FOXO1 (Forkhead box protein O1) is a transcription factor of the FOXO family that functions as a key integrator of insulin/PI3K-AKT signaling with metabolic homeostasis and stress responses. FOXO1 binds to insulin response elements (IRE; 5'-TT[G/A]TTTTG-3') and DAF-16 binding elements (DBE; 5'-TT[G/A]TTTAC-3') via its conserved forkhead/winged-helix DNA-binding domain. FOXO1 is implicated in regulation of hepatic gluconeogenic gene programs (e.g., G6PC1, PCK1), though the FOXO1βPGC-1alpha interaction has been reported as indirect in PMID:17024043. FOXO1 activity is tightly regulated by post-translational modifications: AKT phosphorylation at T24/S256/S319 promotes 14-3-3 binding, nuclear export, and cytoplasmic sequestration, while stress kinases (MST1, JNK, AMPK) and deacetylation by sirtuins promote nuclear retention and transcriptional activation. FOXO1 shuttles between nucleus and cytoplasm based on metabolic and stress cues, functioning as a molecular switch for metabolic adaptation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: FOXO1 is established as a sequence-specific DNA-binding transcription factor that recognizes IRE and DBE motifs and regulates transcription by RNA polymerase II. Structural studies confirm the forkhead DNA-binding domain binds DNA directly (PMID:18786403). This is a core molecular function. Reason: This is the fundamental molecular function of FOXO1 - it is a transcription factor that binds specific DNA sequences (IRE/DBE) and regulates gene expression. Extensively supported by structural, biochemical, and functional evidence. Supporting Evidence: PMID:18786403 Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification PMID:37891184 FOXO proteins have a structured winged-helix type of DNA binding domain (DBD) file:human/FOXO1/FOXO1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: FOXO1 localizes to the nucleus where it carries out its transcription factor function. Nuclear localization is well-documented and is the active state of the protein. Multiple IDA studies confirm nuclear localization. Reason: Nuclear localization is essential for FOXO1's transcription factor function. This is where FOXO1 binds DNA and activates target genes. Supported by numerous experimental studies. Supporting Evidence: PMID:11311120 Ser(329) phosphorylation also decreases the ability of FKHR to stimulate gene transactivation and reduces the proportion of FKHR present in the nucleus. PMID:12228231 Studies with GFP(1) fusion proteins indicate that Ser-256 phosphorylation is critical for nuclear exclusion of FKHR. |
| GO:0045722 positive regulation of gluconeogenesis | IBA GO_REF:0000033 | ACCEPT | Summary: FOXO1's role in promoting gluconeogenesis is a core evolved function, particularly in hepatocytes. Evidence supports FOXO1 involvement in gluconeogenic gene expression, while the FOXO1βPGC-1alpha interaction has been reported as indirect. Reason: This is a core function of FOXO1 based on phylogenetic and systems-level evidence. PMID:17024043 indicates FOXO1 is not required or sufficient for PGC-1alpha-driven G6Pase reporter activation, suggesting the interaction is indirect, but FOXO1 remains implicated in gluconeogenic programs. Supporting Evidence: PMID:17024043 the transcription factor FOXO1 and the transcriptional co-activator PGC-1alpha act synergistically to stimulate the expression of genes in the gluconeogenesis pathway PMID:37891184 This indicates that FOXO1 is required for the control and promotion of the hepatic glucose production, even in the presence of FOXO3 isoform, being FOXO3 able to compensate for chronic but not acute FOXO1 ablation |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: As a transcription factor, FOXO1 regulates transcription by RNA polymerase II. This is the fundamental biological process in which FOXO1 participates. Reason: Core biological process annotation for a transcription factor. FOXO1 is established to regulate both activation and repression of Pol II-transcribed genes. Supporting Evidence: PMID:37710009 FOXO transcription factors as mediators of stress adaptation |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: FOXO1 binds to specific cis-regulatory sequences (IRE and DBE motifs) in promoters of target genes. X-ray crystallography has defined the structural basis for sequence-specific DNA recognition by the forkhead domain. Reason: Core molecular function - FOXO1 recognizes and binds specific DNA sequences in regulatory regions. The consensus sequences (DBE: 5'-TTGTTTAC-3'; IRE: 5'-TT[G/A]TTTTG-3') are well characterized. Supporting Evidence: PMID:18786403 Structural basis for DNA recognition by FoxO1 PMID:38466341 While FOXO proteins recognize two distinct response elements, the insulin-responsive element (IRE) and the DAF-16 family member binding element (DBE), they bind to the DBE with a higher affinity |
| GO:0008286 insulin receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: FOXO1 is a central downstream target of insulin receptor signaling. Insulin activates PI3K-AKT, which phosphorylates FOXO1 at T24/S256/S319, leading to 14-3-3 binding, nuclear export, and inactivation. This represents FOXO1's role as a key effector of insulin signaling. Reason: Core biological process - FOXO1 is the main target of insulin signaling and mediates many of insulin's effects on metabolism. The insulin-AKT-FOXO1 axis is extensively characterized. Supporting Evidence: PMID:10358076 Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin PMID:37891184 In the presence of insulin, and many other growth factors, the canonical regulator AKT phosphorylates FOXO proteins in the nucleus, at three conserved RxRxxS/T residues. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000108 | ACCEPT | Summary: While FOXO1 is primarily known as a transcriptional activator, it can also repress transcription of certain target genes. For example, FOXO1 suppresses PDX1 expression in pancreatic beta cells and can repress PPARG during adipogenesis. Reason: FOXO1 can function as both an activator and repressor depending on context and target gene. Repression of PDX1 and PPARG is documented. This represents a legitimate molecular function. Supporting Evidence: UniProt:Q12778 Acts as an inhibitor of glucose sensing in pancreatic beta cells by acting as a transcription repressor and suppressing expression of PDX1 (By similarity). |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: General DNA binding term. FOXO1 binds DNA via its forkhead domain. While accurate, this is less informative than the more specific GO:0000978 (sequence-specific DNA binding) annotation. Reason: Correct but general. The more specific term GO:0000978 is preferred, but this annotation is not incorrect. DNA binding is fundamental to FOXO1's function. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: FOXO1 is a DNA-binding transcription factor. This is correct but less specific than GO:0000981 (RNA polymerase II-specific) which better captures FOXO1's function. Reason: Correct general annotation. FOXO1 is a transcription factor that binds DNA and regulates gene expression. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of IBA annotation for nucleus. FOXO1 localizes to nucleus where it functions. Reason: Correct cellular component annotation. Nuclear localization is well-established for FOXO1. |
