Hif1a encodes hypoxia-inducible factor 1-alpha, the oxygen-regulated subunit of the HIF-1 basic helix-loop-helix PAS transcription factor. In normoxia HIF-1alpha is hydroxylated on two prolines in its oxygen-dependent degradation domain by the PHD/EGLN prolyl hydroxylases, bound by the von Hippel-Lindau E3 ubiquitin ligase and degraded by the proteasome, while asparaginyl hydroxylation of its C-terminal transactivation domain by FIH blocks recruitment of the coactivators CBP/p300. When oxygen falls, or when iron chelators, cobalt, carbon monoxide, reactive oxygen species, cytokines or growth-factor signalling intervene, HIF-1alpha accumulates, enters the nucleus and heterodimerises through its bHLH-PAS region with ARNT (and with the neuronal paralogue ARNT2). The heterodimer binds hypoxia response elements containing the core 5'-RCGTG-3' in promoters and enhancers and recruits CBP/p300 to activate RNA polymerase II transcription of genes for erythropoietin, vascular endothelial growth factor, glucose transporters and glycolytic enzymes, among many others; at some promoters HIF-1 instead represses transcription. Through this target programme HIF-1alpha drives cellular and systemic adaptation to hypoxia, including angiogenesis, erythropoiesis, glycolytic metabolism and cell survival, and it is required for normal cardiovascular and placental development. In rat it is expressed in kidney (higher in the medulla than the cortex), perivenous hepatocytes, heart, lung and brain.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:20496369 Hypoxia-inducible factor regulation of ANK expression in nuc... | ACCEPT | Summary: In rat nucleus pulposus cells HIF-1 binds HREs in the ANK promoter and represses it. Reason: Full text (PMID:20496369): HIF-1alpha silencing raises and overexpression suppresses ANK promoter activity through its HREs, so HIF-1 represses this RNA polymerase II gene directly. Repression is a genuine, if less common, mode of the same DNA-binding activity and is carried in core_functions beside the activator role. Supporting Evidence: PMID:20496369 We found that HIF-1 can bind to either of the HREs and can suppress promoter activity PMID:20496369 Both HIF-1 and HIF-2 serve as negative regulators of ANK expression in the disc. |
| GO:0000302 response to reactive oxygen species | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1alpha is stabilised by reactive oxygen species and drives the ROS-triggered transcriptional response. Reason: Human HIF1A IDA (PMID:32697943) transferred by ISO/ISS. Consistent with UniProt activity regulation and rat data that ROS mediate non-hypoxic HIF-1alpha activation (PMID:12101082). Non-core: a non-hypoxic input into the same transcriptional activity. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Induced by reactive oxygen species (ROS). |
| GO:0000302 response to reactive oxygen species | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: HIF-1alpha is stabilised by reactive oxygen species and drives the ROS-triggered transcriptional response. Reason: Human HIF1A IDA (PMID:32697943) transferred by ISO/ISS. Consistent with UniProt activity regulation and rat data that ROS mediate non-hypoxic HIF-1alpha activation (PMID:12101082). Non-core: a non-hypoxic input into the same transcriptional activity. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Induced by reactive oxygen species (ROS). |
| GO:0000785 chromatin | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 binds HREs in chromatin of target genes (ChIP). Reason: Human IDA (ChIP; PMID:19782034) via ISO, consistent with rat ChIP at the frataxin HRE (PMID:26071548). Chromatin is where the DNA-bound factor resides; kept as non-core, the nucleus being the core location. Supporting Evidence: PMID:26071548 Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. |
| GO:0000791 euchromatin | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse IDA (PMID:25587068) places HIF-1alpha in euchromatin, consistent with binding active promoters. Reason: Transferred from a mouse IDA; plausible for an activator bound at transcribed loci. Non-core sub-nuclear location. Supporting Evidence: PMID:26071548 Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | MODIFY | Summary: HIF-1 binds HREs in promoters and enhancers of target genes; the cis-regulatory region term already carried by this gene is more precise. Reason: Correct but general. Rat HIF-1 binds HREs in the proximal TH promoter (PMID:12675925) and frataxin promoter (PMID:26071548); GO:0000978 (an is_a descendant, carried by this gene) captures this. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001889196 SUPPORTS TRANSFER Transfer is sound; HRE binding is in cis-regulatory regions, so a more specific term applies. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter PMID:26071548 Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1 binds HREs in promoters and enhancers of target genes; the cis-regulatory region term already carried by this gene is more precise. Reason: Correct but general. Rat HIF-1 binds HREs in the proximal TH promoter (PMID:12675925) and frataxin promoter (PMID:26071548); GO:0000978 (an is_a descendant, carried by this gene) captures this. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Transfer is sound; HRE binding is in cis-regulatory regions, so a more specific term applies. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter PMID:26071548 Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISO GO_REF:0000121 | ACCEPT | Summary: As the HIF-1alpha/ARNT heterodimer, HIF-1alpha binds the HRE core 5'-RCGTG-3' in promoters and enhancers of RNA polymerase II target genes. Reason: Supported for rat by HRE-dependent promoter activation (PMID:12675925), ChIP (PMID:26071548) and EMSA (PMID:18614764), and by UniProt. DNA binding requires the ARNT partner, each subunit contributing a basic region to one HRE half-site. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter PMID:26071548 Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISO GO_REF:0000121 | ACCEPT | Summary: As the HIF-1alpha/ARNT heterodimer, HIF-1alpha binds the HRE core 5'-RCGTG-3' in promoters and enhancers of RNA polymerase II target genes. Reason: Supported for rat by HRE-dependent promoter activation (PMID:12675925), ChIP (PMID:26071548) and EMSA (PMID:18614764), and by UniProt. DNA binding requires the ARNT partner, each subunit contributing a basic region to one HRE half-site. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter PMID:26071548 Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | MODIFY | Summary: HIF-1alpha is a DNA-binding transcription factor for RNA polymerase II genes; it is predominantly an activator. Reason: Correct but general; the activator child GO:0001228 (carried by this gene) is supported by rat reporter assays (PMID:11237857, PMID:12675925) and UniProt. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001889196 SUPPORTS TRANSFER Function is inherited and correct; activator child term is more informative. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha is a DNA-binding transcription factor for RNA polymerase II genes; it is predominantly an activator. Reason: Correct but general; the activator child GO:0001228 (carried by this gene) is supported by rat reporter assays (PMID:11237857, PMID:12675925) and UniProt. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Function is inherited and correct; activator child term is more informative. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha is a DNA-binding transcription factor for RNA polymerase II genes; it is predominantly an activator. Reason: Correct but general; the activator child GO:0001228 (carried by this gene) is supported by rat reporter assays (PMID:11237857, PMID:12675925) and UniProt. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Function is inherited and correct; activator child term is more informative. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha is a DNA-binding transcription factor for RNA polymerase II genes; it is predominantly an activator. Reason: Correct but general; the activator child GO:0001228 (carried by this gene) is supported by rat reporter assays (PMID:11237857, PMID:12675925) and UniProt. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Function is inherited and correct; activator child term is more informative. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0000987 cis-regulatory region sequence-specific DNA binding | ISO GO_REF:0000121 | MODIFY | Summary: HRE binding by HIF-1 is in RNA polymerase II cis-regulatory regions. Reason: Correct but general; refine to GO:0000978 (descendant, carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct transfer; more specific term available. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter |
| GO:0001216 DNA-binding transcription activator activity | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha is a transcription activator of RNA polymerase II genes. Reason: Correct but general; refine to the RNA polymerase II-specific child GO:0001228 (carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct transfer; RNA polymerase II-specific child applies. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0001217 DNA-binding transcription repressor activity | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1 can repress some target genes through HREs (e.g. ANK in nucleus pulposus cells). Reason: Human IMP (PMID:31368162) transferred by ISO; rat evidence shows HIF-1 binding to ANK promoter HREs suppresses activity (PMID:20496369). The repressed genes are RNA polymerase II transcribed, so the RNA polymerase II-specific child GO:0001227 is the precise term. A secondary, context-dependent activity. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Repression via HREs is also seen in rat (PMID:20496369). Proposed replacements: DNA-binding transcription repressor activity, RNA polymerase II-specific Supporting Evidence: PMID:20496369 We found that HIF-1 can bind to either of the HREs and can suppress promoter activity |
| GO:0001222 transcription corepressor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human HIF1A IPI with HIF1AN/FIH (PMID:19071119) transferred by ISO. Reason: FIH binds and hydroxylates the CTAD and was first described as repressing HIF activity with HDACs; the binding is real but HIF-1alpha is the substrate in this interaction, so it is peripheral to its own function. Supporting Evidence: PMID:21335549 Asparaginyl hydroxylation blocks the recruitment of p300/CBP co-activators to a C-terminal activation domain in HIF-Ξ±. |
| GO:0001223 transcription coactivator binding | ISO GO_REF:0000121 | ACCEPT | Summary: The CTAD/NTAD of HIF-1alpha recruit the coactivators CBP/p300, required for transactivation. Reason: Supported for rat by co-immunoprecipitation of HIF-1 with p300 and Ref-1 on the VEGF HRE (PMID:15084519) and by the FIH mechanism, which blocks p300/CBP recruitment (PMID:21335549). Core part of the activator mechanism. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 PMID:15084519 Co-immunoprecipitation experiments indicated that Ref-1/Ape present in nuclear extract interacted with HIF-1 and p300 but not ATF/CREB. PMID:21335549 Asparaginyl hydroxylation blocks the recruitment of p300/CBP co-activators to a C-terminal activation domain in HIF-Ξ±. |
| GO:0001223 transcription coactivator binding | ISS GO_REF:0000024 | ACCEPT | Summary: The CTAD/NTAD of HIF-1alpha recruit the coactivators CBP/p300, required for transactivation. Reason: Supported for rat by co-immunoprecipitation of HIF-1 with p300 and Ref-1 on the VEGF HRE (PMID:15084519) and by the FIH mechanism, which blocks p300/CBP recruitment (PMID:21335549). Core part of the activator mechanism. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 PMID:15084519 Co-immunoprecipitation experiments indicated that Ref-1/Ape present in nuclear extract interacted with HIF-1 and p300 but not ATF/CREB. PMID:21335549 Asparaginyl hydroxylation blocks the recruitment of p300/CBP co-activators to a C-terminal activation domain in HIF-Ξ±. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISO GO_REF:0000121 | ACCEPT | Summary: Core activity: HIF-1alpha, as part of HIF-1, activates RNA polymerase II transcription of hypoxia-responsive genes through HREs. Reason: Rat HIF-1alpha cDNA activates an HRE reporter (PMID:11237857); rat HIF-1 activates TH (PMID:12675925), frataxin (PMID:26071548) and enolase-1 (PMID:20496369) promoters. Matches UniProt function. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISO GO_REF:0000121 | ACCEPT | Summary: Core activity: HIF-1alpha, as part of HIF-1, activates RNA polymerase II transcription of hypoxia-responsive genes through HREs. Reason: Rat HIF-1alpha cDNA activates an HRE reporter (PMID:11237857); rat HIF-1 activates TH (PMID:12675925), frataxin (PMID:26071548) and enolase-1 (PMID:20496369) promoters. Matches UniProt function. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter |
