central biological role of the protein. supported_by: - *id003 - *id004 - *id005 - *id001 - *id002 - term: id: GO:0000785 label: chromatin evidence_type: ISA original_reference_id: GO_REF:0000113 qualifier: located_in review: summary: >- Chromatin localization is consistent with ARNT as a DNA-binding transcription factor subunit. action: ACCEPT reason: >- AHR-ARNT and HIF-alpha:ARNT complexes bind regulatory DNA in chromatin to regulate Pol II transcription. supported_by: - reference_id: PMID:30429208 supporting_text: >- both HIF‐α isoforms bind chromatin in a stoichiometric ratio with HIF‐1β - reference_id: PMID:28396409 supporting_text: >- mammalian AHR-ARNT heterodimer in complex with the DRE - term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence_type: ISA original_reference_id: GO_REF:0000113 qualifier: enables review: summary: >- DNA-binding transcription factor activity, RNA polymerase II-specific captures the transcription-factor activity of ARNT-containing RNA polymerase II regulatory complexes. action: ACCEPT reason: >- The activity is best interpreted as the activity of ARNT-containing heterodimers. ARNT contributes DNA-binding and PAS-dimerization surfaces to AHR/HIF complexes that regulate Pol II target genes. supported_by: - *id006 - *id007 - *id008 - *id012 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16181639 qualifier: enables review: summary: >- The interaction evidence is real, but the GO term protein binding is uninformative for ARNT. action: MODIFY reason: >- For ARNT, these interaction papers support bHLH-PAS transcription factor heterodimerization or AHR binding rather than a generic protein-binding molecular function. Replace with an informative dimerization or AHR-binding term where appropriate. proposed_replacement_terms: *id011 supported_by: - *id012 - *id013 - *id006 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28396409 qualifier: enables review: summary: >- The interaction evidence is real, but the GO term protein binding is uninformative for ARNT. action: MODIFY reason: >- For ARNT, these interaction papers support bHLH-PAS transcription factor heterodimerization or AHR binding rather than a generic protein-binding molecular function. Replace with an informative dimerization or AHR-binding term where appropriate. proposed_replacement_terms: *id018 supported_by: - *id012 - *id013 - *id006 - term: id: GO:0042803 label: protein homodimerization activity evidence_type: IDA original_reference_id: PMID:16181639 qualifier: enables review: summary: >- ARNT PAS-B homodimerization is experimentally observed but is not the main physiological ARNT function. action: KEEP_AS_NON_CORE reason: >- The cited structural study reports concentration-dependent self-association of the ARNT PAS-B domain, but the established cellular functions are heterodimeric AHR/HIF-family transcription complexes. supported_by: - reference_id: PMID:16181639 supporting_text: >- this domain self-associates in a concentration-dependent manner - reference_id: PMID:16181639 supporting_text: >- the interface used in this homodimeric complex is very similar to that used in the formation of heterodimer - term: id: GO:0046982 label: protein heterodimerization activity evidence_type: IDA original_reference_id: PMID:16181639 qualifier: enables review: summary: >- ARNT heterodimerization is a core molecular function. action: ACCEPT reason: >- Multiple structural and functional studies show ARNT forming heterodimers with AHR and HIF-alpha proteins through bHLH-PAS/PAS-B interfaces; these heterodimers are the active transcriptional regulatory complexes. supported_by: - *id012 - *id013 - *id001 - *id002 - term: id: GO:1990837 label: sequence-specific double-stranded DNA binding evidence_type: IDA original_reference_id: PMID:28396409 qualifier: enables review: summary: >- sequence-specific double-stranded DNA binding is consistent with ARNT-containing AHR and HIF transcription factor complexes binding regulatory DNA. action: ACCEPT reason: >- ARNT is a bHLH-PAS transcription factor subunit. Primary AHR and HIF studies show ARNT-containing heterodimers binding DRE/XRE or HRE-like regulatory DNA and activating transcription. supported_by: - *id006 - *id007 - *id008 - *id003 - term: id: GO:0090575 label: RNA polymerase II transcription regulator complex evidence_type: IDA original_reference_id: PMID:7539918 qualifier: part_of review: summary: >- ARNT is part of RNA polymerase II transcription regulator complexes. action: ACCEPT reason: >- HIF and AHR transcription complexes contain ARNT and regulate Pol II target genes through HRE/DRE regulatory elements. supported_by: - *id006 - *id007 - *id008 - *id003 - term: id: GO:0090575 label: RNA polymerase II transcription regulator complex evidence_type: IDA original_reference_id: PMID:8756616 qualifier: part_of review: summary: >- ARNT is part of RNA polymerase II transcription regulator complexes. action: ACCEPT reason: >- HIF and AHR transcription complexes contain ARNT and regulate Pol II target genes through HRE/DRE regulatory elements. supported_by: - *id006 - *id007 - *id008 - *id003 - term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence_type: IDA original_reference_id: PMID:7539918 qualifier: contributes_to review: summary: >- DNA-binding transcription factor activity, RNA polymerase II-specific captures the transcription-factor activity of ARNT-containing RNA polymerase II regulatory complexes. action: ACCEPT reason: >- The activity is best interpreted as the activity of ARNT-containing heterodimers. ARNT contributes DNA-binding and PAS-dimerization surfaces to AHR/HIF complexes that regulate Pol II target genes. supported_by: - *id006 - *id007 - *id008 - *id012 - term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence_type: IDA original_reference_id: PMID:8756616 qualifier: contributes_to review: summary: >- DNA-binding transcription factor activity, RNA polymerase II-specific captures the transcription-factor activity of ARNT-containing RNA polymerase II regulatory complexes. action: ACCEPT reason: >- The activity is best interpreted as the activity of ARNT-containing heterodimers. ARNT contributes DNA-binding and PAS-dimerization surfaces to AHR/HIF complexes that regulate Pol II target genes. supported_by: - *id006 - *id007 - *id008 - *id012 - term: id: GO:0001666 label: response to hypoxia evidence_type: IDA original_reference_id: PMID:8756616 qualifier: involved_in review: summary: >- response to hypoxia is supported through ARNT/HIF transcriptional response to low oxygen. action: ACCEPT reason: >- ARNT is HIF-1 beta, the constitutive dimerization partner for HIF-alpha proteins. Loss of ARNT/HIF-1 beta disrupts hypoxia-inducible VEGF expression, and HIF-alpha:ARNT complexes drive hypoxia transcriptional programs. supported_by: *id014 - term: id: GO:0001938 label: positive regulation of endothelial cell proliferation evidence_type: IC original_reference_id: PMID:8756616 qualifier: involved_in review: summary: >- Endothelial proliferation is downstream of VEGF induction and too indirect for ARNT. action: MARK_AS_OVER_ANNOTATED reason: >- PMID:8756616 supports HIF-1-dependent VEGF transcription and loss of hypoxic VEGF induction in ARNT-deficient cells. Endothelial proliferation is a downstream biological consequence, not a direct ARNT gene-product function. supported_by: - reference_id: PMID:8756616 supporting_text: >- These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells. - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:8089148 qualifier: located_in review: summary: >- nucleus is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors - term: id: GO:0010575 label: positive regulation of vascular endothelial growth factor production evidence_type: IDA original_reference_id: PMID:8756616 qualifier: involved_in review: summary: >- Positive regulation of VEGF production is supported as a downstream HIF-1 transcriptional output. action: KEEP_AS_NON_CORE reason: >- ARNT/HIF-1 beta is required for hypoxia-induced VEGF expression, but this is a pathway output rather than ARNT molecular core function. supported_by: - reference_id: PMID:8756616 supporting_text: >- VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. - reference_id: PMID:8756616 supporting_text: >- These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells. - term: id: GO:0017162 label: aryl hydrocarbon receptor binding evidence_type: IPI original_reference_id: PMID:9079689 qualifier: enables review: summary: >- aryl hydrocarbon receptor binding is a supported molecular interaction function for ARNT. action: ACCEPT reason: >- ARNT is the common dimerization partner for AHR/HIF-family DNA-binding transcription factors. Specific transcription-factor binding and AHR-binding terms are more informative than generic protein binding. supported_by: - *id001 - *id002 - *id015 - *id012 - term: id: GO:0030949 label: positive regulation of vascular endothelial growth factor receptor signaling pathway evidence_type: IC original_reference_id: PMID:8756616 qualifier: involved_in review: summary: >- VEGF receptor signaling is a downstream inference from VEGF production and should not be asserted for ARNT. action: MARK_AS_OVER_ANNOTATED reason: >- The experimental evidence supports ARNT/HIF-dependent VEGF transcription, not direct positive regulation of VEGF receptor signaling by ARNT. supported_by: - reference_id: PMID:8756616 supporting_text: >- These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells. - term: id: GO:0045648 label: positive regulation of erythrocyte differentiation evidence_type: IC original_reference_id: PMID:1448077 qualifier: involved_in review: summary: >- positive