| GO:0005654 nucleoplasm | IEA GO_REF:0000117 | ACCEPT | Summary: FOXO1 is present in the nucleoplasm where it functions as a transcription factor. More specific than nucleus. Reason: Correct subcellular localization. FOXO1 functions in the nucleoplasm to regulate gene transcription. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: FOXO1 shuttles between nucleus and cytoplasm. Cytoplasmic localization is the inactive state, induced by insulin/AKT-mediated phosphorylation and 14-3-3 binding. This is part of the regulatory mechanism controlling FOXO1 activity. Reason: Correct - cytoplasmic localization is a key aspect of FOXO1 regulation. AKT phosphorylation promotes nuclear export and cytoplasmic sequestration. Supporting Evidence: PMID:11237865 insulin-like growth factor (IGF)-1 and serum-induced nuclear exclusion of FKHR[S256A] depends on the degree of overexpression of this mutant. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: General term for transcription regulation. FOXO1 regulates transcription of its target genes. Reason: Correct general annotation for a transcription factor. |
| GO:0006914 autophagy | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: FOXO1 can promote autophagy through both transcription-dependent (activating autophagy genes like ATG12, BNIP3, LC3) and transcription-independent mechanisms (cytosolic interaction with ATG7). However, this represents a downstream effect of FOXO1's transcription factor activity rather than its core evolved function. Reason: While FOXO1 can transcriptionally activate autophagy-related genes and has been shown to interact with ATG7 in the cytoplasm, autophagy regulation is a downstream consequence of FOXO1's stress response program rather than its primary evolved function. FOXO1's core role is metabolic regulation; autophagy induction is one of many pleiotropic effects. The direct cytosolic ATG7 interaction (PMID:20543840) represents a non-canonical mechanism. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: FOXO1 can promote apoptosis by transcriptionally activating pro-apoptotic genes (FASLG, BIM/BCL2L11, NOXA). This is a consequence of its stress-responsive transcription factor activity. Reason: FOXO1 does regulate apoptosis through transcription of pro-apoptotic genes, particularly under stress conditions. However, this is a downstream pleiotropic effect rather than the core evolved function (gluconeogenesis/metabolic regulation). Valid but non-core. Supporting Evidence: PMID:31063815 Moreover, CyPA induced FoxO1-dependent expression of downstream genes involved in EC chemotaxis and apoptosis, including monocyte chemoattractant protein-1 and BCL-2-interacting mediator of cell death, and stimulated the apoptosis of human umbilical vein ECs in vitro. |
| GO:0008013 beta-catenin binding | IEA GO_REF:0000117 | ACCEPT | Summary: FOXO1 interacts with beta-catenin. This interaction has functional consequences for FOXO1-dependent transcription and may relieve autoinhibition of the DNA-binding domain. Reason: Beta-catenin binding is documented and functionally relevant. IDA evidence also exists for this interaction (PMID:15905404). The further suggestion that beta-catenin binding relieves autoinhibition of the FOXO1 DNA-binding domain is our own reading of the structural literature and is not supported by any reference cached for this review; PMID:37710009 is available here as abstract only and does not discuss beta-catenin. Supporting Evidence: PMID:15905404 Functional interaction between beta-catenin and FOXO in oxidative stress signaling |
| GO:0030154 cell differentiation | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: FOXO1 influences various differentiation processes including adipogenesis (negative regulation), myogenesis, and osteoblast differentiation. This is a broad pleiotropic effect rather than a specific core function. Reason: "Cell differentiation" is too broad and vague. While FOXO1 does influence differentiation in multiple cell types, this is a downstream consequence of its transcriptional regulatory function rather than a core evolved function. More specific annotations (e.g., negative regulation of fat cell differentiation) are preferable. |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: FOXO1 binds DNA in a sequence-specific manner, recognizing IRE and DBE consensus sequences. Reason: Core molecular function - sequence-specific DNA binding is fundamental to FOXO1's transcription factor activity. |
| GO:0005515 protein binding | IPI PMID:11237865 Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphoryla... | MODIFY | Summary: This reference documents FOXO1 interaction with 14-3-3 proteins (YWHAG, YWHAZ). This is a functionally important interaction that mediates nuclear export after AKT phosphorylation. Reason: While FOXO1 does bind proteins, "protein binding" is uninformative. The 14-3-3 interaction is functionally critical but should be annotated to a more specific term if available (e.g., 14-3-3 protein binding or phosphoserine/phosphothreonine binding protein interaction). Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:11237865 Thr-24 phosphorylation alone is critical for interaction with 14-3-3 proteins |
| GO:0005515 protein binding | IPI PMID:11353774 Forkhead homologue in rhabdomyosarcoma functions as a bifunc... | MODIFY | Summary: Reference describes FOXO1 functioning as a nuclear receptor coactivator/corepressor. Reason: "Protein binding" is uninformative. The interaction with nuclear receptors could be more specifically annotated as nuclear receptor binding (GO:0016922), which matches the IPI evidence type; the paper describes FOXO1 as a bifunctional nuclear receptor-interacting protein (coactivator and corepressor), so a coactivator-only activity term would capture only half of it. Proposed replacements: nuclear receptor binding Supporting Evidence: PMID:11353774 2001 May 15. Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions. |