| GO:0001525 angiogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a mutants have defective vascularisation/angiogenesis. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease |
| GO:0001568 blood vessel development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-null mouse embryos have defective blood vessel development. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease |
| GO:0001666 response to hypoxia | IDA PMID:12388599 Activation of hypoxia-inducible factor-1 in the rat cerebral... | MODIFY | Summary: HIF-1alpha accumulates in rat cerebral cortex after transient global ischemia, with induction of EPO and Glut-1. Reason: Correct but general; the accumulation and target-gene induction reflect the cellular response to hypoxia (GO:0071456, accepted). Note this is accumulation data (closer to IEP than IDA). Proposed replacements: cellular response to hypoxia Supporting Evidence: PMID:12388599 Our results showed that HIF-1alpha accumulates as early as 1 hr of recovery and persists for at least 7 d. |
| GO:0001666 response to hypoxia | IDA PMID:12675925 Regulation of tyrosine hydroxylase promoter activity by the ... | MODIFY | Summary: Rat HIF-1 binds the TH promoter HRE and mediates hypoxic TH induction in PC12 cells. Reason: Correct but general; the cell-level term GO:0071456 (accepted) applies. Proposed replacements: cellular response to hypoxia Supporting Evidence: PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter |
| GO:0001666 response to hypoxia | IEA GO_REF:0000117 | MODIFY | Summary: ARBA prediction of response to hypoxia. Reason: Correct but general; refine to GO:0071456 cellular response to hypoxia (accepted). Proposed replacements: cellular response to hypoxia Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:0001666 response to hypoxia | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha mediates the cellular transcriptional response to hypoxia. Reason: Correct but general; the cellular response to hypoxia (is_a descendant, carried by this gene and accepted) is the level at which HIF-1alpha acts. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Correct; cellular child term applies. Proposed replacements: cellular response to hypoxia Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0001666 response to hypoxia | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha mediates the cellular transcriptional response to hypoxia. Reason: Correct but general; the cellular response to hypoxia (is_a descendant, carried by this gene and accepted) is the level at which HIF-1alpha acts. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct; cellular child term applies. Proposed replacements: cellular response to hypoxia Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0001666 response to hypoxia | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha mediates the cellular transcriptional response to hypoxia. Reason: Correct but general; the cellular response to hypoxia (is_a descendant, carried by this gene and accepted) is the level at which HIF-1alpha acts. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Correct; cellular child term applies. Proposed replacements: cellular response to hypoxia Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0001666 response to hypoxia | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha mediates the cellular transcriptional response to hypoxia. Reason: Correct but general; the cellular response to hypoxia (is_a descendant, carried by this gene and accepted) is the level at which HIF-1alpha acts. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct; cellular child term applies. Proposed replacements: cellular response to hypoxia Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0001666 response to hypoxia | ISS GO_REF:0000024 | MODIFY | Summary: HIF-1alpha mediates the cellular transcriptional response to hypoxia. Reason: Correct but general; the cellular response to hypoxia (is_a descendant, carried by this gene and accepted) is the level at which HIF-1alpha acts. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct; cellular child term applies. Proposed replacements: cellular response to hypoxia Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0001678 intracellular glucose homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 regulates cellular glucose uptake and use through target genes (human IDA, PMID:30125331). Reason: Metabolic consequence of the target programme; non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0001678 intracellular glucose homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: HIF-1 regulates cellular glucose uptake and use through target genes (human IDA, PMID:30125331). Reason: Metabolic consequence of the target programme; non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0001755 neural crest cell migration | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-null mouse embryos show neural crest cell migration defects. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0001837 epithelial to mesenchymal transition | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a mutant (PMID:18037992) reports reduced epithelial to mesenchymal transition. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0001892 embryonic placenta development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a is required for mouse placental development. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0001922 B-1 B cell homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-deficient mouse chimeras show abnormal B-1 B cell homeostasis. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0001944 vasculature development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-null mouse embryos show defective vasculature development. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease |
| GO:0001947 heart looping | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-null mouse embryos show abnormal heart looping. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease |
| GO:0002039 p53 binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1alpha binds p53 (human IPI, PMID:15629713). Reason: Real interaction transferred from human; it mediates p53-dependent HIF-1alpha degradation (cf. rat H9c2 data, PMID:19950214). HIF-1alpha is the regulated partner; peripheral. |
| GO:0002052 positive regulation of neuroblast proliferation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: reduced neuroblast proliferation. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0002248 connective tissue replacement involved in inflammatory response wound healing | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a mutant (PMID:18037992) shows impaired connective tissue replacement during wound healing. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0003151 outflow tract morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-null mouse embryos show outflow tract defects. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0003208 cardiac ventricle morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-null mouse embryos show cardiac ventricle morphogenesis defects. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0003677 DNA binding | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1 binds DNA at HREs in cis-regulatory regions. Reason: Correct but general; refine to GO:0000978 (descendant, carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Correct transfer; more specific term available. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | MODIFY | Summary: HIF-1alpha is a DNA-binding transcription factor; specifically an RNA polymerase II activator. Reason: Correct but general; refine to GO:0001228 (descendant, carried by this gene), supported by rat reporter assays. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0003700 DNA-binding transcription factor activity | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha is a DNA-binding transcription factor; specifically an RNA polymerase II activator. Reason: Correct but general; refine to GO:0001228 (descendant, carried by this gene), supported by rat reporter assays. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Correct transfer; activator child term applies. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0003700 DNA-binding transcription factor activity | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha is a DNA-binding transcription factor; specifically an RNA polymerase II activator. Reason: Correct but general; refine to GO:0001228 (descendant, carried by this gene), supported by rat reporter assays. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct transfer; activator child term applies. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0003700 DNA-binding transcription factor activity | ISS GO_REF:0000024 | MODIFY | Summary: HIF-1alpha is a DNA-binding transcription factor; specifically an RNA polymerase II activator. Reason: Correct but general; refine to GO:0001228 (descendant, carried by this gene), supported by rat reporter assays. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct transfer; activator child term applies. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear transcription factor; PAINT node for the bHLH-PAS clade. Reason: Sound phylogenetic inference consistent with rat nuclear accumulation data (PMID:18614764). Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia PMID:18614764 Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity |
| GO:0005634 nucleus | IDA PMID:18614764 Astrocyte responses to injury: VEGF simultaneously modulates... | ACCEPT | Summary: HIF-1alpha nuclear accumulation in rat astrocytes under near-anoxia. Reason: Direct assay in rat cells (abstract reports DNA-binding activity from stabilised protein); nucleus is the core location. Supporting Evidence: PMID:18614764 Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity |
| GO:0005634 nucleus | IDA PMID:26071548 Cardioprotective HIF-1Ξ±-frataxin signaling against ischemia-... | ACCEPT | Summary: Nuclear HIF-1alpha in rat H9C2 cardiomyocytes binding the frataxin promoter (ChIP). Reason: Direct evidence consistent with its activity; deferred to the curator for the specific assay (abstract only). Supporting Evidence: PMID:26071548 Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: HIF-1alpha accumulates in the nucleus when stabilised, where it acts as a transcription factor. Reason: Nuclear accumulation of HIF-1alpha shown in rat astrocytes, PC12 cells and cardiomyocytes (PMID:18614764, PMID:18248612, PMID:22129453); consistent with UniProt and with the PAINT node for the bHLH-PAS family. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia PMID:18614764 Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity |
| GO:0005634 nucleus | ISO GO_REF:0000121 | ACCEPT | Summary: HIF-1alpha accumulates in the nucleus when stabilised, where it acts as a transcription factor. Reason: Nuclear accumulation of HIF-1alpha shown in rat astrocytes, PC12 cells and cardiomyocytes (PMID:18614764, PMID:18248612, PMID:22129453); consistent with UniProt and with the PAINT node for the bHLH-PAS family. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia PMID:18614764 Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity |
| GO:0005634 nucleus | ISO GO_REF:0000121 | ACCEPT | Summary: HIF-1alpha accumulates in the nucleus when stabilised, where it acts as a transcription factor. Reason: Nuclear accumulation of HIF-1alpha shown in rat astrocytes, PC12 cells and cardiomyocytes (PMID:18614764, PMID:18248612, PMID:22129453); consistent with UniProt and with the PAINT node for the bHLH-PAS family. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia PMID:18614764 Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: HIF-1alpha accumulates in the nucleus when stabilised, where it acts as a transcription factor. Reason: Nuclear accumulation of HIF-1alpha shown in rat astrocytes, PC12 cells and cardiomyocytes (PMID:18614764, PMID:18248612, PMID:22129453); consistent with UniProt and with the PAINT node for the bHLH-PAS family. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia PMID:18614764 Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity |
| GO:0005654 nucleoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Nucleoplasmic transcription factor. Reason: Human IDA transferred; consistent with its activity at nuclear chromatin. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia |
| GO:0005667 transcription regulator complex | IBA GO_REF:0000033 | MODIFY | Summary: HIF-1alpha is part of the HIF-1 (HIF-1alpha/ARNT) transcription factor complex. Reason: Correct but general; GO:0090575 RNA polymerase II transcription regulator complex (is_a descendant, carried by this gene) is precise for HIF-1. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000548864 SUPPORTS TRANSFER PAINT placement sound; more specific complex term available. Proposed replacements: RNA polymerase II transcription regulator complex Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:15084519 Co-immunoprecipitation experiments indicated that Ref-1/Ape present in nuclear extract interacted with HIF-1 and p300 but not ATF/CREB. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: Under normoxia HIF-1alpha is cytoplasmic, where it is hydroxylated and degraded. Reason: Correct but general; the cytosol term (descendant, carried by this gene from human) is the specific compartment of the soluble normoxic pool. Proposed replacements: cytosol Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | MODIFY | Summary: Under normoxia HIF-1alpha is cytoplasmic, where it is hydroxylated and degraded. Reason: Correct but general; the cytosol term (descendant, carried by this gene from human) is the specific compartment of the soluble normoxic pool. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Location transfer sound; cytosol is more specific. Proposed replacements: cytosol Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | MODIFY | Summary: Under normoxia HIF-1alpha is cytoplasmic, where it is hydroxylated and degraded. Reason: Correct but general; the cytosol term (descendant, carried by this gene from human) is the specific compartment of the soluble normoxic pool. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Location transfer sound; cytosol is more specific. Proposed replacements: cytosol Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | MODIFY | Summary: Under normoxia HIF-1alpha is cytoplasmic, where it is hydroxylated and degraded. Reason: Correct but general; the cytosol term (descendant, carried by this gene from human) is the specific compartment of the soluble normoxic pool. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Location transfer sound; cytosol is more specific. Proposed replacements: cytosol Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia |
| GO:0005829 cytosol | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Soluble cytosolic pool of HIF-1alpha in normoxia, subject to PHD hydroxylation and VHL-mediated degradation. Reason: Human IDA transferred; real but not where the protein acts. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia |
| GO:0005829 cytosol | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Soluble cytosolic pool of HIF-1alpha in normoxia, subject to PHD hydroxylation and VHL-mediated degradation. Reason: Human IDA transferred; real but not where the protein acts. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia |
| GO:0006089 lactate metabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a mutants show altered lactate metabolism (HIF-1 induces LDHA and other glycolytic genes). Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0006110 regulation of glycolysis | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1 positively regulates glycolysis by inducing glycolytic enzyme and glucose transporter genes. Reason: The direction is known: HIF-1 increases glycolytic flux. Refine to GO:0045821 positive regulation of glycolytic process (child, carried by this gene). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Correct transfer; positive-regulation child applies. Proposed replacements: positive regulation of glycolytic process Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0006110 regulation of glycolysis | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1 positively regulates glycolysis by inducing glycolytic enzyme and glucose transporter genes. Reason: The direction is known: HIF-1 increases glycolytic flux. Refine to GO:0045821 positive regulation of glycolytic process (child, carried by this gene). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct transfer; positive-regulation child applies. Proposed replacements: positive regulation of glycolytic process Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0006110 regulation of glycolysis | ISS GO_REF:0000024 | MODIFY | Summary: HIF-1 positively regulates glycolysis by inducing glycolytic enzyme and glucose transporter genes. Reason: The direction is known: HIF-1 increases glycolytic flux. Refine to GO:0045821 positive regulation of glycolytic process (child, carried by this gene). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct transfer; positive-regulation child applies. Proposed replacements: positive regulation of glycolytic process Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | MODIFY | Summary: HIF-1alpha regulates RNA polymerase II transcription, mostly positively. Reason: Correct but general; refine to the RNA polymerase II activation term (core) and, for repressed genes, negative regulation (both carried by this gene). Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:20496369 We found that HIF-1 can bind to either of the HREs and can suppress promoter activity |
| GO:0006355 regulation of DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha regulates RNA polymerase II transcription, mostly positively. Reason: Correct but general; refine to the RNA polymerase II activation term (core) and, for repressed genes, negative regulation (both carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Correct transfer; more specific terms available. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:20496369 We found that HIF-1 can bind to either of the HREs and can suppress promoter activity |
| GO:0006355 regulation of DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha regulates RNA polymerase II transcription, mostly positively. Reason: Correct but general; refine to the RNA polymerase II activation term (core) and, for repressed genes, negative regulation (both carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct transfer; more specific terms available. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:20496369 We found that HIF-1 can bind to either of the HREs and can suppress promoter activity |
| GO:0006355 regulation of DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha regulates RNA polymerase II transcription, mostly positively. Reason: Correct but general; refine to the RNA polymerase II activation term (core) and, for repressed genes, negative regulation (both carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct transfer; more specific terms available. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:20496369 We found that HIF-1 can bind to either of the HREs and can suppress promoter activity |
| GO:0006355 regulation of DNA-templated transcription | TAS PMID:12388599 Activation of hypoxia-inducible factor-1 in the rat cerebral... | MODIFY | Summary: TAS statement that HIF-1 regulates transcription of EPO and Glut-1 in rat brain after ischemia. Reason: Correct but general; refine to GO:0045944 (accepted). Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:12388599 Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in mammalian cells. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | MODIFY | Summary: HIF-1alpha regulates RNA polymerase II transcription, mostly positively. Reason: Correct but general; refine to the RNA polymerase II activation term (core) and, for repressed genes, negative regulation (both carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000548738 SUPPORTS TRANSFER Correct transfer; more specific terms available. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:20496369 We found that HIF-1 can bind to either of the HREs and can suppress promoter activity |
| GO:0006357 regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha regulates RNA polymerase II transcription, mostly positively. Reason: Correct but general; refine to the RNA polymerase II activation term (core) and, for repressed genes, negative regulation (both carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Correct transfer; more specific terms available. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:20496369 We found that HIF-1 can bind to either of the HREs and can suppress promoter activity |
| GO:0006879 intracellular iron ion homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a deficiency alters iron homeostasis (HIF-1 targets include transferrin and its receptor). Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0006953 acute-phase response | IEP PMID:19840250 Hepatic changes of erythropoietin gene expression in a rat m... | MARK AS OVER ANNOTATED | Summary: Hif1a mRNA rises in rat liver in a turpentine-oil acute-phase model, in parallel with EPO. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. The study proposes EPO as an acute-phase protein; HIF-1alpha is not shown to perform the acute-phase response. |
| GO:0007165 signal transduction | ISO GO_REF:0000121 | TOO GENERAL | Summary: HIF-1alpha mediates hypoxia signalling. Reason: True but uninformative; GO:0097411 hypoxia-inducible factor-1alpha signaling pathway, accepted in this review, is a descendant. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:0007507 heart development | IEP PMID:9398602 Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic l... | MARK AS OVER ANNOTATED | Summary: Hif1a mRNA increases transiently at birth in rat heart. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. A developmental expression profile does not establish a role in heart development for rat. |
| GO:0007595 lactation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mammary-specific Hif1a deletion in mouse impairs lactation (PMID:12620994). Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0008284 positive regulation of cell population proliferation | IMP PMID:11029639 Two splice variants of the hypoxia-inducible factor HIF-1alp... | KEEP AS NON CORE | Summary: Antisense downregulation of HIF-1alpha in PC12 cells reduced [3H]thymidine incorporation. Reason: Rat IMP (abstract only) consistent with other rat proliferation data; a context-dependent downstream effect. Supporting Evidence: PMID:11029639 downregulation of either HIF-1alpha or ARNT2, obtained with selective antisense nucleotides, resulted in inhibition of [3H]thymidine incorporation |
| GO:0008542 visual learning | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Neural Hif1a deletion in mouse causes hydrocephalus and impaired spatial/visual learning (PMID:12972594). Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0009410 response to xenobiotic stimulus | IEP PMID:14574457 Amifostine induces anaerobic metabolism and hypoxia-inducibl... | MARK AS OVER ANNOTATED | Summary: Amifostine increases HIF-1alpha accumulation in rat tissues. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0009612 response to mechanical stimulus | IEP PMID:21106323 Prolonged mechanical stretch is associated with upregulation... | MARK AS OVER ANNOTATED | Summary: Prolonged stretch of rat inferior vena cava increases HIF-1alpha and HIF-2alpha expression. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0009651 response to salt stress | IEP PMID:20232302 Different protective actions of losartan and tempol on the r... | MARK AS OVER ANNOTATED | Summary: Acute sodium overload increases renal HIF-1alpha immunostaining in rats. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0009749 response to glucose | IEP PMID:12189448 Myocardial infarction in diabetic rats: role of hyperglycaem... | MARK AS OVER ANNOTATED | Summary: Hyperglycaemia/high glucose alters myocardial HIF-1alpha expression in rats. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0010039 response to iron ion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Iron represses HIF-1alpha through Fe(II)-dependent prolyl hydroxylases; iron availability therefore modulates the HIF-1 response. Reason: Human IEP transferred; consistent with UniProt. Non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Repressed by iron ion, via Fe(2+) prolyl hydroxylase (PHD) enzymes-mediated hydroxylation and subsequent proteasomal degradation. |
| GO:0010165 response to X-ray | IEP PMID:15161688 Hypoxia and hypoxia-inducible factor-1 target genes in centr... | MARK AS OVER ANNOTATED | Summary: HIF-1alpha-expressing cells increase in irradiated rat spinal cord. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. The rise follows radiation-induced tissue hypoxia. |
| GO:0010468 regulation of gene expression | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha regulates gene expression as a transcription factor. Reason: Correct but general; refine to the transcriptional terms carried by this gene. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct; more specific terms available. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0010573 vascular endothelial growth factor production | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1 induces VEGF expression; it regulates, rather than performs, VEGF production. Reason: The gene product does not perform VEGF production; it activates VEGF transcription. The positive-regulation term (carried by this gene, IMP in rat) is correct. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Human evidence is for HIF-dependent induction of VEGF, i.e. regulation. Proposed replacements: positive regulation of vascular endothelial growth factor production Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor PMID:30052311 the loss of HIF-1Ξ± resulted in deficient expression levels of VEGF-A, Flk-1, NRP1, and Dll4 in the ischemic brains, bmEPCs, and astrocytes |