regulation of erythrocyte differentiation is an indirect downstream annotation from early hypoxia/EPO enhancer work. action: MARK_AS_OVER_ANNOTATED reason: >- PMID:1448077 identifies a hypoxia-inducible enhancer-binding factor for erythropoietin regulation but does not specifically establish ARNT as directly regulating erythrocyte differentiation or hormone biosynthesis. Modern ARNT annotations should emphasize HIF/AHR transcription-factor activity and hypoxia response. supported_by: - reference_id: PMID:1448077 supporting_text: >- We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia - reference_id: PMID:1448077 supporting_text: >- Factor binding was induced by hypoxia - term: id: GO:0046886 label: positive regulation of hormone biosynthetic process evidence_type: IDA original_reference_id: PMID:1448077 qualifier: involved_in review: summary: >- positive regulation of hormone biosynthetic process is an indirect downstream annotation from early hypoxia/EPO enhancer work. action: MARK_AS_OVER_ANNOTATED reason: >- PMID:1448077 identifies a hypoxia-inducible enhancer-binding factor for erythropoietin regulation but does not specifically establish ARNT as directly regulating erythrocyte differentiation or hormone biosynthesis. Modern ARNT annotations should emphasize HIF/AHR transcription-factor activity and hypoxia response. supported_by: - reference_id: PMID:1448077 supporting_text: >- We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia - reference_id: PMID:1448077 supporting_text: >- Factor binding was induced by hypoxia - term: id: GO:0046982 label: protein heterodimerization activity evidence_type: IPI original_reference_id: PMID:9079689 qualifier: enables review: summary: >- ARNT heterodimerization is a core molecular function. action: ACCEPT reason: >- Multiple structural and functional studies show ARNT forming heterodimers with AHR and HIF-alpha proteins through bHLH-PAS/PAS-B interfaces; these heterodimers are the active transcriptional regulatory complexes. supported_by: - *id012 - *id013 - *id001 - *id002 - term: id: GO:0003700 label: DNA-binding transcription factor activity evidence_type: TAS original_reference_id: PMID:10777486 qualifier: enables review: summary: >- The broad DNA-binding transcription factor annotation is directionally correct but should be represented by RNA polymerase II-specific DNA-binding transcription factor terms. action: MODIFY reason: >- ARNT is not a generic transcription factor; its curated role is as a bHLH-PAS subunit of RNA polymerase II regulatory complexes that bind defined cis-regulatory DNA elements. A more specific Pol II DNA-binding transcription factor term is preferable. proposed_replacement_terms: *id017 supported_by: *id009 - term: id: GO:0003700 label: DNA-binding transcription factor activity evidence_type: TAS original_reference_id: PMID:1317062 qualifier: enables review: summary: >- The broad DNA-binding transcription factor annotation is directionally correct but should be represented by RNA polymerase II-specific DNA-binding transcription factor terms. action: MODIFY reason: >- ARNT is not a generic transcription factor; its curated role is as a bHLH-PAS subunit of RNA polymerase II regulatory complexes that bind defined cis-regulatory DNA elements. A more specific Pol II DNA-binding transcription factor term is preferable. proposed_replacement_terms: *id017 supported_by: *id009 - term: id: GO:0005634 label: nucleus evidence_type: TAS original_reference_id: PMID:1317062 qualifier: located_in review: summary: >- nucleus is a supported nuclear localization for ARNT. action: ACCEPT reason: >- ARNT functions in nuclear transcription factor complexes and is reported as nuclear by UniProt, primary AHR/HIF studies, Reactome complex events, and HPA-derived nucleoplasm annotations. supported_by: - reference_id: file:human/ARNT/ARNT-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Nucleus - reference_id: PMID:1317062 supporting_text: >- Arnt and the ligand-binding subunit of the receptor were extracted as a complex from the nuclei of cells treated with ligand. - reference_id: PMID:34521881 supporting_text: >- ARNT is a nuclear protein that acts as dimerization partner for several transcription factors references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000108 title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links findings: [] - id: GO_REF:0000113 title: Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass database findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10085255 title: 'Induction and nuclear translocation of hypoxia-inducible factor-1 (HIF-1): heterodimerization with ARNT is not necessary for nuclear accumulation of HIF-1alpha.' findings: [] - id: PMID:10395741 title: Interactions of nuclear receptor coactivator/corepressor proteins with the aryl hydrocarbon receptor