| GO:0005515 protein binding | IPI PMID:15084259 Integration of Smad and forkhead pathways in the control of ... | MODIFY | Summary: Reference describes integration of Smad and forkhead pathways - FOXO1 interacts with Smad proteins. Reason: Smad binding would be more informative than generic protein binding. Proposed replacements: R-SMAD binding Supporting Evidence: PMID:15084259 Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. |
| GO:0005515 protein binding | IPI PMID:15220471 Silent information regulator 2 potentiates Foxo1-mediated tr... | MODIFY | Summary: Reference documents FOXO1 interaction with SIRT1. SIRT1 deacetylates FOXO1 and potentiates its transcriptional activity. Reason: The SIRT1 interaction is functionally important. A more specific term would be informative. Proposed replacements: identical protein binding Supporting Evidence: PMID:15220471 Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity |
| GO:0005515 protein binding | IPI PMID:15692560 Suppression of FOXO1 activity by FHL2 through SIRT1-mediated... | MODIFY | Summary: Reference describes FOXO1 interaction with FHL2 and SIRT1-mediated deacetylation. Reason: Generic protein binding annotation should be made more specific. Proposed replacements: identical protein binding Supporting Evidence: PMID:15692560 Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. |
| GO:0005515 protein binding | IPI PMID:18235501 DBC1 is a negative regulator of SIRT1 | ACCEPT | Summary: Reference documents DBC1 as a negative regulator of SIRT1, affecting FOXO1 indirectly. Reason: The interaction data is valid even if the generic term is uninformative. Supporting Evidence: PMID:18235501 DBC1 is a negative regulator of SIRT1. |
| GO:0005515 protein binding | IPI PMID:18408765 CDK1 promotes cell proliferation and survival via phosphoryl... | MODIFY | Summary: Reference describes CDK1 phosphorylation and inhibition of FOXO1. Reason: Could be more specifically annotated as kinase binding or protein serine/threonine kinase activity. Proposed replacements: cyclin binding Supporting Evidence: PMID:18408765 CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. |
| GO:0005515 protein binding | IPI PMID:18786403 Structural basis for DNA recognition by FoxO1 and its regula... | ACCEPT | Summary: Reference is the structural study of FOXO1 DNA binding domain and its regulation by PTMs. Reason: Valid protein binding evidence from structural study. Supporting Evidence: PMID:18786403 Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification. |
| GO:0005515 protein binding | IPI PMID:24419615 Crystallization and preliminary X-ray analysis of a complex ... | ACCEPT | Summary: Reference describes crystallization of FOXO1/ETS1 DNA-binding complex. Reason: Valid protein-protein interaction evidence. Supporting Evidence: PMID:24419615 Crystallization and preliminary X-ray analysis of a complex of the FOXO1 and Ets1 DNA-binding domains and DNA. |
| GO:0005515 protein binding | IPI PMID:24983498 Inhibition of FoxO1 acetylation by INHAT subunit SET/TAF-IΞ² ... | ACCEPT | Summary: Reference describes FOXO1 interaction with SET/TAF-Ibeta (INHAT subunit). Reason: Valid interaction data. Supporting Evidence: PMID:24983498 Epub 2014 Jun 28. Inhibition of FoxO1 acetylation by INHAT subunit SET/TAF-IΞ² induces p21 transcription. |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | ACCEPT | Summary: Large-scale proximity ligation assay study of protein-protein interactions. Reason: High-throughput interaction data, acceptable as supporting evidence. Supporting Evidence: PMID:25241761 Oct 9. Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network. |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | ACCEPT | Summary: Proteomic study of chromatin-associated transcription factor complexes. Reason: Valid high-throughput interaction data. Supporting Evidence: PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | ACCEPT | Summary: Large-scale human interactome mapping study. Reason: Valid high-throughput interaction data. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | ACCEPT | Summary: Dual proteome-scale network study of human interactome. Reason: Valid high-throughput interaction data. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | ACCEPT | Summary: OpenCell study using endogenous tagging for cellular organization mapping. Reason: Valid high-throughput interaction and localization data. Supporting Evidence: PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | ACCEPT | Summary: Study of mutation-directed neo-protein-protein interactions in cancer. Reason: Valid interaction data. Supporting Evidence: PMID:35512704 2022 May 4. Systematic discovery of mutation-directed neo-protein-protein interactions in cancer. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: Study describing 14-3-3 proteins as central chaperones with FOXO1 as a client. Reason: This specifically documents 14-3-3 binding which should be annotated more specifically. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human cells. |
| GO:0000785 chromatin | IEA GO_REF:0000107 | ACCEPT | Summary: FOXO1 associates with chromatin when functioning as a transcription factor. Reason: FOXO1 binds to chromatin at target gene promoters. This is consistent with its transcription factor function, which is directly evidenced elsewhere in this review (sequence-specific binding to the DBE/IRE elements of target promoters). The additional claim that FOXO family members act as pioneer factors opening condensed chromatin is not supported by any reference cached for this review and has been dropped rather than cited; PMID:37710009 is available here as abstract only and does not mention chromatin or pioneer-factor activity. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate of IBA annotation. FOXO1 binds to specific cis-regulatory sequences. Reason: Core molecular function annotation. |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: FOXO1 can function as a transcriptional repressor for certain genes (e.g., PDX1, PPARG). Reason: Valid molecular function - FOXO1 has documented repressor activity for specific target genes. Supporting Evidence: UniProt:Q12778 Acts as an inhibitor of glucose sensing in pancreatic beta cells by acting as a transcription repressor and suppressing expression of PDX1 (By similarity). |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: FOXO1's primary function is as a transcriptional activator of target genes involved in metabolism, stress responses, and cell cycle regulation; its gluconeogenic role is supported in context, with an indirect FOXO1βPGC-1alpha interaction reported. Reason: Core molecular function - FOXO1 is primarily a transcriptional activator. Supporting Evidence: PMID:17024043 FOXO1 and the transcriptional co-activator PGC-1alpha act synergistically to stimulate the expression of genes in the gluconeogenesis pathway |
