Existing Annotations Review

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 santos2023foxofamilyisoforms FOXO1 is a forkhead box O transcription factor that binds DNA via a conserved winged-helix 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 FOXO1–PGC-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 santos2023foxofamilyisoforms hepatic FOXO1 (with FOXO3/4) controls gluconeogenic programs
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: rodriguezcolman2024foxotranscriptionfactors 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 cheng2024forkheadboxo FOXO proteins recognize the DAF-16 family binding element (DBE; 5'-TTGTTTAC-3') with high 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 santos2023foxofamilyisoforms AKT/PKB phosphorylation at conserved FOXO1 residues Thr24, Ser256, and Ser319 creates 14-3-3 docking sites
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). Supporting Evidence: PMID:15905404 Functional interaction between beta-catenin and FOXO in oxidative stress signaling rodriguezcolman2024foxotranscriptionfactors β-catenin can relieve autoinhibition of the DBD
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 coactivator activity or similar. Proposed replacements: nuclear receptor transcription coactivator activity 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	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	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-Iβ ...	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-Iβ 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	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. Recent evidence suggests FOXOs can act as pioneer factors to open condensed chromatin. Reason: FOXO1 binds to chromatin at target gene promoters. This is consistent with its transcription factor function. Supporting Evidence: rodriguezcolman2024foxotranscriptionfactors FOXO family members can act as pioneer factors to open condensed chromatin
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 FOXO1–PGC-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: santos2023foxofamilyisoforms FOXO1 activates genes involved in DNA repair and stress resistance
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: rodriguezcolman2024foxotranscriptionfactors 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 FOXO1–PGC-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 FOXO1–PGC-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 FOXO1–PGC-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 FOXO1–PGC-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	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 FOXO1–PGC-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: santos2023foxofamilyisoforms hepatic FOXO1 controls gluconeogenic programs 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	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.

Core Functions

FOXO1 is a sequence-specific DNA-binding transcription factor that 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 domain to regulate transcription of target genes.

Molecular Function:

DNA-binding transcription factor activity, RNA polymerase II-specific

Directly Involved In:

positive regulation of gluconeogenesis

FOXO1 is the main downstream effector of insulin signaling through the PI3K-AKT pathway. Insulin-activated AKT phosphorylates FOXO1 at T24/S256/S319, promoting 14-3-3 binding, nuclear export, and transcriptional inactivation. This represents FOXO1's role as the transcriptional switch for insulin signaling.

Molecular Function:

DNA-binding transcription factor activity, RNA polymerase II-specific

Directly Involved In:

insulin receptor signaling pathway

FOXO1 mediates cellular adaptation to oxidative stress by translocating to the nucleus and activating transcription of antioxidant and stress resistance genes. This represents one of FOXO1's primary evolved functions alongside metabolic regulation.

Molecular Function:

DNA-binding transcription factor activity, RNA polymerase II-specific

Directly Involved In:

cellular response to oxidative stress

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000113

Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass database

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10358076

Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR

FOXO1 binds to IRE consensus sequence and is suppressed by insulin-activated AKT

PMID:10871843

Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR.

PMID:11237865

Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting.

AKT phosphorylation of T24/S256/S319 promotes 14-3-3 binding and nuclear export

PMID:11311120

The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site.

FOXO1 is largely nuclear in unstimulated cells

PMID:11353774

Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions.

PMID:12228231

Phosphorylation of serine 256 suppresses transactivation by FKHR

Ser256 phosphorylation decreases DNA binding and promotes nuclear exclusion

PMID:15084259

Integration of Smad and forkhead pathways

PMID:15220471

Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.

SIRT1 deacetylates FOXO1 and enhances transcriptional activity

PMID:15692560

Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation

PMID:15890677

The coactivator p300 directly acetylates the forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription.

p300/CBP acetylate FOXO1 and modulate its activity

PMID:15905404

Functional interaction between beta-catenin and FOXO in oxidative stress signaling

Beta-catenin interacts with FOXO1 and modulates oxidative stress response

PMID:17024043

Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection

The original model proposed FOXO1 and PGC-1alpha act synergistically to stimulate gluconeogenic gene expression.