| GO:0010575 positive regulation of vascular endothelial growth factor production | IMP PMID:18614764 Astrocyte responses to injury: VEGF simultaneously modulates... | KEEP AS NON CORE | Summary: Hif1a knockdown in rat astrocytes partly reduced VEGF induction after injury. Reason: Rat IMP; the abstract states the effect is only partial. A downstream target-gene effect. Supporting Evidence: PMID:18614764 Hif-1alpha knockdown studies showed that elevated VEGF levels following increased insult was only partially due to HIF-1alpha induction |
| GO:0010575 positive regulation of vascular endothelial growth factor production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 induces VEGF transcription, a classical target. Reason: Supported in rat (PMID:30052311, partially PMID:18614764) and human. A downstream consequence of the core activator activity. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor PMID:30052311 the loss of HIF-1Ξ± resulted in deficient expression levels of VEGF-A, Flk-1, NRP1, and Dll4 in the ischemic brains, bmEPCs, and astrocytes |
| GO:0010575 positive regulation of vascular endothelial growth factor production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: HIF-1 induces VEGF transcription, a classical target. Reason: Supported in rat (PMID:30052311, partially PMID:18614764) and human. A downstream consequence of the core activator activity. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor PMID:30052311 the loss of HIF-1Ξ± resulted in deficient expression levels of VEGF-A, Flk-1, NRP1, and Dll4 in the ischemic brains, bmEPCs, and astrocytes |
| GO:0010595 positive regulation of endothelial cell migration | IMP PMID:30052311 Knockdown of HIF-1Ξ± impairs post-ischemic vascular reconstru... | KEEP AS NON CORE | Summary: HIF-1alpha knockdown impairs homing/migration of bmEPCs to ischemic rat brain via CXCL12/CXCR4 and HMGB1. Reason: Rat IMP (full text); a downstream effect of HIF-1 target genes. Supporting Evidence: PMID:30052311 the loss of HIF-1Ξ± resulted in deficient expression levels of VEGF-A, Flk-1, NRP1, and Dll4 in the ischemic brains, bmEPCs, and astrocytes |
| GO:0010628 positive regulation of gene expression | IMP PMID:19220706 Hypoxic stress-induced changes in adrenergic function: role ... | MODIFY | Summary: HIF1alpha overexpression raises Egr-1, Sp1 and PNMT expression in PC12 cells. Reason: Correct but general; the effect is transcriptional (Egr-1/Sp1 induction drives PNMT), refine to GO:0045944 (accepted). Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:19220706 Hypoxia and HIF1alpha over-expression also elevate PNMT promoter-driven luciferase activity in PC12 cells. |
| GO:0010628 positive regulation of gene expression | ISO GO_REF:0000121 | MODIFY | Summary: HIF1A increases target gene expression transcriptionally. Reason: Correct but general; refine to GO:0045944 (accepted). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct; transcriptional child term available. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:0010629 negative regulation of gene expression | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human IMP (PMID:26879375) shows HIF1A-dependent decrease in expression of some genes. Reason: Transferred from human; the mechanism in the source is not established as direct transcriptional repression, so the general term is as precise as the evidence allows. Non-core. Supporting Evidence: PMID:20496369 We found that HIF-1 can bind to either of the HREs and can suppress promoter activity |
| GO:0010634 positive regulation of epithelial cell migration | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a mutant (PMID:18037992) shows reduced epithelial cell migration. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0010996 response to auditory stimulus | IEP PMID:19840840 Stress induces transient auditory hypersensitivity in rats. | MARK AS OVER ANNOTATED | Summary: Hif1a mRNA changes in rat auditory tissues after 24 h stress. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0014074 response to purine-containing compound | IEP PMID:18248612 HIF-1 alpha is an essential effector for purine nucleoside-m... | KEEP AS NON CORE | Summary: Adenosine/inosine induce HIF-1alpha and HIF-1alpha siRNA abolishes purine-mediated neuroprotection in PC12 cells and neurons. Reason: Rat data go beyond expression: HIF-1alpha is required for the protective response to purine nucleosides. Non-core. Supporting Evidence: PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0014823 response to activity | IEP PMID:19913571 Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skelet... | MARK AS OVER ANNOTATED | Summary: Exercise training lowers HIF-1alpha expression in aged rat skeletal muscle. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0014850 response to muscle activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse muscle-specific Hif1a deletion alters the response to exercise. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0016239 positive regulation of macroautophagy | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 promotes hypoxic macroautophagy through BNIP3 induction (mouse). Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0016604 nuclear body | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha localises to nuclear speckles. Reason: Correct but general; the nuclear speck term (descendant, carried by this gene) is the specific body reported. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Human localisation sound; nuclear speck is more specific. Proposed replacements: nuclear speck Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Colocalizes with HIF3A in the nucleus and speckles |
| GO:0016607 nuclear speck | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: HIF-1alpha colocalises with HIF3A in nuclear speckles (by similarity to mouse). Reason: Plausible sub-nuclear location; not the site of its core activity. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Colocalizes with HIF3A in the nucleus and speckles |
| GO:0016607 nuclear speck | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1alpha colocalises with HIF3A in nuclear speckles (by similarity to mouse). Reason: Plausible sub-nuclear location; not the site of its core activity. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Colocalizes with HIF3A in the nucleus and speckles |
| GO:0016607 nuclear speck | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: HIF-1alpha colocalises with HIF3A in nuclear speckles (by similarity to mouse). Reason: Plausible sub-nuclear location; not the site of its core activity. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Colocalizes with HIF3A in the nucleus and speckles |
| GO:0016922 nuclear receptor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human HIF1A binds RORA (IPI, PMID:18658046), which stabilises HIF-1alpha. Reason: Real but peripheral regulatory interaction. |
| GO:0019896 axonal transport of mitochondrion | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Hypoxic redistribution of axonal mitochondria depends on HUMMR, a mitochondrial protein induced by HIF-1. Reason: The human source (PMID:19528298) shows HIF-1 induces HUMMR expression and HUMMR, with Miro, biases mitochondrial transport. HIF-1alpha performs no step of axonal transport; at most it regulates it transcriptionally. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q16665 SUPPORTS SOURCE BUT NOT TARGET Source shows transcriptional induction of HUMMR, not participation in transport. Supporting Evidence: PMID:19528298 HUMMR, a novel mitochondrial protein induced by HIF-1 and hypoxia, biases mitochondria transport in the anterograde direction. |
| GO:0019896 axonal transport of mitochondrion | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Hypoxic redistribution of axonal mitochondria depends on HUMMR, a mitochondrial protein induced by HIF-1. Reason: The human source (PMID:19528298) shows HIF-1 induces HUMMR expression and HUMMR, with Miro, biases mitochondrial transport. HIF-1alpha performs no step of axonal transport; at most it regulates it transcriptionally. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q16665 SUPPORTS SOURCE BUT NOT TARGET Source shows transcriptional induction of HUMMR, not participation in transport. Supporting Evidence: PMID:19528298 HUMMR, a novel mitochondrial protein induced by HIF-1 and hypoxia, biases mitochondria transport in the anterograde direction. |
| GO:0019899 enzyme binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human HIF1A IPI with the asparaginyl hydroxylase FIH (HIF1AN) (PMID:11641274). Reason: HIF-1alpha binds several modifying enzymes for which it is the substrate (FIH, PHDs). No more specific binding term describes FIH binding; peripheral to its own activity. Supporting Evidence: PMID:21335549 Asparaginyl hydroxylation blocks the recruitment of p300/CBP co-activators to a C-terminal activation domain in HIF-Ξ±. |
| GO:0019901 protein kinase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human HIF1A binds PLK3 (IPI, PMID:20889502), which phosphorylates and destabilises it. Reason: Regulatory interaction in which HIF-1alpha is the substrate; peripheral. |
| GO:0019904 protein domain specific binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: The CTAD binds the TAZ1 domain of CBP (human IPI, PMID:14594809). Reason: True; the functional content is captured by transcription coactivator binding (accepted). Kept as non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 |
| GO:0021502 neural fold elevation formation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-null mouse embryos fail neural fold elevation. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0021987 cerebral cortex development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Neural Hif1a deletion in mouse impairs cerebral cortex development. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0030154 cell differentiation | ISO GO_REF:0000121 | TOO GENERAL | Summary: Mouse Hif1a mutants show differentiation defects in several lineages. Reason: True but uninformative; specific differentiation terms kept in this review (e.g. GO:0071542 dopaminergic neuron differentiation) entail it. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease |
| GO:0030279 negative regulation of ossification | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Osteoblast/chondrocyte Hif1a studies in mouse (PMID:22081627) show negative regulation of ossification. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0030324 lung development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA prediction of lung development. Reason: An unvetted ARBA prediction; the rat evidence for this term is only expression profiling (PMID:9398602). Not established as a direct role for rat Hif1a. |
| GO:0030324 lung development | IEP PMID:9398602 Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic l... | MARK AS OVER ANNOTATED | Summary: Hif1a mRNA is expressed at a constant level during rat lung development. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. Constant expression is not evidence of a role in lung development. |
| GO:0030502 negative regulation of bone mineralization | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: negative regulation of bone mineralization. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0030949 positive regulation of vascular endothelial growth factor receptor signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 promotes VEGF receptor signalling by inducing VEGF (mouse). Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0031514 motile cilium | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: A mouse study localised a putative testis-specific HIF-1alpha isoform (mHIF-1alphaI.1) to the sperm flagellar midpiece. Reason: The mouse IDA (PMID:11818497) concerns an isoform from a mouse-specific alternative first exon, of unknown function; whether rat produces such an isoform or localises HIF-1alpha to motile cilia is not established, so the transfer over-reaches. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS SOURCE BUT NOT TARGET Mouse isoform-specific antibody localisation; not shown for rat. Supporting Evidence: PMID:11818497 expression of the putative mHIF-1alphaI.1 protein in spermatozoa of the testis and epididymis was oxygen independent and located to the midpiece of the spermatozoal flagellum |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:19950214 PKB/Akt activation inhibits p53-mediated HIF1A degradation t... | KEEP AS NON CORE | Summary: HIF1A co-precipitates with an E3 ubiquitin ligase in rat H9c2 cells during p53-mediated degradation. Reason: Rat IPI (abstract only). HIF-1alpha is the substrate in this interaction; real but peripheral. Supporting Evidence: PMID:19950214 HIF1A protein decrease accompanied upregulated HIF1A ubiquitination. |