| GO:0006357 regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate annotation. FOXO1 regulates Pol II-mediated transcription. Reason: Core biological process for a transcription factor. |
| GO:0006974 DNA damage response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FOXO1 participates in DNA damage response by activating genes involved in DNA repair and cell cycle arrest. This is part of its broader stress response function. Reason: FOXO1 does contribute to DNA damage response through transcriptional regulation of relevant genes, but this is a downstream effect of its stress-responsive transcription factor activity rather than its primary evolved function (gluconeogenesis). Supporting Evidence: PMID:37891184 elevated levels of reactive oxygen species (ROS), nutrient deprivation, or DNA damage, can activate FOXOs to restore cellular homeostasis |
| GO:0008286 insulin receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate of IBA annotation. FOXO1 is a key component of insulin signaling. Reason: Core biological process - FOXO1 is the main transcriptional target of insulin-PI3K-AKT signaling. |
| GO:0031490 chromatin DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: FOXO1 binds to DNA within chromatin context at target gene promoters and enhancers. Reason: Specific subtype of DNA binding that accurately describes how FOXO1 functions in the cell. |
| GO:0032869 cellular response to insulin stimulus | IEA GO_REF:0000107 | ACCEPT | Summary: FOXO1 mediates cellular responses to insulin - it is phosphorylated and inactivated by the insulin-stimulated PI3K-AKT pathway. Reason: Core function - FOXO1's regulation by insulin is central to its role in metabolic homeostasis. Supporting Evidence: PMID:10358076 Insulin disrupts IRS-dependent transactivation by FKHR |
| GO:0034599 cellular response to oxidative stress | IEA GO_REF:0000107 | ACCEPT | Summary: FOXO1 is activated by and mediates cellular responses to oxidative stress. Oxidative stress promotes FOXO1 nuclear localization and transcriptional activation of antioxidant genes. Reason: Core function - oxidative stress response is one of FOXO1's primary evolved roles alongside metabolic regulation. FOXOs are described as "mediators of stress adaptation." Supporting Evidence: PMID:37710009 FOXO transcription factors as mediators of stress adaptation |
| GO:0045599 negative regulation of fat cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FOXO1 inhibits adipogenesis by repressing PPARG expression. This is a documented function in adipocyte biology. Reason: Valid annotation with experimental support. FOXO1 does negatively regulate adipogenesis, but this is a tissue-specific function rather than the core evolved function (gluconeogenesis in liver). Mark as non-core. Supporting Evidence: UniProt:Q12778 Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation |
| GO:0045722 positive regulation of gluconeogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate of IBA annotation. Core function of FOXO1. Reason: Core function - regulation of gluconeogenesis is FOXO1's primary evolved metabolic role. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: FOXO1 activates transcription of target genes. This is its primary molecular activity. Reason: Core biological process - FOXO1 is primarily a transcriptional activator. |
| GO:0046676 negative regulation of insulin secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FOXO1 can negatively regulate insulin secretion in pancreatic beta cells through suppression of PDX1 expression. Reason: This is a tissue-specific function in beta cells, not the core evolved function. Valid but non-core. Supporting Evidence: UniProt:Q12778 Acts as an inhibitor of glucose sensing in pancreatic beta cells |
| GO:0051721 protein phosphatase 2A binding | IEA GO_REF:0000107 | ACCEPT | Summary: FOXO1 interacts with PP2A (via PPP2R1A subunit). PP2A dephosphorylates FOXO1 at T24 and S256, promoting nuclear import. Reason: Valid molecular function - PP2A interaction is important for FOXO1 regulation. Supporting Evidence: UniProt:Q12778 Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin- dependent BGLAP expression in osteoblasts Interacts with PPP2R1A; the interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser- 256 leading to its nuclear import |
| GO:0070542 response to fatty acid | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FOXO1 responds to fatty acids and regulates lipid metabolism genes. In chondrogenic commitment, FOXO1 responds to low lipid levels. Reason: Valid but represents a context-specific response rather than core function. FOXO1's role in lipid sensing is secondary to its primary metabolic function in gluconeogenesis. Supporting Evidence: UniProt:Q12778 key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability |
| GO:0071732 cellular response to nitric oxide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FOXO1 mediates cellular responses to nitric oxide, including transcriptional activation of DNA repair genes in beta cells. Reason: Valid stress response function but represents one of many stress stimuli that activate FOXO1 rather than a core evolved function. Supporting Evidence: UniProt:Q12778 Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells |
| GO:1990841 promoter-specific chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: FOXO1 binds to chromatin at specific promoters of target genes. Reason: Accurate molecular function describing how FOXO1 engages chromatin at target gene promoters. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence data showing FOXO1 in nucleoplasm. Reason: Direct experimental evidence for nucleoplasm localization. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence data showing FOXO1 in cytosol. Reason: Direct experimental evidence. Cytosolic localization is the inactive, phosphorylated state. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:28851713 SCP4 promotes gluconeogenesis through FoxO1/3a dephosphoryla... | ACCEPT | Summary: SCP4 dephosphorylates FOXO1, promoting gluconeogenesis. This demonstrates FOXO1's transcriptional activator function. Reason: Core molecular function with direct experimental evidence. Supporting Evidence: PMID:28851713 SCP4 Promotes Gluconeogenesis Through FoxO1/3a Dephosphorylation. |