"FOXO1 and the transcriptional co-activator PGC-1alpha act synergistically to stimulate the expression of genes in the gluconeogenesis pathway"
This report finds FOXO1 is neither required nor sufficient for PGC-1alpha-driven activation of G6Pase reporter expression.

"FOXO1 is neither required nor sufficient for the stimulation of G6Pase-luciferase fusion gene expression by PGC-1alpha"
The data indicate the FOXO1–PGC-1alpha transcriptional interaction is indirect.

"the transcriptional interaction between FOXO1 and PGC-1alpha is indirect"

PMID:17030088

APPL1, APPL2, Akt2 and FOXO1a interact with FSHR

PMID:18235501

DBC1 is a negative regulator of SIRT1

PMID:18356527

Activation of FOXO1 by Cdk1

CDK1 phosphorylates FOXO1 at Ser249

PMID:18408765

CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor.

PMID:18680538

GAS6-induced signaling in human endothelial cells is mediated by FOXO1a.

PMID:18786403

Structural basis for DNA recognition by FoxO1

X-ray crystallography of FOXO1 DNA-binding domain

PMID:19483080

C terminus of Hsc70-interacting protein promotes smooth muscle cell proliferation and survival through ubiquitin-mediated degradation of FoxO1.

STUB1/CHIP ubiquitinates and degrades FOXO1

PMID:19696738

FoxM1, a critical regulator of oxidative stress during oncogenesis.

PMID:20543840

Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.

Acetylated cytosolic FOXO1 interacts with ATG7 to promote autophagy

PMID:22510882

Novel repressor regulates insulin sensitivity through interaction with Foxo1.

PMID:24419615

Crystallization and preliminary X-ray analysis of a complex of the FOXO1 and Ets1 DNA-binding domains and DNA.

PMID:24983498

Inhibition of FoxO1 acetylation by INHAT subunit SET/TAF-Iβ induces p21 transcription.

PMID:25009184

Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion.

SIRT6 deacetylates FOXO1 at K423 promoting cytoplasmic translocation

PMID:25241761

Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.

PMID:25609649

Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.

PMID:27577745

MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor

PMID:28514442

Architecture of the human interactome

PMID:28851713

SCP4 promotes gluconeogenesis through FoxO1/3a dephosphorylation

PMID:31063815

Cyclophilin A-FoxO1 signaling pathway in endothelial cell apoptosis.

PPIA promotes FOXO1 dephosphorylation and nuclear accumulation

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:35512704

Systematic discovery of mutation-directed neo-protein-protein interactions

PMID:36931259

A central chaperone-like role for 14-3-3 proteins in human cells.

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.

santos2023foxofamilyisoforms

FOXO family isoforms

FOXO1 is a forkhead box O transcription factor with conserved winged-helix DBD
AKT phosphorylation creates 14-3-3 binding sites driving nuclear export

cheng2024forkheadboxo

Forkhead box O proteins - steering the course of stem cell fate

FOXO proteins recognize DBE (5'-TTGTTTAC-3') with high affinity

rodriguezcolman2024foxotranscriptionfactors

FOXO transcription factors as mediators of stress adaptation

FOXOs can act as pioneer factors to open condensed chromatin
PTM code determines context-specific genome engagement