| GO:0031625 ubiquitin protein ligase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1alpha binds E3 ubiquitin ligases (VHL, MDM2) that target it for degradation. Reason: Real interactions in which HIF-1alpha is the substrate (PMID:21335549 for VHL; PMID:19950214 in rat H9c2 cells). Peripheral to its own activity. Supporting Evidence: PMID:21335549 Prolyl hydroxylation at two sites within a central degradation domain promotes association of HIF-Ξ± with the von Hippel-Lindau ubiquitin E3 ligase and destruction by the ubiquitin-proteasome pathways. |
| GO:0032007 negative regulation of TOR signaling | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 represses mTOR signalling via REDD1 induction (mouse). Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0032025 response to cobalt ion | IEP PMID:19384568 Neuronal and glial alterations due to focal cortical hypoxia... | KEEP AS NON CORE | Summary: CoCl2 injection into rat cortex stabilises HIF-1alpha. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, cobalt being a hypoxia mimetic that inhibits the prolyl hydroxylases. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. |
| GO:0032355 response to estradiol | IEP PMID:17716391 The effect of 2-methoxyestradiol, a HIF-1 alpha inhibitor, i... | MARK AS OVER ANNOTATED | Summary: 2-methoxyestradiol reduces HIF-1alpha in rat global cerebral ischemia. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. 2ME2 is a pharmacological HIF inhibitor; this does not show HIF-1alpha participates in a response to estradiol. |
| GO:0032364 intracellular oxygen homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: The HIF-1 transcriptional programme restores oxygen delivery and adjusts oxygen consumption, maintaining cellular oxygen homeostasis. Reason: PAINT IBA for the HIF-alpha clade and ISO transfers; this is the physiological purpose of the HIF system and directly follows from its activity. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:0032364 intracellular oxygen homeostasis | ISO GO_REF:0000121 | ACCEPT | Summary: The HIF-1 transcriptional programme restores oxygen delivery and adjusts oxygen consumption, maintaining cellular oxygen homeostasis. Reason: PAINT IBA for the HIF-alpha clade and ISO transfers; this is the physiological purpose of the HIF system and directly follows from its activity. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:0032364 intracellular oxygen homeostasis | ISO GO_REF:0000121 | ACCEPT | Summary: The HIF-1 transcriptional programme restores oxygen delivery and adjusts oxygen consumption, maintaining cellular oxygen homeostasis. Reason: PAINT IBA for the HIF-alpha clade and ISO transfers; this is the physiological purpose of the HIF system and directly follows from its activity. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:0032869 cellular response to insulin stimulus | IEP PMID:16506055 Insulin activates hypoxia-inducible factor-1alpha in human a... | KEEP AS NON CORE | Summary: Insulin increases HIF-1alpha content and HIF-1 DNA binding in rat VSMC. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, and the study shows HIF-1 DNA-binding activity on the VEGF gene increases. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. |
| GO:0032909 regulation of transforming growth factor beta2 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 regulates TGF-beta2 production (human IMP, PMID:12411310). Reason: Target-gene consequence; non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0032963 collagen metabolic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Mouse Hif1a mutant fibroblasts/wounds show altered collagen content (PMID:18037992). Reason: involved_in collagen metabolic process implies HIF-1alpha performs steps of collagen metabolism; it acts by inducing genes such as prolyl 4-hydroxylases. Over-annotation of an indirect effect. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:106918 SUPPORTS SOURCE BUT NOT TARGET Mouse IMP phenotype reflects downstream target genes. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0032991 protein-containing complex | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha is a subunit of the HIF-1 heterodimeric transcription factor. Reason: Correct but uninformative; refine to GO:0090575 (descendant, carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct; specific complex term available. Proposed replacements: RNA polymerase II transcription regulator complex Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters |
| GO:0034599 cellular response to oxidative stress | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 mediates transcriptional responses to oxidative stress. Reason: Human IDA transferred; ROS stabilise HIF-1alpha. Non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Induced by reactive oxygen species (ROS). |
| GO:0035162 embryonic hemopoiesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-null mouse embryos show embryonic hemopoiesis defects. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0035470 positive regulation of vascular wound healing | IMP PMID:30052311 Knockdown of HIF-1Ξ± impairs post-ischemic vascular reconstru... | KEEP AS NON CORE | Summary: HIF-1alpha knockdown impairs post-ischemic vascular reconstruction in rat brain. Reason: Rat IMP (full text); downstream of VEGF-A/Flk-1/Dll4 induction. Non-core. Supporting Evidence: PMID:30052311 the loss of HIF-1Ξ± resulted in deficient expression levels of VEGF-A, Flk-1, NRP1, and Dll4 in the ischemic brains, bmEPCs, and astrocytes |
| GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-cell Hif1a deletion in mouse impairs glucose-stimulated insulin secretion. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0042127 regulation of cell population proliferation | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1 activity promotes proliferation of several cell types. Reason: Correct but general; rat IMP data show positive regulation (PMID:11029639, PMID:16489407), so the positive child GO:0008284 (carried by this gene) applies. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Correct; positive child supported in rat. Proposed replacements: positive regulation of cell population proliferation Supporting Evidence: PMID:16489407 The RNAi inhibited the expression of HIF-1alpha mRNA in the PASMCs, and subsequently it remarkably suppressed the proliferation of PASMCs in hypoxia. |
| GO:0042541 hemoglobin biosynthetic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: altered hemoglobin biosynthesis. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0042593 glucose homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: altered glucose homeostasis. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0042826 histone deacetylase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1alpha binds HDAC1/HDAC7 (IPI, PMID:19071119). Reason: Real interactions modulating its activity; peripheral. |
| GO:0042826 histone deacetylase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1alpha binds HDAC1/HDAC7 (IPI, PMID:19071119). Reason: Real interactions modulating its activity; peripheral. |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:20224844 The effect of hypoxia-inducible factor 1-alpha on hypoxia-in... | KEEP AS NON CORE | Summary: Pharmacological HIF-1alpha suppression (YC-1) blocks hypoxia-induced apoptosis and Bnip3 induction in rat ventricular myocytes. Reason: Rat data (full text) with a non-selective inhibitor; HIF-1 promotes apoptosis via target genes such as BNIP3 in this context. Context-dependent, non-core. Supporting Evidence: PMID:20224844 Suppression of HIF-1alpha activity by YC-1 treatment was followed by blockade of hypoxia-induced apoptosis and Bnip3 expression |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:20498255 HIF-1 inhibition decreases systemic vascular remodelling dis... | KEEP AS NON CORE | Summary: HIF-1 inhibition promotes VSMC apoptosis via a hexokinase 2-dependent mechanism; dominant-negative HIF-1alpha prevents rat carotid remodelling. Reason: Context-dependent anti-apoptotic effect through metabolic target genes; non-core. Supporting Evidence: PMID:20498255 localized HIF-1 inhibition, using a dominant-negative HIF-1Ξ± adenoviral construct, prevented carotid artery post-injury remodelling in rats |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: increased apoptosis in Hif1a-deficient tissues. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0043279 response to alkaloid | IEP PMID:15067214 Chronic hypoxia- and monocrotaline-induced elevation of hypo... | MARK AS OVER ANNOTATED | Summary: Monocrotaline (a pyrrolizidine alkaloid) raises lung HIF-1alpha in rats via lung hypoxia. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0043524 negative regulation of neuron apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Neural Hif1a deletion in mouse increases neuronal apoptosis. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0043536 positive regulation of blood vessel endothelial cell migration | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 promotes endothelial cell migration via angiogenic targets (human IMP). Reason: Downstream of VEGF induction; non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease |
| GO:0043565 sequence-specific DNA binding | IDA PMID:18614764 Astrocyte responses to injury: VEGF simultaneously modulates... | MODIFY | Summary: HIF-1 DNA-binding activity is induced in rat astrocytes under near-anoxia. Reason: Correct but general; HRE binding is cis-regulatory region binding (GO:0000978, accepted). Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:18614764 Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity |
| GO:0043565 sequence-specific DNA binding | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1 binds HRE sequences in cis-regulatory regions of target genes. Reason: Correct but general; refine to GO:0000978 (descendant, carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct; more specific term available. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:18614764 Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity |
| GO:0043565 sequence-specific DNA binding | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1 binds HRE sequences in cis-regulatory regions of target genes. Reason: Correct but general; refine to GO:0000978 (descendant, carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Correct; more specific term available. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:18614764 Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity |
| GO:0043627 response to estrogen | IEP PMID:20487002 Down-regulation of hypoxia inducible factor-1alpha: a possib... | MARK AS OVER ANNOTATED | Summary: Estrogen treatment lowers HIF-1alpha in rat genioglossus after chronic intermittent hypoxia. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0044877 protein-containing complex binding | IDA PMID:11029639 Two splice variants of the hypoxia-inducible factor HIF-1alp... | MODIFY | Summary: Rat brain HIF-1alpha splice variants heterodimerise with ARNT1 and ARNT2. Reason: The experiment shows heterodimerisation with ARNT partners; protein-containing complex binding is uninformative. Refine to GO:0046982 protein heterodimerization activity (accepted). Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:11029639 We also identify two splice variants of HIF-1alpha in brain, one of which dimerizes with ARNT2 even more avidly than with ARNT1. |
| GO:0044877 protein-containing complex binding | IMP PMID:10559391 Protection from oxidative stress-induced apoptosis in cortic... | MODIFY | Summary: In neuronal cultures iron chelators induce HIF-1 binding to the HRE, identified by antibody disruption and supershift. Reason: The full text shows HIF-1alpha/beta in an HRE-binding complex (EMSA). The activity shown is HRE DNA binding (GO:0000978, accepted), not protein-containing complex binding; an IMP code is also unusual for EMSA/supershift. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:10559391 Addition of individual subunit-specific antibodies during in vitro DNA binding revealed that the HIF-1Ξ± and HIF-1Ξ² were present in the slower-migrating complex |
| GO:0044877 protein-containing complex binding | IPI PMID:15084519 Ref-1/Ape is critical for formation of the hypoxia-inducible... | MODIFY | Summary: HIF-1 co-immunoprecipitates with p300 and Ref-1/APE1 in the complex on the rat VEGF HRE. Reason: The interaction recorded is recruitment of coactivators (p300, Ref-1) by HIF-1; transcription coactivator binding (GO:0001223, accepted) is the informative term. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:15084519 Co-immunoprecipitation experiments indicated that Ref-1/Ape present in nuclear extract interacted with HIF-1 and p300 but not ATF/CREB. |