| GO:0005515 protein binding | IPI PMID:28851713 SCP4 promotes gluconeogenesis through FoxO1/3a dephosphoryla... | ACCEPT | Summary: FOXO1 interaction with SCP4 phosphatase. Reason: Valid protein-protein interaction. Supporting Evidence: PMID:28851713 SCP4 Promotes Gluconeogenesis Through FoxO1/3a Dephosphorylation. |
| GO:0005634 nucleus | IDA PMID:28851713 SCP4 promotes gluconeogenesis through FoxO1/3a dephosphoryla... | ACCEPT | Summary: Direct assay showing nuclear localization. Reason: Direct experimental evidence for nuclear localization. Supporting Evidence: PMID:28851713 SCP4 Promotes Gluconeogenesis Through FoxO1/3a Dephosphorylation. |
| GO:0005515 protein binding | IPI PMID:19483080 C terminus of Hsc70-interacting protein promotes smooth musc... | MODIFY | Summary: FOXO1 interaction with STUB1/CHIP E3 ligase. Reason: Could be more specifically annotated as ubiquitin ligase binding. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:19483080 2009 May 29. C terminus of Hsc70-interacting protein promotes smooth muscle cell proliferation and survival through ubiquitin-mediated degradation of FoxO1. |
| GO:0034393 positive regulation of smooth muscle cell apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FOXO1 promotes apoptosis in smooth muscle cells through transcriptional activation of pro-apoptotic genes. Reason: Tissue-specific function. FOXO1 can promote apoptosis but this is a downstream effect rather than core function. Valid but non-core. Supporting Evidence: PMID:19483080 overexpression of CHIP repressed FoxO1-mediated transactivation and its proapoptotic function following tumor necrosis factor-alpha treatment. |
| GO:0060260 regulation of transcription initiation by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: FOXO1 regulates transcription initiation at target gene promoters. Reason: Appropriate biological process term for a transcription factor. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5692779 | ACCEPT | Summary: MAPKAPK5 phosphorylates FOXO1 in nucleoplasm. Reason: Supported by Reactome pathway annotation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5692785 | ACCEPT | Summary: Phosphorylated FOXO1 binds RAG gene in nucleoplasm. Reason: Supported by Reactome pathway annotation. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:17024043 Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connecti... | MARK AS OVER ANNOTATED | Summary: PMID:17024043 is a comment re-evaluating the FOXO1βPGC-1alpha model and does not provide direct experimental evidence for FOXO1 transcriptional activation. Reason: The abstract reports FOXO1 is neither required nor sufficient for PGC-1alpha-driven G6Pase reporter activation and that the FOXO1βPGC-1alpha interaction is indirect, so this PMID alone is not strong IDA support for transcription activator activity. Supporting Evidence: PMID:17024043 FOXO1 is neither required nor sufficient for the stimulation of G6Pase-luciferase fusion gene expression by PGC-1alpha |
| GO:0005634 nucleus | IDA PMID:25009184 Tumor suppressor p53 cooperates with SIRT6 to regulate gluco... | ACCEPT | Summary: p53 and SIRT6 cooperate to regulate FOXO1 nuclear localization and gluconeogenesis. Reason: Direct experimental evidence for nuclear localization. Supporting Evidence: PMID:25009184 Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. |
| GO:0005737 cytoplasm | IDA PMID:25009184 Tumor suppressor p53 cooperates with SIRT6 to regulate gluco... | ACCEPT | Summary: SIRT6-mediated deacetylation promotes FOXO1 cytoplasmic translocation. Reason: Direct experimental evidence showing cytoplasmic localization after SIRT6 deacetylation. Supporting Evidence: PMID:25009184 whose interaction with FoxO1 leads to FoxO1 deacetylation and export to the cytoplasm. |
| GO:0045722 positive regulation of gluconeogenesis | IDA PMID:17024043 Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connecti... | MARK AS OVER ANNOTATED | Summary: PMID:17024043 re-evaluates the FOXO1βPGC-1alpha connection and reports FOXO1 is not required or sufficient for PGC-1alpha-driven G6Pase reporter activation. Reason: This comment does not provide direct evidence that FOXO1 positively regulates gluconeogenesis; it instead reports an indirect FOXO1βPGC-1alpha interaction and lack of requirement for FOXO1 in PGC-1alpha-driven G6Pase reporter activity. Supporting Evidence: PMID:17024043 FOXO1 is neither required nor sufficient for the stimulation of G6Pase-luciferase fusion gene expression by PGC-1alpha |
| GO:0045722 positive regulation of gluconeogenesis | IDA PMID:25009184 Tumor suppressor p53 cooperates with SIRT6 to regulate gluco... | ACCEPT | Summary: SIRT6 inhibits FOXO1-mediated gluconeogenesis by promoting nuclear exclusion. Reason: Additional evidence for FOXO1's core gluconeogenic function. Supporting Evidence: PMID:25009184 Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. |
| GO:0046676 negative regulation of insulin secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FOXO1 inhibits insulin secretion in beta cells. Reason: Tissue-specific function in pancreatic beta cells, not core evolved function. |
| GO:0003676 nucleic acid binding | EXP PMID:18786403 Structural basis for DNA recognition by FoxO1 and its regula... | ACCEPT | Summary: Structural study demonstrating FOXO1's DNA binding activity. Reason: General term but supported by structural evidence. More specific terms also present. Supporting Evidence: PMID:18786403 Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:17024043 Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connecti... | MARK AS OVER ANNOTATED | Summary: PMID:17024043 discusses FOXO1 in the context of gluconeogenic gene regulation but provides limited direct evidence for transcription factor activity. Reason: This comment focuses on re-evaluating the FOXO1βPGC-1alpha relationship and reports an indirect interaction; it is not primary experimental evidence of FOXO1 transcription factor activity. Supporting Evidence: PMID:17024043 Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection. |
| GO:0003700 DNA-binding transcription factor activity | IMP PMID:31063815 Cyclophilin A-FoxO1 signaling pathway in endothelial cell ap... | ACCEPT | Summary: Cyclophilin A-FOXO1 signaling in endothelial cell apoptosis demonstrates FOXO1's transcription factor activity. Reason: Mutant phenotype evidence for transcription factor function. Supporting Evidence: PMID:31063815 May 4. Cyclophilin A-FoxO1 signaling pathway in endothelial cell apoptosis. |
| GO:0005515 protein binding | IPI PMID:31063815 Cyclophilin A-FoxO1 signaling pathway in endothelial cell ap... | ACCEPT | Summary: FOXO1 interacts with cyclophilin A (PPIA). Reason: Valid protein-protein interaction. Supporting Evidence: PMID:31063815 May 4. Cyclophilin A-FoxO1 signaling pathway in endothelial cell apoptosis. |