Reactome:R-HSA-199299

AKT phosphorylates FOXO transcription factors

Reactome:R-HSA-211164

AKT phosphorylates FOXO1A

Reactome:R-HSA-211178

Phosphorylated FOXO1A is excluded from the nucleus

Reactome:R-HSA-2399992

AKT1 E17K mutant phosphorylates forkhead box transcription factors

Reactome:R-HSA-5692779

p-T182 MAPKAPK5 phosphorylates FOXO1

Reactome:R-HSA-5692785

p-S215 FOXO1 binds RAG gene

Reactome:R-HSA-6790036

Expression of STAT3-upregulated nuclear proteins

Reactome:R-HSA-9614414

AKT-phosphorylated FOXO1,FOXO3,FOXO4 translocate to the cytosol

Reactome:R-HSA-9614423

14-3-3 proteins bind AKT-phosphorylated FOXO1

Reactome:R-HSA-9614662

FOXO1,FOXO3,(FOXO4) bind FASLG gene promoter

Reactome:R-HSA-9617840

FOXO1,FOXO3,FOXO4 bind CDKN1A gene promoter

Reactome:R-HSA-9617996

FOXO1,FOXO3,FOXO4 bind p-2S-SMAD2/3:SMAD4

Reactome:R-HSA-9622980

FOXO1 binds NPY gene promoter

Reactome:R-HSA-9623415

FOXO1,FOXO3,FOXO4 bind IGFBP1 gene promoter

Reactome:R-HSA-9624976

FOXO1,FOXO3 binds CAV1 gene promoter

Reactome:R-HSA-9625091

FOXO1,FOXO3 bind ABCA6 gene promoter

Reactome:R-HSA-9626928

CREBBP binds FOXO1

Reactome:R-NUL-9620806

FOXO1,FOXO3 binds Rbl2 gene

Reactome:R-NUL-9620857

FOXO1,FOXO3 binds Ccng2 gene

Reactome:R-NUL-9624599

FOXO1 binds Fbxo32 gene promoter

Reactome:R-NUL-9625492

FOXO1 and p-2S-Smad2/3:Smad4 bind Mstn gene promoter

Reactome:R-NUL-9625758

FOXO1,FOXO3 and SMAD3 bind Trim63 gene promoter

file:human/FOXO1/FOXO1-deep-research-falcon.md

Deep research report on FOXO1

Suggested Experiments

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.

📚 Additional Documentation

Deep Research Falcon

(FOXO1-deep-research-falcon.md)

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gene_id: FOXO1
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protein_description: 'RecName: Full=Forkhead box protein O1 {ECO:0000305}; AltName:
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Synonyms=FKHR {ECO:0000303|PubMed:9479491}, FOXO1A;
organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: FH_FOXO1. (IPR047408); Fork_head_dom. (IPR001766); FOXO-TAD. (IPR032067);
FOXO_KIX-bd. (IPR032068); TF_fork_head_CS_2. (IPR030456)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q12778
Protein Description: RecName: Full=Forkhead box protein O1 {ECO:0000305}; AltName: Full=Forkhead box protein O1A; AltName: Full=Forkhead in rhabdomyosarcoma {ECO:0000303|PubMed:8275086};
Gene Information: Name=FOXO1 {ECO:0000303|PubMed:12228231, ECO:0000312|HGNC:HGNC:3819}; Synonyms=FKHR {ECO:0000303|PubMed:9479491}, FOXO1A;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: FH_FOXO1. (IPR047408); Fork_head_dom. (IPR001766); FOXO-TAD. (IPR032067); FOXO_KIX-bd. (IPR032068); TF_fork_head_CS_2. (IPR030456)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "FOXO1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'FOXO1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene FOXO1 (gene ID: FOXO1, UniProt: Q12778) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q12778
Protein Description: RecName: Full=Forkhead box protein O1 {ECO:0000305}; AltName: Full=Forkhead box protein O1A; AltName: Full=Forkhead in rhabdomyosarcoma {ECO:0000303|PubMed:8275086};
Gene Information: Name=FOXO1 {ECO:0000303|PubMed:12228231, ECO:0000312|HGNC:HGNC:3819}; Synonyms=FKHR {ECO:0000303|PubMed:9479491}, FOXO1A;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: FH_FOXO1. (IPR047408); Fork_head_dom. (IPR001766); FOXO-TAD. (IPR032067); FOXO_KIX-bd. (IPR032068); TF_fork_head_CS_2. (IPR030456)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "FOXO1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene FOXO1 (gene ID: FOXO1, UniProt: Q12778) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
We verified the target identity and nomenclature: FOXO1 (UniProt Q12778) encodes the human Forkhead box protein O1 (aliases: FKHR/FOXO1A), a FOXO-family transcription factor with a conserved forkhead (winged-helix) DNA-binding domain, nuclear localization and export signals, and a C-terminal transactivation domain; these match the UniProt domain annotations (Fork_head_dom, FOXO-TAD, KIX-binding interface) and recent structural reviews (2023–2024) (santos2023foxofamilyisoforms pages 4-6, cheng2024forkheadboxo pages 3-4, rodriguezcolman2024foxotranscriptionfactors pages 2-3).