| GO:0045648 positive regulation of erythrocyte differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: reduced erythrocyte differentiation. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0045722 positive regulation of gluconeogenesis | IMP PMID:24177414 HNF4Ξ± contributes to glucose formation in aged rat hepatocyt... | UNDECIDED | Summary: Hypoxia induces PEPCK and glucose output in aged rat hepatocytes, in parallel with HIF1alpha. Reason: The abstract (full text not available) describes HNF4alpha siRNA as the perturbation that reduces glucose production; no Hif1a perturbation is described. The curator may have seen a Hif1a knockdown in the full text, so the row cannot be judged. Supporting Evidence: PMID:24177414 Glucose production increased under hypoxic conditions, but this increment diminished by HNF4Ξ± siRNA in young hepatocytes. |
| GO:0045766 positive regulation of angiogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 promotes angiogenesis by inducing VEGF and other angiogenic genes. Reason: Well established downstream role (human; rat PMID:30052311). Non-core consequence of the activator function. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease PMID:30052311 the loss of HIF-1Ξ± resulted in deficient expression levels of VEGF-A, Flk-1, NRP1, and Dll4 in the ischemic brains, bmEPCs, and astrocytes |
| GO:0045793 positive regulation of cell size | IEP PMID:22129453 Mild hypoxia-induced cardiomyocyte hypertrophy via up-regula... | KEEP AS NON CORE | Summary: Mild hypoxia causes HIF-1alpha-dependent hypertrophy of neonatal rat cardiomyocytes via TRPC3/6. Reason: Full text uses an HIF-1alpha blocker and overexpression, i.e. perturbation evidence; a context-dependent downstream effect. The IEP code understates the evidence. Supporting Evidence: PMID:22129453 MH-induced cardiomyocytes hypertrophy, TRPC up-regulation and enhanced Ca(2+)-calcineurin signals were inhibited by an HIF-1Ξ± specific blocker |
| GO:0045821 positive regulation of glycolysis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 increases glycolytic flux by inducing glycolytic enzymes and glucose transporters. Reason: Human IDA (PMID:8089148) transferred with acts_upstream_of. A classic target programme; non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0045893 positive regulation of DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha activates transcription by RNA polymerase II. Reason: Correct but general; refine to GO:0045944 (descendant, carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct; RNA polymerase II-specific child applies. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0045893 positive regulation of DNA-templated transcription | ISS GO_REF:0000024 | MODIFY | Summary: HIF-1alpha activates transcription by RNA polymerase II. Reason: Correct but general; refine to GO:0045944 (descendant, carried by this gene). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q16665 SUPPORTS TRANSFER Correct; RNA polymerase II-specific child applies. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0045906 negative regulation of vasoconstriction | IMP PMID:21106323 Prolonged mechanical stretch is associated with upregulation... | MARK AS OVER ANNOTATED | Summary: Prolonged stretch reduces rat IVC contraction; HIF inhibitors (U0126, echinomycin) restore it. Reason: Full text relies on pharmacological inhibitors, one of which (U0126) is a MEK inhibitor, and the effect is attributed to MMP induction. HIF-1alpha performs no step of vasoconstriction; the row over-interprets indirect, non-selective pharmacology. Supporting Evidence: PMID:21106323 PHE-induced contraction was restored in IVC exposed to prolonged 2-g tension plus the HIF inhibitor U0126 |
| GO:0045926 negative regulation of growth | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: negative regulation of growth. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:11237857 Perivenous expression of the mRNA of the three hypoxia-induc... | ACCEPT | Summary: Rat HIF-1alpha activates an HRE-driven luciferase reporter. Reason: Direct rat assay of transactivation (PMID:11237857). Supporting Evidence: PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of positive regulation of transcription by RNA polymerase II. Reason: Consistent with direct rat evidence (PMID:11237857, PMID:12675925). Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:20496369 Hypoxia-inducible factor regulation of ANK expression in nuc... | ACCEPT | Summary: HIF-1alpha silencing suppresses enolase-1 promoter activity in rat nucleus pulposus cells. Reason: Rat IMP (full text). Supporting Evidence: PMID:20496369 When HIF-1Ξ± is silenced, in both normoxia and hypoxia, there is significant suppression of enolase-1 promoter activity, a known HIF-1Ξ± target gene in nucleus pulposus cells (not shown). |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | ACCEPT | Summary: Core process: HIF-1alpha/ARNT activates RNA polymerase II transcription from HRE-containing promoters. Reason: Rat HRE-reporter activation (PMID:11237857), TH promoter activation (PMID:12675925) and enolase-1 promoter dependence (PMID:20496369). Supporting Evidence: PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | ACCEPT | Summary: Core process: HIF-1alpha/ARNT activates RNA polymerase II transcription from HRE-containing promoters. Reason: Rat HRE-reporter activation (PMID:11237857), TH promoter activation (PMID:12675925) and enolase-1 promoter dependence (PMID:20496369). Supporting Evidence: PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | ACCEPT | Summary: Core process: HIF-1alpha/ARNT activates RNA polymerase II transcription from HRE-containing promoters. Reason: Rat HRE-reporter activation (PMID:11237857), TH promoter activation (PMID:12675925) and enolase-1 promoter dependence (PMID:20496369). Supporting Evidence: PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | ACCEPT | Summary: Core process: HIF-1alpha/ARNT activates RNA polymerase II transcription from HRE-containing promoters. Reason: Rat HRE-reporter activation (PMID:11237857), TH promoter activation (PMID:12675925) and enolase-1 promoter dependence (PMID:20496369). Supporting Evidence: PMID:11237857 All three cDNAs encoded functionally active proteins, of 825, 874 and 662 amino acids. After transfection they were able to activate luciferase activity of a luciferase gene construct containing three HIF-responsive elements. PMID:12675925 induction of TH gene expression involves activation of the hypoxia-inducible transcription factors (HIFs) that interact with a specific hypoxia-responsive element (HRE) in the proximal region of the TH promoter file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:0046716 muscle cell cellular homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Muscle Hif1a deletion in mouse alters muscle cell homeostasis. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0046886 positive regulation of hormone biosynthetic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 activates EPO and other hormone genes (human IDA, PMID:1448077). Reason: Target-gene consequence; non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0046982 protein heterodimerization activity | ISO GO_REF:0000121 | ACCEPT | Summary: HIF-1alpha heterodimerises with ARNT (and with ARNT2 in neurons) through its bHLH-PAS domains to form HIF-1. Reason: Rat brain HIF-1alpha splice variants dimerise with ARNT1 and ARNT2 (PMID:11029639); UniProt. Heterodimerisation is obligatory for DNA binding. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:11029639 We also identify two splice variants of HIF-1alpha in brain, one of which dimerizes with ARNT2 even more avidly than with ARNT1. |
| GO:0046982 protein heterodimerization activity | ISO GO_REF:0000121 | ACCEPT | Summary: HIF-1alpha heterodimerises with ARNT (and with ARNT2 in neurons) through its bHLH-PAS domains to form HIF-1. Reason: Rat brain HIF-1alpha splice variants dimerise with ARNT1 and ARNT2 (PMID:11029639); UniProt. Heterodimerisation is obligatory for DNA binding. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:11029639 We also identify two splice variants of HIF-1alpha in brain, one of which dimerizes with ARNT2 even more avidly than with ARNT1. |
| GO:0046982 protein heterodimerization activity | ISS GO_REF:0000024 | ACCEPT | Summary: HIF-1alpha heterodimerises with ARNT (and with ARNT2 in neurons) through its bHLH-PAS domains to form HIF-1. Reason: Rat brain HIF-1alpha splice variants dimerise with ARNT1 and ARNT2 (PMID:11029639); UniProt. Heterodimerisation is obligatory for DNA binding. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:11029639 We also identify two splice variants of HIF-1alpha in brain, one of which dimerizes with ARNT2 even more avidly than with ARNT1. |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | MODIFY | Summary: bHLH/PAS dimerisation; for HIF-1alpha specifically heterodimerisation with ARNT. Reason: Correct but general; refine to GO:0046982 (descendant, carried by this gene). Proposed replacements: protein heterodimerization activity Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:11029639 We also identify two splice variants of HIF-1alpha in brain, one of which dimerizes with ARNT2 even more avidly than with ARNT1. |
| GO:0048250 iron import into the mitochondrion | IMP PMID:26071548 Cardioprotective HIF-1Ξ±-frataxin signaling against ischemia-... | MARK AS OVER ANNOTATED | Summary: HIF-1alpha induces frataxin in hypoxic cardiomyocytes; frataxin limits mitochondrial iron overload. Reason: HIF-1alpha transcriptionally induces frataxin; it performs no step of iron import, and the reported outcome is reduced mitochondrial iron overload rather than increased import. Supporting Evidence: PMID:26071548 Our data also suggest that increased frataxin mitigated mitochondrial iron overload and subsequent ROS production |
| GO:0048514 blood vessel morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-null mouse embryos show blood vessel morphogenesis defects. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease |
| GO:0048546 digestive tract morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: digestive tract morphogenesis defect. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0048593 camera-type eye morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: camera-type eye morphogenesis defect. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0048661 positive regulation of smooth muscle cell proliferation | IMP PMID:16489407 [Effects of RNAi on hypoxia inducible factor-1alpha activity... | KEEP AS NON CORE | Summary: HIF-1alpha RNAi suppresses hypoxic proliferation of rat pulmonary artery smooth muscle cells. Reason: Rat IMP (abstract); downstream effect of HIF-1 target genes in hypoxic pulmonary vascular remodelling. Supporting Evidence: PMID:16489407 The RNAi inhibited the expression of HIF-1alpha mRNA in the PASMCs, and subsequently it remarkably suppressed the proliferation of PASMCs in hypoxia. |
| GO:0048771 tissue remodeling | IEP PMID:23887904 Exposure to diesel exhaust particulates induces cardiac dysf... | MARK AS OVER ANNOTATED | Summary: Diesel exhaust particles decrease cardiac HIF-1alpha expression during rat cardiac remodelling. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0051216 cartilage development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Chondrocyte Hif1a deletion in mouse disrupts cartilage development (growth-plate chondrocyte survival). Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0051240 positive regulation of multicellular organismal process | IEA GO_REF:0000117 | TOO GENERAL | Summary: ARBA prediction of positive regulation of multicellular organismal process. Reason: True but uninformative; descendants kept in this review (positive regulation of angiogenesis, positive regulation of VEGF production) entail it. |
| GO:0051384 response to glucocorticoid | IEP PMID:18385541 Vulnerability of gastric mucosa to prednisolone in rats chro... | MARK AS OVER ANNOTATED | Summary: HIF-1alpha levels in gastric mucosa of smoke-exposed rats treated with prednisolone. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0051541 elastin metabolic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Mouse Hif1a mutant shows altered elastin content (PMID:18037992). Reason: involved_in elastin metabolic process over-states a phenotype; HIF-1alpha performs no step of elastin metabolism. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:106918 SUPPORTS SOURCE BUT NOT TARGET Mouse IMP phenotype reflects downstream target genes. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0051879 Hsp90 protein binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HSP90 binds the PAS-B region of HIF-1alpha (human IDA, PMID:9079689), affecting its stability. Reason: Chaperone client interaction; peripheral. |
| GO:0060135 maternal process involved in female pregnancy | IEP PMID:20181619 Stretch-induced uterine myocyte differentiation during rat p... | MARK AS OVER ANNOTATED | Summary: HIF1A immunostaining in pregnant rat myometrium. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. HIF1A was used as a hypoxia marker. |