| GO:0005634 nucleus | IDA PMID:31063815 Cyclophilin A-FoxO1 signaling pathway in endothelial cell ap... | ACCEPT | Summary: Nuclear localization demonstrated in endothelial cell study. Reason: Direct experimental evidence. Supporting Evidence: PMID:31063815 May 4. Cyclophilin A-FoxO1 signaling pathway in endothelial cell apoptosis. |
| GO:0005737 cytoplasm | IDA PMID:31063815 Cyclophilin A-FoxO1 signaling pathway in endothelial cell ap... | ACCEPT | Summary: Cytoplasmic localization in endothelial cells. Reason: Direct experimental evidence. Supporting Evidence: PMID:31063815 May 4. Cyclophilin A-FoxO1 signaling pathway in endothelial cell apoptosis. |
| GO:0006915 apoptotic process | IMP PMID:31063815 Cyclophilin A-FoxO1 signaling pathway in endothelial cell ap... | KEEP AS NON CORE | Summary: FOXO1 regulates endothelial cell apoptosis through transcription of BCL2L11. Reason: Valid annotation showing FOXO1's role in apoptosis, but this is a downstream effect of transcriptional regulation rather than core function. Supporting Evidence: PMID:31063815 Moreover, CyPA induced FoxO1-dependent expression of downstream genes involved in EC chemotaxis and apoptosis, including monocyte chemoattractant protein-1 and BCL-2-interacting mediator of cell death, and stimulated the apoptosis of human umbilical vein ECs in vitro. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence similarity-based evidence for transcriptional activator function. Reason: Core function supported by multiple evidence types. |
| GO:0070542 response to fatty acid | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FOXO1 responds to fatty acid levels. Reason: Context-specific response, not core function. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass database annotation for chromatin association. Reason: Valid cellular component annotation. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass database annotation for Pol II transcription factor activity. Reason: Core molecular function. |
| GO:1903243 negative regulation of cardiac muscle hypertrophy in response to stress | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FOXO1 can inhibit cardiac hypertrophy. Reason: Tissue-specific function in heart. Valid but not core function. Supporting Evidence: UniProt:Q12778 Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:27577745 MARCH1 regulates insulin sensitivity by controlling cell sur... | ACCEPT | Summary: MARCH1 study showing FOXO1's transcriptional activation function. Reason: Core biological process. Supporting Evidence: PMID:27577745 MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels. |
| GO:0008013 beta-catenin binding | IDA PMID:15905404 Functional interaction between beta-catenin and FOXO in oxid... | ACCEPT | Summary: Direct evidence for FOXO1-beta-catenin interaction in oxidative stress signaling. Reason: Direct experimental evidence for specific protein-protein interaction. Supporting Evidence: PMID:15905404 Functional interaction between beta-catenin and FOXO in oxidative stress signaling |
| GO:0005515 protein binding | IPI PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ... | ACCEPT | Summary: FOXO1 interacts with ATG7 in cytoplasm for autophagy induction. Reason: Valid protein-protein interaction data. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. |
| GO:0005634 nucleus | IDA PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ... | ACCEPT | Summary: Nuclear localization in autophagy study. Reason: Direct experimental evidence. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. |
| GO:0005737 cytoplasm | IDA PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ... | ACCEPT | Summary: Cytoplasmic localization important for autophagy function. Reason: Direct experimental evidence. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. |
| GO:0009267 cellular response to starvation | IDA PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ... | ACCEPT | Summary: FOXO1 mediates cellular response to starvation/nutrient deprivation. Reason: Core function - FOXO1 is activated by starvation to promote gluconeogenesis and autophagy. Supporting Evidence: PMID:20543840 Endogenous FoxO1 was required for autophagy in human cancer cell lines in response to oxidative stress or serum starvation, but this process was independent of the transcriptional activity of FoxO1. |
| GO:0010508 positive regulation of autophagy | IMP PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ... | KEEP AS NON CORE | Summary: FOXO1 promotes autophagy through both transcriptional and non-transcriptional mechanisms. Reason: Valid but represents a downstream stress response rather than core function. The core function is metabolic regulation. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ... | ACCEPT | Summary: FOXO1 interacts with ubiquitin E3 ligases including STUB1/CHIP. Reason: Valid molecular function relevant to FOXO1 regulation. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ... | KEEP AS NON CORE | Summary: FOXO1 promotes apoptosis under stress conditions. Reason: Valid but downstream effect of FOXO1's transcriptional activity rather than core function. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. |
| GO:0045732 positive regulation of protein catabolic process | IMP PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ... | KEEP AS NON CORE | Summary: FOXO1 promotes protein catabolism through autophagy induction. Reason: Downstream effect of autophagy induction, not core function. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. |
| GO:0071455 cellular response to hyperoxia | IDA PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy ... | ACCEPT | Summary: FOXO1 responds to oxidative stress including hyperoxia. Reason: Part of FOXO1's stress response function. Supporting Evidence: PMID:20543840 Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. |
| GO:0032869 cellular response to insulin stimulus | ISS GO_REF:0000024 | ACCEPT | Summary: Duplicate annotation for insulin response. Reason: Core function. |
| GO:0045599 negative regulation of fat cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FOXO1 inhibits adipogenesis. Reason: Tissue-specific function, not core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-211178 | ACCEPT | Summary: Phosphorylated FOXO1 is excluded from nucleus and found in cytosol. Reason: Valid localization annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9614414 | ACCEPT | Summary: AKT-phosphorylated FOXO translocates to cytosol. Reason: Valid localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9614423 | ACCEPT | Summary: 14-3-3 binds phosphorylated FOXO1 in cytosol. Reason: Valid localization. |