Comprehensive research report: FOXO1 (human; UniProt Q12778)

1) Key concepts and definitions with current understanding
- Molecular identity and domains: FOXO1 is a forkhead box O transcription factor that binds DNA via a conserved winged-helix DBD whose recognition helix (H3) targets FOXO motifs; the protein is largely intrinsically disordered outside the DBD and contains conserved CR1/CR2/CR3 regions that mediate interactions with co-regulators (e.g., CBP/p300) and an activation domain (TAD). An overlapping NLS/NES controls nuclear–cytoplasmic shuttling (santos2023foxofamilyisoforms pages 4-6, cheng2024forkheadboxo pages 3-4).
- Consensus DNA motifs: FOXO proteins recognize the DAF-16 family binding element (DBE; 5′-TTGTTTAC-3′) with high affinity, and also bind insulin-responsive elements (IREs); FOXO1 predominantly binds as a monomer to these motifs, though dimeric binding to palindromic sites has been described (cheng2024forkheadboxo pages 3-4, rodriguezcolman2024foxotranscriptionfactors pages 2-3).
- Biochemical role: FOXO1 functions as a transcriptional regulator integrating nutrient, insulin/PI3K–AKT, and stress signaling to control programs of metabolism (e.g., gluconeogenesis), autophagy, cell cycle arrest, and stress resistance. FOXO family members can act as pioneer factors to open condensed chromatin, and CR3/CR2 can autoinhibit the DBD, relieved by cofactor binding (e.g., β-catenin) (rodriguezcolman2024foxotranscriptionfactors pages 2-3, santos2023foxofamilyisoforms pages 12-13).
- Post-translational modifications (PTMs) and localization control:
• AKT/PKB phosphorylation at conserved FOXO1 residues Thr24, Ser256, and Ser319 creates 14‑3‑3 docking sites, driving CRM1-dependent nuclear export and cytosolic sequestration (and promoting degradation under sustained insulin signaling) (santos2023foxofamilyisoforms pages 6-7, cheng2024forkheadboxo pages 3-4, rodriguezcolman2024foxotranscriptionfactors pages 2-3).
• Additional kinases modulate FOXO1: AMPK, JNK, p38, MST1 often promote nuclear localization/activation under stress; ERK, CK1, CDK2, IKK can negatively regulate activity or stability in a context-dependent manner (cheng2024forkheadboxo pages 3-4, santos2023foxofamilyisoforms pages 6-7, rodriguezcolman2024foxotranscriptionfactors pages 2-3).
• Acetylation/deacetylation: CBP/p300 acetylate FOXO1 lysines within the regulatory region (e.g., K245, K248, K262, K265), modulating DNA binding and transactivation, while sirtuin deacetylases (e.g., SIRT family) deacetylate FOXOs to tune activity and target gene selection (santos2023foxofamilyisoforms pages 6-7, asadi2025foxosandtheir pages 2-4).
• Ubiquitylation: FOXO ubiquitylation states correlate with localization and stability; monoubiquitylation can favor nuclear import, whereas polyubiquitylation drives proteasomal degradation. E3s such as MDM2/SKP2 and DUBs like USP7 are implicated across FOXOs (rodriguezcolman2024foxotranscriptionfactors pages 2-3, asadi2025foxosandtheir pages 2-4).
• 14-3-3 and nuclear transport: AKT-site phosphorylation generates 14‑3‑3 binding that masks the NLS and exposes the NES, enabling CRM1-dependent export; conversely, stress kinases and redox cues promote nuclear import via importins (cheng2024forkheadboxo pages 3-4, rodriguezcolman2024foxotranscriptionfactors pages 2-3).