complex. findings: [] - id: PMID:10692439 title: Cardiovascular basic helix loop helix factor 1, a novel transcriptional repressor expressed preferentially in the developing and adult cardiovascular system. findings: [] - id: PMID:10777486 title: Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. findings: [] - id: PMID:11018023 title: CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression. findings: [] - id: PMID:1317062 title: Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. findings: [] - id: PMID:1448077 title: A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. findings: [] - id: PMID:14668441 title: Structural basis for PAS domain heterodimerization in the basic helix--loop--helix-PAS transcription factor hypoxia-inducible factor. findings: [] - id: PMID:16181639 title: 'Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization.' findings: [] - id: PMID:19129502 title: Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. findings: [] - id: PMID:20562859 title: Network organization of the human autophagy system. findings: [] - id: PMID:20603618 title: RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma. findings: [] - id: PMID:20932347 title: Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide. findings: [] - id: PMID:21620138 title: Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. findings: [] - id: PMID:23033253 title: Identification of Cys255 in HIF-1α as a novel site for development of covalent inhibitors of HIF-1α/ARNT PasB domain protein-protein interaction. findings: [] - id: PMID:23275542 title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TiPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. findings: [] - id: PMID:23434853 title: Allosteric inhibition of hypoxia inducible factor-2 with small molecules. findings: [] - id: PMID:24434214 title: Cbx4 governs HIF-1α to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity. findings: [] - id: PMID:24981860 title: Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation. findings: [] - id: PMID:28396409 title: Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:28602820 title: Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene Activation. findings: [] - id: PMID:29454749 title: Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor. findings: [] - id: PMID:30429208 title: 'Inherent DNA-binding specificities of the HIF-1α and HIF-2α transcription factors in chromatin.' findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:34521881 title: The role of DNA-binding and ARNT dimerization on the nucleo-cytoplasmic translocation of the aryl hydrocarbon receptor. findings: [] - id: PMID:7539918 title: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. findings: [] - id: PMID:8089148 title: Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. findings: [] - id: PMID:8756616 title: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. findings: [] - id: PMID:9079689 title: Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. findings: [] - id: PMID:9704006 title: Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock. findings: [] - id: Reactome:R-HSA-1234167 title: Formation of HIF:CBP:p300 complex at promoters findings: [] - id: Reactome:R-HSA-1234171 title: HIF-alpha binds ARNT (HIF1-beta) forming HIF-alpha:ARNT findings: [] - id: Reactome:R-HSA-8936851 title: AHRR binds ARNT findings: [] - id: Reactome:R-HSA-8937144 title: Aryl hydrocarbon receptor signalling findings: [] - id: Reactome:R-HSA-8937177 title: AHR:TCDD binds ARNT findings: [] - id: Reactome:R-HSA-9634850 title: NPAS4 binds ARNT findings: [] - id: file:human/ARNT/ARNT-uniprot.txt title: UniProt text export for ARNT (P27540) findings: - statement: UniProt summarizes ARNT as a nuclear bHLH-PAS partner for AHR and HIF-family transcription factor complexes. - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv title: Proteostasis PN projection report row for ARNT findings: - statement: The PN projection suggests GO:1990756 for ARNT from a Cul4A/Cul4B substrate adaptor group, but this review does not accept the propagation for ARNT without direct adaptor evidence. - id: file:projects/PROTEOSTASIS/mappings/ubiquitin_proteasome_system.yaml title: Proteostasis UPS mapping YAML findings: - statement: The specific AHR / ARNT / TBL3 complex type/subtype nodes are curated as no_mapping, indicating that gene-level propagation from those narrower labels requires caution. - id: file:human/ARNT/ARNT-deep-research-falcon.md title: Falcon deep research report for ARNT findings: - statement: Falcon supports ARNT as a heterodimeric transcription-factor scaffold/partner for AHR and HIF-alpha proteins rather than an enzyme, transporter, or proteostasis adaptor. supporting_text: ARNT functions primarily as a **heterodimeric transcription-factor scaffold/partner**, enabling DNA binding and transcriptional activation