| GO:0060574 intestinal epithelial cell maturation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse intestinal Hif1a phenotype: epithelial cell maturation. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0060992 response to fungicide | IMP PMID:18347136 Mitochondrial regulation by c-Myc and hypoxia-inducible fact... | MARK AS OVER ANNOTATED | Summary: HIF-1alpha knockdown in c-Myc-negative rat fibroblasts increases mitochondrial content and econazole sensitivity. Reason: Abstract only; HIF-1alpha modulates mitochondrial biogenesis and so drug-induced ROS, but it performs no step of a response to fungicide. A pharmacological sensitivity phenotype. Supporting Evidence: PMID:18347136 Knockdown of HIF-1alpha in c-myc-negative cells increased mitochondrial content restored ROS generation in response to econazole and increased sensitivity to the drug. |
| GO:0061030 epithelial cell differentiation involved in mammary gland alveolus development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mammary Hif1a deletion in mouse impairs alveolar epithelial differentiation. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0061072 iris morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: iris morphogenesis defect. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0061298 retina vasculature development in camera-type eye | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: retinal vasculature development defect. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1alpha binds the RNA polymerase II-specific transcription factor ARNT (human IPI, PMID:7539918). Reason: True; the same interaction is captured more informatively by protein heterodimerization activity (accepted). Non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters |
| GO:0062029 positive regulation of cytoplasmic stress granule assembly | IMP PMID:30404558 RNA interference may suppress stress granule formation by pr... | REMOVE | Summary: Stress-granule suppression in Hif1a shRNA cells is shown by the authors to be an RNAi artefact. Reason: Full text (PMID:30404558): stress-granule assembly was reduced in Hif1a shRNA cells but not in Hif1a knockout cells, and the effect was reversed by blocking RISC loading. The paper attributes the phenotype to RNAi sequestering Ago2, not to loss of HIF-1alpha, so the annotation is contradicted by its own source. Supporting Evidence: PMID:30404558 SG formation was suppressed in heat shock transcription factor 1 (Hsf1) or hypoxia-inducible factor-1Ξ± (Hif1Ξ±) shRNA-transfected cells but not in Hsf1 or Hif1Ξ±-knockout cells, suggesting that RNAi per se (rather than gene deficiency) may account for the suppressive effect on SG. |
| GO:0070101 positive regulation of chemokine-mediated signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 positively regulates chemokine (CXCL12) signalling (human IDA, PMID:17178876). Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0070243 regulation of thymocyte apoptotic process | ISO GO_REF:0000121 | MODIFY | Summary: Mouse Hif1a-deficient thymocytes show increased apoptosis. Reason: Correct but general; the sign is known, so refine to GO:0070244 negative regulation of thymocyte apoptotic process (child, carried by this gene). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:106918 SUPPORTS TRANSFER Mouse phenotype; negative child term applies. Proposed replacements: negative regulation of thymocyte apoptotic process Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0070244 negative regulation of thymocyte apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a-deficient mouse thymocytes show increased apoptosis. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0070301 cellular response to hydrogen peroxide | IEP PMID:16735674 An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv... | KEEP AS NON CORE | Summary: Mitochondrial ROS/H2O2 control normoxic HIF-1alpha activation in fawn-hooded rat PASMC; dominant-negative HIF-1alpha restores Kv1.5. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, and dominant-negative HIF-1alpha reverses the downstream channel phenotype. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. |
| GO:0070888 E-box binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse IMP (PMID:24011070) for E-box binding. Reason: The HRE core (T/G)ACGTG overlaps the CACGTG E-box and HIF can act at such sites; however the canonical HIF site is the HRE, captured by GO:0000978. Kept as non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters |
| GO:0071222 cellular response to lipopolysaccharide | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA prediction of cellular response to LPS. Reason: HIF-1alpha is induced by LPS in myeloid cells and drives inflammatory gene expression (consistent with the human cytokine production rows); non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0071222 cellular response to lipopolysaccharide | IEP PMID:19940979 Ambivalent effects of compound C (dorsomorphin) on inflammat... | KEEP AS NON CORE | Summary: HIF-1alpha expression in LPS-stimulated rat microglia is reduced by compound C. Reason: Consistent with the established induction of HIF-1alpha by LPS in myeloid cells and its role in inflammatory gene expression; non-core. |
| GO:0071245 cellular response to carbon monoxide | IEP PMID:17475674 Rat carotid body chemosensory discharge and glomus cell HIF-... | KEEP AS NON CORE | Summary: CO increases HIF-1alpha in rat carotid body glomus cells; CO exposure also induces renal HIF-1alpha in rats. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, CO inhibiting mitochondrial cytochrome a3 and mimicking hypoxia. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. Supporting Evidence: PMID:21335549 we studied HIF-1Ξ± from kidneys of rats that had been exposed to 0.1% carbon monoxide to create functional anemia |
| GO:0071250 cellular response to nitrite | IEP PMID:23227543 [Sodium nitrite induces PC12 cell differentiation]. | KEEP AS NON CORE | Summary: Sodium nitrite induces HIF-1alpha in PC12 cells; YC-1 antagonises nitrite-induced neurite outgrowth. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, and HIF-1alpha inhibition antagonises the nitrite effects in this study. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. |
| GO:0071257 cellular response to electrical stimulus | IEP PMID:12193088 Enhancement of glycolysis in cardiomyocytes elevates endothe... | MARK AS OVER ANNOTATED | Summary: Electrical stimulation of cultured rat cardiomyocytes lowers HIF-1alpha mRNA. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0071260 cellular response to mechanical stimulus | IEP PMID:15183444 Cyclic strain influences the expression of the vascular endo... | MARK AS OVER ANNOTATED | Summary: Cyclic strain activates HIF-1alpha in rat tendon fibroblasts (Western blot). Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. |
| GO:0071279 cellular response to cobalt ion | IEP PMID:10559391 Protection from oxidative stress-induced apoptosis in cortic... | KEEP AS NON CORE | Summary: Cobalt activates HIF-1 DNA binding in rat cortical neuronal cultures. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, cobalt being a hypoxia mimetic. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. |
| GO:0071333 cellular response to glucose stimulus | IEP PMID:12234775 Glucose uptake and adenoviral mediated GLUT1 infection decre... | MARK AS OVER ANNOTATED | Summary: Glucose and GLUT1 overexpression reduce hypoxia-induced HIF-1alpha in rat cardiac myocytes via proteasomal degradation. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. Here HIF-1alpha is the regulated substrate. |
| GO:0071347 cellular response to interleukin-1 | IEP PMID:12101082 Recombinant human interleukin (IL)-1 beta-mediated regulatio... | KEEP AS NON CORE | Summary: IL-1beta induces ROS-dependent HIF-1alpha nuclear translocation and activation in rat alveolar epithelial cells. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, with demonstrated activation of HIF-1. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. |
| GO:0071347 cellular response to interleukin-1 | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: IL-1beta activates HIF-1alpha (human IDA, PMID:12958148). Reason: Consistent with rat data (PMID:12101082); non-hypoxic cytokine activation of HIF-1. Non-core. |
| GO:0071391 cellular response to estrogen stimulus | IEP PMID:17272396 Estrogen-induced activation of hypoxia-inducible factor-1alp... | KEEP AS NON CORE | Summary: Estradiol activates HIF-1alpha, which binds the VEGF promoter in rat uterus (in vivo ChIP). Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, with HIF-1alpha recruitment to the VEGF promoter shown by ChIP. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. |
| GO:0071396 cellular response to lipid | IEP PMID:19423865 Sphingosine-1-phosphate: a novel nonhypoxic activator of hyp... | KEEP AS NON CORE | Summary: Sphingosine-1-phosphate stabilises HIF-1alpha and forms a transcriptionally active HIF-1 complex in vascular cells. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, the S1P-induced complex being shown to bind HREs. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. |
| GO:0071454 cellular response to anoxia | IEP PMID:18614764 Astrocyte responses to injury: VEGF simultaneously modulates... | KEEP AS NON CORE | Summary: Near-anoxia stabilises HIF-1alpha and induces DNA binding in rat astrocytes. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, anoxia being the extreme of hypoxia. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. Supporting Evidence: PMID:18614764 Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity |
| GO:0071456 cellular response to hypoxia | IBA GO_REF:0000033 | ACCEPT | Summary: Core process: HIF-1alpha is the oxygen-regulated master transcriptional regulator of the cellular response to hypoxia. Reason: In rat cells, siRNA knockdown abolishes purine-mediated protection from hypoxia (PMID:18248612) and hypoxic activation of the PNMT and TH promoters depends on HIF1alpha (PMID:19220706, PMID:12675925). UniProt and PAINT agree. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0071456 cellular response to hypoxia | IEP PMID:19220706 Hypoxic stress-induced changes in adrenergic function: role ... | ACCEPT | Summary: Hypoxia (5% O2) increases HIF1alpha mRNA, nuclear protein and HRE binding in PC12 cells, driving PNMT promoter activation. Reason: Rat data place HIF1alpha in the cellular hypoxic response (IEP plus overexpression data in the same paper). Supporting Evidence: PMID:19220706 Hypoxia and HIF1alpha over-expression also elevate PNMT promoter-driven luciferase activity in PC12 cells. |
| GO:0071456 cellular response to hypoxia | IMP PMID:18248612 HIF-1 alpha is an essential effector for purine nucleoside-m... | ACCEPT | Summary: siRNA against HIF-1alpha abolishes purine-nucleoside protection of hypoxic PC12 cells and neurons. Reason: Rat IMP (full text). Supporting Evidence: PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0071456 cellular response to hypoxia | ISO GO_REF:0000121 | ACCEPT | Summary: Core process: HIF-1alpha is the oxygen-regulated master transcriptional regulator of the cellular response to hypoxia. Reason: In rat cells, siRNA knockdown abolishes purine-mediated protection from hypoxia (PMID:18248612) and hypoxic activation of the PNMT and TH promoters depends on HIF1alpha (PMID:19220706, PMID:12675925). UniProt and PAINT agree. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0071456 cellular response to hypoxia | ISO GO_REF:0000121 | ACCEPT | Summary: Core process: HIF-1alpha is the oxygen-regulated master transcriptional regulator of the cellular response to hypoxia. Reason: In rat cells, siRNA knockdown abolishes purine-mediated protection from hypoxia (PMID:18248612) and hypoxic activation of the PNMT and TH promoters depends on HIF1alpha (PMID:19220706, PMID:12675925). UniProt and PAINT agree. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0071456 cellular response to hypoxia | ISS GO_REF:0000024 | ACCEPT | Summary: Core process: HIF-1alpha is the oxygen-regulated master transcriptional regulator of the cellular response to hypoxia. Reason: In rat cells, siRNA knockdown abolishes purine-mediated protection from hypoxia (PMID:18248612) and hypoxic activation of the PNMT and TH promoters depends on HIF1alpha (PMID:19220706, PMID:12675925). UniProt and PAINT agree. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia PMID:18248612 small interfering RNA-mediated reduction of HIF-1alpha completely abolished adenosine- and inosine-mediated protection in PC12 cells |
| GO:0071466 cellular response to xenobiotic stimulus | IEP PMID:20193759 An antagonism between the AKT and beta-adrenergic signaling ... | MARK AS OVER ANNOTATED | Summary: Isoproterenol and AKT activation alter HIF-1alpha expression in rat cardiomyocytes via miR-199a-5p. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. HIF-1alpha is the regulated target here. |