2) Recent developments and latest research (emphasis 2023–2024)
- Engineered T cells and immunotherapy: Two independent studies established FOXO1 as a master regulator of human CAR T cell memory and metabolic fitness. In Nature (2024), FOXO1 inhibition or gene editing impaired memory programs and antitumor function, while FOXO1 overexpression enforced a memory-like state, increased chromatin accessibility at FOXO motifs, preserved function under chronic stimulation, and improved in vivo persistence and tumor control; notably, TCF1 overexpression did not substitute for FOXO1, underscoring FOXO1’s unique role (published online April 10, 2024; https://doi.org/10.1038/s41586-024-07300-8) (doan2024foxo1isa pages 1-2). A 2023 preprint similarly reported that FOXO1 overexpression enhanced memory markers (CD62L, IL7R), suppressed exhaustion programs, and improved metabolic fitness and tumor control, whereas FOXO1 inhibition had the opposite effects (posted Nov 2023; https://doi.org/10.21203/rs.3.rs-2802998/v1) (mackall2023foxo1isa pages 6-8).
- FOXO1 in metabolism: Isoform-focused review synthesis indicates hepatic FOXO1 (with FOXO3/4) controls gluconeogenic programs; combined hepatic deletion of FOXO1/3/4 in mice reduces blood glucose and insulin with improved insulin sensitivity. FOXO1 can interact with PPARα to attenuate FGF21 induction, linking FOXO1 to systemic fuel metabolism and endocrine signaling (2023; https://doi.org/10.1038/s41419-023-06177-1) (santos2023foxofamilyisoforms pages 12-13). Mechanistic overviews in 2024 detail how PI3K–AKT phosphorylation drives nuclear exclusion, while stress kinases (JNK/p38/MST1/AMPK) promote nuclear FOXO activation during fasting/stress, consistent with FOXO1’s role in gluconeogenesis and autophagy (cheng2024forkheadboxo pages 3-4, rodriguezcolman2024foxotranscriptionfactors pages 2-3).
- Endothelial biology and angiogenesis: State-of-the-art reviews in 2024 synthesize that FOXOs (including FOXO1) restrain endothelial proliferation and regulate metabolic state, with insulin/AKT inhibition of FOXOs shifting endothelial programs and stress kinases promoting nuclear FOXO entry under oxidative stress; redox-dependent importin interactions (e.g., TNPO1/IPO7/8 pathways) facilitate nuclear import under oxidative cues (2024; https://doi.org/10.1038/s41580-023-00649-0) (rodriguezcolman2024foxotranscriptionfactors pages 2-3) and outline the NLS/NES-based shuttling critical to endothelium (cheng2024forkheadboxo pages 3-4).
- Fusion-positive alveolar rhabdomyosarcoma (ARMS): Recent narrative and mechanistic reviews consolidate that PAX3–FOXO1 and PAX7–FOXO1 are pathognomonic drivers of fusion-positive ARMS, functioning as pioneer-like oncoproteins that establish super-enhancers and reprogram the myogenic transcriptional circuitry (MYOD1, MYOG, MYCN) with extensive chromatin binding and enhancer–promoter looping via CBP/p300, BRD4, and Mediator dependency (2025 synthesis of the 2017–2024 literature; https://doi.org/10.3390/ijms26115204, May 2025) (ziemba2025moleculartargetsin pages 2-4, ziemba2025moleculartargetsin pages 4-6). Fusion status is prognostic and diagnostic (detected in ~70–80% of ARMS) and correlates with aggressive disease; fusion-specific antibodies can assist IHC-based detection (ziemba2025moleculartargetsin pages 1-2, ziemba2025moleculartargetsin pages 48-50). While direct fusion targeting remains elusive, preclinical dependencies and strategies include epigenetic modulators (BET inhibitors), cell-cycle kinase inhibitors (CDK4/6, Aurora A), and newly proposed vulnerabilities (e.g., metabolic DHFR dependency leading to methotrexate sensitivity) summarized in 2025 (ziemba2025moleculartargetsin pages 45-47, ziemba2025moleculartargetsin pages 2-4, ziemba2025moleculartargetsin pages 48-50, ziemba2025moleculartargetsin pages 1-2).