by AHR and HIF-α proteins rather than acting as an enzyme or transporter. core_functions: - description: >- ARNT contributes to sequence-specific RNA polymerase II transcription factor activity as the nuclear bHLH-PAS beta subunit of HIF-alpha:ARNT and AHR:ARNT complexes. These complexes bind hypoxia response elements and xenobiotic/dioxin response elements in regulatory DNA and control hypoxia-adaptive and xenobiotic-response transcriptional programs. contributes_to_molecular_function: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific directly_involved_in: - id: GO:0006357 label: regulation of transcription by RNA polymerase II - id: GO:0001666 label: response to hypoxia - id: GO:0006805 label: xenobiotic metabolic process locations: - id: GO:0005634 label: nucleus in_complex: id: GO:0090575 label: RNA polymerase II transcription regulator complex supported_by: - *id006 - *id007 - *id008 - *id003 - *id004 - *id001 - *id002 - reference_id: file:human/ARNT/ARNT-deep-research-falcon.md supporting_text: >- ARNT functions primarily as a **heterodimeric transcription-factor scaffold/partner**, enabling DNA binding and transcriptional activation by AHR and HIF-α proteins rather than acting as an enzyme or transporter. - description: >- ARNT provides partner-specific bHLH-PAS/PAS-B dimerization surfaces for AHR, HIF1A, EPAS1, and related bHLH-PAS transcription factors. Heterodimer formation is required for stable DNA-binding transcription complexes and is the central molecular interaction mode for ARNT. molecular_function: id: GO:0046982 label: protein heterodimerization activity directly_involved_in: - id: GO:0006357 label: regulation of transcription by RNA polymerase II locations: - id: GO:0005634 label: nucleus supported_by: - *id012 - *id013 - reference_id: PMID:23033253 supporting_text: >- Biophysical characterization of the interaction between PasB domains of HIF-1α and ARNT revealed that covalent binding of COMPOUND 5 to Cys255 reduced binding affinity between HIF-1α and ARNT PasB domains approximately 10-fold. - description: >- ARNT participates in the AHR transcriptional complex by binding AHR and forming a DRE/XRE-binding heterodimer that regulates xenobiotic-response gene expression. This role is distinct from the PN-projected Cul4A/Cul4B substrate adaptor activity, which is not accepted here for ARNT. molecular_function: id: GO:0017162 label: aryl hydrocarbon receptor binding directly_involved_in: - id: GO:0006805 label: xenobiotic metabolic process - id: GO:0045944 label: positive regulation of transcription by RNA polymerase II locations: - id: GO:0005634 label: nucleus in_complex: id: GO:0034753 label: nuclear aryl hydrocarbon receptor complex supported_by: - *id001 - *id002 - *id015 - reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv supporting_text: >- ARNT ... GO:1990756 ... ubiquitin-like ligase-substrate adaptor activity ... new_to_goa ... Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor|AHR / ARNT / TBL3 complex|PAS - reference_id: file:projects/PROTEOSTASIS/mappings/ubiquitin_proteasome_system.yaml supporting_text: >- Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node. proposed_new_terms: [] suggested_questions: - question: >- Does any primary literature directly show ARNT functioning as a Cul4A/Cul4B ubiquitin-like ligase substrate adaptor, or is the PN workbook row reflecting AHR/ARNT/TBL3 complex context rather than ARNT molecular activity? - question: >- Should generic ARNT protein-binding annotations from large-scale interactome studies be replaced systematically with partner-specific transcription factor binding or heterodimerization terms where the original evidence supports that interpretation? - question: >- For downstream HIF outputs such as VEGF production, glycolytic gene expression, and erythropoietin-related phenotypes, which annotations should remain on ARNT as pathway-level non-core annotations rather than direct core gene-product functions? suggested_experiments: - hypothesis: ARNT does not directly act as a CRL4 substrate adaptor. description: >- Test epitope-tagged ARNT for stable association with DDB1, CUL4A/CUL4B, RBX1, DDA1, and candidate CRL4 substrates under conditions that preserve known AHR/HIF complexes. Compare with positive-control DCAF substrate receptors and require substrate ubiquitination or degradation evidence before assigning GO:1990756. experiment_type: co-immunoprecipitation and ubiquitination assay - hypothesis: ARNT protein-binding annotations can be converted to informative transcription-factor dimerization annotations. description: >- Re-curate ARNT interaction papers by partner class (AHR, HIF1A, EPAS1, NPAS/SIM factors, co-regulators) and validate whether each supports GO:0046982, GO:0061629, or GO:0017162 instead of generic GO:0005515. experiment_type: literature curation audit