| GO:0005739 mitochondrion | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | UNDECIDED | Summary: Some evidence for mitochondrial localization of FOXO1. Reason: Mitochondrial localization of FOXO1 is not well-established. The primary localizations are nucleus and cytoplasm. This may represent a minor or context-specific localization. Need more evidence. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0005634 nucleus | IDA PMID:18680538 GAS6-induced signaling in human endothelial cells is mediate... | ACCEPT | Summary: Nuclear localization evidence. Reason: Direct evidence for nuclear localization. Supporting Evidence: PMID:18680538 GAS6-induced signaling in human endothelial cells is mediated by FOXO1a. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-199299 | ACCEPT | Summary: AKT phosphorylates FOXO transcription factors in nucleoplasm. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-211164 | ACCEPT | Summary: AKT phosphorylates FOXO1A in nucleoplasm. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-211178 | ACCEPT | Summary: Phosphorylated FOXO1A is excluded from the nucleus. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2399992 | ACCEPT | Summary: AKT1 E17K mutant phosphorylates FOXO transcription factors. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6790036 | ACCEPT | Summary: STAT3-upregulated nuclear proteins including FOXO. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9614414 | ACCEPT | Summary: AKT-phosphorylated FOXOs translocate to cytosol. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9614662 | ACCEPT | Summary: FOXO1 binds FASLG gene promoter. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9617840 | ACCEPT | Summary: FOXO1 binds CDKN1A gene promoter. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9617996 | ACCEPT | Summary: FOXO1 binds SMAD2/3:SMAD4 complex. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9622980 | ACCEPT | Summary: FOXO1 binds NPY gene promoter. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9623415 | ACCEPT | Summary: FOXO1 binds IGFBP1 gene promoter. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9624976 | ACCEPT | Summary: FOXO1 binds CAV1 gene promoter. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9625091 | ACCEPT | Summary: FOXO1 binds ABCA6 gene promoter. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9626928 | ACCEPT | Summary: CREBBP binds FOXO1. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-9620806 | ACCEPT | Summary: FOXO1 binds Rbl2 gene. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-9620857 | ACCEPT | Summary: FOXO1 binds Ccng2 gene. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-9624599 | ACCEPT | Summary: FOXO1 binds Fbxo32 gene promoter. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-9625492 | ACCEPT | Summary: FOXO1 and Smad2/3:Smad4 bind Mstn gene promoter. Reason: Supported by Reactome pathway. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-9625758 | ACCEPT | Summary: FOXO1 and SMAD3 bind Trim63 gene promoter. Reason: Supported by Reactome pathway. |
| GO:0006974 DNA damage response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FOXO1 participates in DNA damage response. Reason: Downstream stress response, not core function. |
| GO:0071732 cellular response to nitric oxide | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FOXO1 responds to nitric oxide. Reason: Stress response, not core function. |
| GO:0034599 cellular response to oxidative stress | ISS GO_REF:0000024 | ACCEPT | Summary: FOXO1 responds to oxidative stress. Reason: Core function - oxidative stress response is one of FOXO1's primary evolved roles. |
| GO:0051721 protein phosphatase 2A binding | ISS GO_REF:0000024 | ACCEPT | Summary: PP2A binding for FOXO1 dephosphorylation. Reason: Valid molecular function. |
| GO:0005515 protein binding | IPI PMID:15890677 The coactivator p300 directly acetylates the forkhead transc... | MODIFY | Summary: FOXO1 interacts with p300 coactivator. Reason: Should be annotated more specifically. Proposed replacements: transcription coactivator activity Supporting Evidence: PMID:15890677 May 12. The coactivator p300 directly acetylates the forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription. |
| GO:0001659 temperature homeostasis | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | KEEP AS NON CORE | Summary: FOXO1 role in temperature homeostasis through metabolic regulation. Reason: Downstream physiological effect, not core molecular function. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0001678 intracellular glucose homeostasis | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | ACCEPT | Summary: FOXO1 regulates glucose homeostasis through gluconeogenic gene transcription. Reason: Core function - glucose homeostasis is central to FOXO1's evolved role. Supporting Evidence: PMID:37891184 Decreased expression of hepatic FOXO1 is associated with lower levels of glucose in mice, both at birth and in adulthood. PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0003682 chromatin binding | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | ACCEPT | Summary: FOXO1 binds chromatin at target gene promoters. Reason: Valid molecular function for a transcription factor. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0005829 cytosol | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | ACCEPT | Summary: Cytosolic localization. Reason: Valid cellular component annotation. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0006473 protein acetylation | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | MARK AS OVER ANNOTATED | Summary: FOXO1 is acetylated; its acetylation status regulates activity. Reason: This term implies FOXO1 has acetyltransferase activity, which is incorrect. FOXO1 is a substrate of acetylation, not an enzyme that performs acetylation. The annotation should be removed or replaced with a term about being modified by acetylation. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0009267 cellular response to starvation | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | ACCEPT | Summary: FOXO1 responds to starvation by promoting gluconeogenesis. Reason: Core function - starvation response through gluconeogenesis is central to FOXO1. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0045444 fat cell differentiation | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | KEEP AS NON CORE | Summary: FOXO1 regulates adipogenesis. Reason: Tissue-specific function, not core. FOXO1 inhibits rather than promotes this process. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0045892 negative regulation of DNA-templated transcription | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | ACCEPT | Summary: FOXO1 can repress transcription of certain genes. Reason: Valid biological process - FOXO1 acts as repressor for some targets. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0070417 cellular response to cold | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | KEEP AS NON CORE | Summary: FOXO1 role in cold response through metabolic adaptation. Reason: Downstream physiological effect, not core molecular function. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0097009 energy homeostasis | ISS PMID:22510882 Novel repressor regulates insulin sensitivity through intera... | ACCEPT | Summary: FOXO1 regulates energy homeostasis through metabolic gene transcription. Reason: Core function - energy/metabolic homeostasis is central to FOXO1. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1. |
| GO:0005737 cytoplasm | IDA PMID:11237865 Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphoryla... | ACCEPT | Summary: Cytoplasmic localization with 14-3-3 binding. Reason: Direct experimental evidence. Supporting Evidence: PMID:11237865 Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting. |
| GO:0008286 insulin receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: FOXO1 in insulin signaling. Reason: Core function. |
| GO:0032873 negative regulation of stress-activated MAPK cascade | IDA PMID:19696738 FoxM1, a critical regulator of oxidative stress during oncog... | UNDECIDED | Summary: FoxM1 paper - may be mislabeled for FOXO1. Reason: The cited reference PMID:19696738 is about FoxM1, not FOXO1. This may be an annotation error. Need verification. Supporting Evidence: PMID:19696738 FoxM1, a critical regulator of oxidative stress during oncogenesis. |
| GO:0005515 protein binding | IPI PMID:17030088 APPL1, APPL2, Akt2 and FOXO1a interact with FSHR in a potent... | ACCEPT | Summary: FOXO1 interacts with APPL1, APPL2, AKT2 in FSH receptor complex. Reason: Valid protein-protein interaction data. Supporting Evidence: PMID:17030088 Epub 2006 Oct 9. APPL1, APPL2, Akt2 and FOXO1a interact with FSHR in a potential signaling complex. |
| GO:0005634 nucleus | IDA PMID:11311120 The kinase DYRK1A phosphorylates the transcription factor FK... | ACCEPT | Summary: DYRK1A phosphorylation study showing nuclear FOXO1. Reason: Direct experimental evidence. Supporting Evidence: PMID:11311120 Ser(329) phosphorylation also decreases the ability of FKHR to stimulate gene transactivation and reduces the proportion of FKHR present in the nucleus. |
| GO:0005634 nucleus | IDA PMID:12228231 Phosphorylation of serine 256 suppresses transactivation by ... | ACCEPT | Summary: Phosphorylation study showing nuclear localization. Reason: Direct experimental evidence. Supporting Evidence: PMID:12228231 2002 Sep 12. Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. |
| GO:0005737 cytoplasm | IDA PMID:11311120 The kinase DYRK1A phosphorylates the transcription factor FK... | ACCEPT | Summary: Cytoplasmic localization after phosphorylation. Reason: Direct experimental evidence. Supporting Evidence: PMID:11311120 The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. |
| GO:0005737 cytoplasm | IDA PMID:12228231 Phosphorylation of serine 256 suppresses transactivation by ... | ACCEPT | Summary: Cytoplasmic localization after insulin stimulation. Reason: Direct experimental evidence. Supporting Evidence: PMID:12228231 2002 Sep 12. Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:10871843 Transcriptional modulation of the anti-apoptotic protein BCL... | UNDECIDED | Summary: PAX3/FKHR fusion study - shows FOXO1 can have anti-apoptotic effects in certain contexts. Reason: This reference is about PAX3-FKHR fusion protein in rhabdomyosarcoma, not wild-type FOXO1 function. The annotation may be misleading as FOXO1 is generally pro-apoptotic. Need clarification. Supporting Evidence: PMID:10871843 Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:12228231 Phosphorylation of serine 256 suppresses transactivation by ... | ACCEPT | Summary: Direct evidence for sequence-specific DNA binding from phosphorylation study. Reason: Core molecular function with direct evidence. Supporting Evidence: PMID:12228231 Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:10871843 Transcriptional modulation of the anti-apoptotic protein BCL... | ACCEPT | Summary: PAX3/FKHR study showing transcriptional activation. Reason: Direct evidence for transcriptional activation function. Supporting Evidence: PMID:10871843 Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:12228231 Phosphorylation of serine 256 suppresses transactivation by ... | ACCEPT | Summary: Evidence for FOXO1 transcriptional activation function. Reason: Core biological process. Supporting Evidence: PMID:12228231 2002 Sep 12. Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:7862145 The PAX3-FKHR fusion protein created by the t(2;13) transloc... | ACCEPT | Summary: Early PAX3-FKHR fusion study showing transcriptional activation. Reason: Early evidence for FOXO1's transactivation domain function. Supporting Evidence: PMID:7862145 The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:10871843 Transcriptional modulation of the anti-apoptotic protein BCL... | ACCEPT | Summary: Evidence for Pol II-mediated transcription activation. Reason: Core biological process. Supporting Evidence: PMID:10871843 Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:12228231 Phosphorylation of serine 256 suppresses transactivation by ... | ACCEPT | Summary: Evidence for Pol II-mediated transcription activation. Reason: Core biological process. Supporting Evidence: PMID:12228231 2002 Sep 12. Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. |
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Download this section (compressed HTML)Q: Is there evidence for isoform-specific functions of FOXO1 versus FOXO3/FOXO4 in specific tissues, particularly in hepatic gluconeogenesis versus other metabolic processes?
Q: What is the relative contribution of FOXO1's transcriptional versus non-transcriptional (cytoplasmic ATG7 interaction) roles in autophagy regulation?
Experiment: ChIP-seq comparison of FOXO1 binding sites in fed versus fasted hepatocytes to define the core gluconeogenic gene regulatory program.
Experiment: Structure-function analysis of FOXO1 acetylation sites to determine which modifications are essential for transcription factor activity versus autophagy induction.
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