| GO:0071482 cellular response to light stimulus | IEP PMID:17475674 Rat carotid body chemosensory discharge and glomus cell HIF-... | MARK AS OVER ANNOTATED | Summary: White light reverses the CO-induced increase in HIF-1alpha in rat glomus cells. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. Light acts on the CO-cytochrome a3 complex, not via HIF-1alpha. |
| GO:0071542 dopaminergic neuron differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hif1a is required for dopaminergic neuron differentiation in mouse. Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:0072347 response to anesthetic | IEP PMID:18218685 Cardiac remodelling hinders activation of cyclooxygenase-2, ... | MARK AS OVER ANNOTATED | Summary: Isoflurane induces nuclear translocation of HIF1alpha in rat hearts. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. The protective effect is attributed to COX-2 and CREB. |
| GO:0072359 circulatory system development | IEA GO_REF:0000117 | TOO GENERAL | Summary: ARBA prediction of circulatory system development. Reason: True of the gene but uninformative; descendants kept in this review (heart looping, blood vessel morphogenesis, angiogenesis) entail it. |
| GO:0090575 RNA polymerase II transcription regulator complex | ISO GO_REF:0000121 | ACCEPT | Summary: HIF-1alpha is the oxygen-regulated subunit of the HIF-1 alpha/ARNT transcription factor complex. Reason: UniProt and rat co-IP data with p300/Ref-1 on the VEGF HRE (PMID:15084519). Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters PMID:15084519 Co-immunoprecipitation experiments indicated that Ref-1/Ape present in nuclear extract interacted with HIF-1 and p300 but not ATF/CREB. |
| GO:0097237 cellular response to toxic substance | IEP PMID:21854848 Cyanide preconditioning protects brain endothelial and NT2 n... | KEEP AS NON CORE | Summary: Cyanide preconditioning activates HIF-1alpha; 2-methoxyestradiol abolishes the protection. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, and the HIF-1alpha inhibitor abolishes the cyanide-induced protection. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. |
| GO:0097411 hypoxia-inducible factor-1alpha signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: HIF-1alpha is the defining mediator of the HIF-1alpha signalling pathway. Reason: By definition this pathway is HIF-1alpha stabilisation, dimerisation with ARNT, nuclear translocation and target-gene activation. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia file:rat/Hif1a/Hif1a-uniprot.txt Cytoplasmic in normoxia, nuclear translocation in response to hypoxia |
| GO:0140537 transcription regulator activator activity | ISO GO_REF:0000121 | MODIFY | Summary: HIF-1alpha CTAD binds the CH1 domain of p300 (human IPI, PMID:11063749). Reason: GO:0140537 describes a regulator that increases the activity of a transcription regulator; here HIF-1alpha is the DNA-binding factor that recruits the coactivator p300, so the interaction is transcription coactivator binding (accepted for this gene), not activation of p300. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q16665 SOURCE BAD Human source row uses a regulator-activator term for coactivator recruitment. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:11063749 HIF1alpha-mediated transcription requires the coactivator p300, at least in part, through interaction with the cysteine- and histidine-rich 1 domain of p300. |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 promotes inflammatory cytokine production (human IDA, PMID:32697943). Reason: Target-gene consequence in myeloid/inflammatory contexts; non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: HIF-1 promotes inflammatory cytokine production (human IDA, PMID:32697943). Reason: Target-gene consequence in myeloid/inflammatory contexts; non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
| GO:1900037 regulation of cellular response to hypoxia | IEP PMID:18054269 Ginkgolides mimic the effects of hypoxic preconditioning to ... | MARK AS OVER ANNOTATED | Summary: Ginkgolides and hypoxic preconditioning increase HIF-1alpha expression in C6 cells. Reason: IEP for a regulation term: the study shows HIF-1alpha is induced, i.e. it is part of the hypoxic response it is said to regulate. HIF-1alpha is the effector of the cellular response to hypoxia, not shown here to regulate it. |
| GO:1902894 negative regulation of miRNA transcription | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF1A represses some miRNA genes (human IMP, PMID:31368162). Reason: Transcriptional regulation of miRNA loci; non-core. Supporting Evidence: PMID:20496369 We found that HIF-1 can bind to either of the HREs and can suppress promoter activity |
| GO:1902895 positive regulation of miRNA transcription | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 activates transcription of hypoxia-induced miRNA genes (e.g. miR-210) through HREs. Reason: Supported by multiple human and mouse experimental annotations; a target class of the core activator function. Non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:1902895 positive regulation of miRNA transcription | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1 activates transcription of hypoxia-induced miRNA genes (e.g. miR-210) through HREs. Reason: Supported by multiple human and mouse experimental annotations; a target class of the core activator function. Non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Functions as a master transcriptional regulator of the adaptive response to hypoxia |
| GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF1A protects neurons from oxidative-stress-induced intrinsic apoptosis (human IDA, PMID:24899725). Reason: Cytoprotective target-gene consequence; non-core. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Induced by reactive oxygen species (ROS). |
| GO:1903427 negative regulation of reactive oxygen species biosynthetic process | IMP PMID:26071548 Cardioprotective HIF-1Ξ±-frataxin signaling against ischemia-... | KEEP AS NON CORE | Summary: HIF-1alpha-dependent frataxin induction limits mitochondrial ROS in hypoxic cardiomyocytes. Reason: Rat/mouse data (abstract); a regulatory, target-gene-mediated effect. Non-core. Supporting Evidence: PMID:26071548 Our data also suggest that increased frataxin mitigated mitochondrial iron overload and subsequent ROS production |
| GO:1903427 negative regulation of reactive oxygen species biosynthetic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HIF-1alpha limits mitochondrial ROS production, e.g. via frataxin induction in cardiomyocytes. Reason: Rat H9C2 data (PMID:26071548) and mouse IDA support a transcriptional effect on ROS production; regulatory and non-core. Supporting Evidence: PMID:26071548 Our data also suggest that increased frataxin mitigated mitochondrial iron overload and subsequent ROS production |
| GO:1903672 positive regulation of sprouting angiogenesis | IMP PMID:30052311 Knockdown of HIF-1Ξ± impairs post-ischemic vascular reconstru... | KEEP AS NON CORE | Summary: HIF-1alpha knockdown inhibits bmEPC spheroid sprouting and sprouting in ischemic rat brain. Reason: Rat IMP (full text); via VEGF-A/Flk-1/NRP1/Dll4. Non-core. Supporting Evidence: PMID:30052311 In vitro, knockdown of HIF-1Ξ± inhibited the spheroid sprouting and tube formation of bmEPCs. |
| GO:1903928 cellular response to cyanide | IEP PMID:21854848 Cyanide preconditioning protects brain endothelial and NT2 n... | KEEP AS NON CORE | Summary: Cyanide preconditioning activates HIF-1alpha in brain endothelial and NT2 cells. Reason: HIF-1alpha accumulation or activation is the mechanism by which cells mount a transcriptional response to this stimulus, and HIF-1alpha inhibition abolishes the protective response. Retained as a non-core, stimulus-specific response; the core role is the HIF-1 response to hypoxia. |
| GO:1904115 axon cytoplasm | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Inferred automatically from the axonal transport of mitochondrion annotation. Reason: The parent annotation is itself an over-annotation (indirect effect via HUMMR, PMID:19528298), and no study localises HIF-1alpha to axon cytoplasm. Supporting Evidence: PMID:19528298 HUMMR, a novel mitochondrial protein induced by HIF-1 and hypoxia, biases mitochondria transport in the anterograde direction. |
| GO:1904568 cellular response to wortmannin | IEP PMID:17272396 Estrogen-induced activation of hypoxia-inducible factor-1alp... | MARK AS OVER ANNOTATED | Summary: Wortmannin blocks estradiol-induced HIF-1alpha activation in rat uterus. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. HIF-1alpha is downstream of PI3K; this does not show it participates in a response to wortmannin. |
| GO:1904628 cellular response to phorbol 13-acetate 12-myristate | IEP PMID:9398602 Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic l... | MARK AS OVER ANNOTATED | Summary: Phorbol myristate acetate increases HIF-1alpha mRNA in rat cardiomyocytes. Reason: IEP: the study records a change in Hif1a mRNA or HIF-1alpha protein under this condition. Expression change alone does not show that HIF-1alpha executes a step of the response; its established role is as the oxygen-regulated subunit of the HIF-1 transcription factor. The same study found no induction by anoxia or cobalt at the mRNA level. |
| GO:2000434 regulation of protein neddylation | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Engagement of HIF-1alpha as a VHL substrate recruits DCNL1 and triggers CUL2 neddylation (PMID:23401859). Reason: HIF-1alpha is the substrate of the CRL2-VHL ligase; DCNL1 is the neddylation activator. Treating substrate engagement as regulation of neddylation over-states the role of HIF-1alpha, which is a substrate rather than a regulator here. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q16665 SUPPORTS SOURCE BUT NOT TARGET Human source shows HIF1A acting as substrate of CRL2-VHL. Supporting Evidence: PMID:23401859 The engagement of the substrate hypoxia-inducible factor 1Ξ± (HIF1Ξ±) to the substrate receptor VHL increases DCNL1 binding to VHL as well as to CUL2. |
| GO:2000434 regulation of protein neddylation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Engagement of HIF-1alpha as a VHL substrate recruits DCNL1 and triggers CUL2 neddylation (PMID:23401859). Reason: HIF-1alpha is the substrate of the CRL2-VHL ligase; DCNL1 is the neddylation activator. Treating substrate engagement as regulation of neddylation over-states the role of HIF-1alpha, which is a substrate rather than a regulator here. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q16665 SUPPORTS SOURCE BUT NOT TARGET Human source shows HIF1A acting as substrate of CRL2-VHL. Supporting Evidence: PMID:23401859 The engagement of the substrate hypoxia-inducible factor 1Ξ± (HIF1Ξ±) to the substrate receptor VHL increases DCNL1 binding to VHL as well as to CUL2. |
| GO:2001054 negative regulation of mesenchymal cell apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Hif1a phenotype: reduced mesenchymal cell survival (e.g. in growth-plate chondrocytes). Reason: ISO transfer from a mouse Hif1a mutant phenotype (MGI:MGI:106918). The acts_upstream_of_or_within qualifier appropriately records that the process depends on HIF-1 activity, which acts through transcription of target genes (VEGF, glycolytic enzymes, EPO, etc.) rather than by performing steps of the process. Retained as a non-core, context-dependent role. Supporting Evidence: file:rat/Hif1a/Hif1a-uniprot.txt Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor |
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Download this section (compressed HTML)Q: Which genes does the neuronal HIF-1alpha/ARNT2 heterodimer regulate in rat? It did not recognise the erythropoietin HRE (PMID:11029639), so its DNA-binding preference and target set are unknown.
Q: Are the two rat Hif1a brain splice variants (PMID:11029639) represented among the isoforms of UniProt O35800, and do they differ functionally from the canonical protein?
Q: Many rat annotations are IEP rows recording that HIF-1alpha protein or mRNA changes under a stimulus. Should GO adopt a convention distinguishing "the factor is induced by X" from "the factor executes the response to X"?
Experiment: ChIP-seq of HIF-1alpha and ARNT (and ARNT2) in rat neurons and cardiomyocytes under hypoxia, to define the direct rat target gene set and to separate activated from repressed targets.
Experiment: Test the repressive mode directly: compare HIF-1 occupancy and coregulator composition (p300 versus corepressors) at an activated HRE (enolase-1) and a repressed HRE (ANK) in rat nucleus pulposus cells.
Experiment: Re-examine the gluconeogenesis claim with a Hif1a-specific knockdown or PHD-inhibitor rescue in aged rat hepatocytes, measuring PEPCK and glucose output, since the cited study perturbed HNF4alpha.
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