3) Current applications and real-world implementations
- T cell engineering: The 2024 Nature study highlights a translational strategy—genetic FOXO1 overexpression in CAR T products—to enforce a memory-like state, enhance persistence and tumor control, and potentially improve outcomes; the work also associates endogenous FOXO1 activity with clinical responses in patients treated with CAR T or TILs (online April 10, 2024; https://doi.org/10.1038/s41586-024-07300-8) (doan2024foxo1isa pages 1-2). The 2023 preprint similarly proposes FOXO1 modulation as an engineering knob for next-generation cell therapies (Nov 2023; https://doi.org/10.21203/rs.3.rs-2802998/v1) (mackall2023foxo1isa pages 6-8).
- Diagnostics/prognostics in ARMS: Reviews summarize clinical adoption of fusion testing (FISH/RT-PCR/NGS) and fusion-junction antibodies for subclassification, risk stratification, and monitoring; fusion positivity is integrated into modern ARMS risk schemas (synthesized 2025; https://doi.org/10.3390/ijms26115204) (ziemba2025moleculartargetsin pages 1-2, ziemba2025moleculartargetsin pages 4-6).

4) Expert opinions and analysis from authoritative sources
- Nature Reviews perspective (2024) emphasizes FOXOs as central stress-adaptation transcription factors with pioneer activity, regulated by a combinatorial PTM code (phosphorylation, acetylation, ubiquitin states) and co-regulator interactions that determine context-specific genome engagement and transcriptional outcomes (Sep 2024; https://doi.org/10.1038/s41580-023-00649-0) (rodriguezcolman2024foxotranscriptionfactors pages 2-3).
- Cross-isoform structural/functional analysis (2023) underscores shared architecture with isoform-specific IDR features; provides curated site-level PTMs in FOXO1 (AKT sites T24/S256/S319; multiple kinase sites; acetyl-lysines; PRMT1 arginine methylation), and highlights therapeutic angles (isoform-selective 14‑3‑3 interactions; protein–protein interaction disruptors; PROTACs) (Oct 2023; https://doi.org/10.1038/s41419-023-06177-1) (santos2023foxofamilyisoforms pages 6-7, santos2023foxofamilyisoforms pages 12-13).
- Cell Regeneration (2024) delineates canonical DNA motifs (DBE vs IRE), NLS/NES mechanisms, and broad kinase/deacetylase regulation in mammalian FOXOs with specific attention to stem cell contexts (Mar 2024; https://doi.org/10.1186/s13619-024-00190-1) (cheng2024forkheadboxo pages 3-4, cheng2024forkheadboxo pages 1-3).

5) Relevant statistics and data from recent studies
- CAR T engineering: FOXO1 overexpression in human CAR T cells increased memory-associated gene programs and improved tumor control in vivo; FOXO1 inhibition reduced memory markers (e.g., CD62L/SELL, IL7R) and increased exhaustion markers (e.g., PD-1/TOX family), with impaired antitumor activity. FOXO1 activity correlated with positive outcomes in patients receiving CAR T/TILs (Nature, online April 10, 2024; https://doi.org/10.1038/s41586-024-07300-8) (doan2024foxo1isa pages 1-2). Concordant preprint data in Nov 2023 documented enhanced OXPHOS/metabolic fitness and serial-stimulation resilience with FOXO1 overexpression, and reduced persistence/efficacy with FOXO1 inhibition (https://doi.org/10.21203/rs.3.rs-2802998/v1) (mackall2023foxo1isa pages 6-8).
- Metabolic regulation: Genetic ablation studies summarized in 2023 show combined liver FOXO1/3/4 deletion reduces blood glucose/insulin and improves insulin sensitivity, indicating synergistic control of gluconeogenesis; FOXO1’s attenuation of PPARα-driven FGF21 links FOXO1 to systemic metabolic endocrine responses (Oct 2023; https://doi.org/10.1038/s41419-023-06177-1) (santos2023foxofamilyisoforms pages 12-13).
- ARMS fusion epidemiology and prognosis: Fusion-positive ARMS is defined by PAX3/7–FOXO1 fusions in ~70–80% of cases, with fusion status linked to aggressive clinical behavior and poorer survival, establishing fusion testing as critical for risk stratification (compiled 2025; https://doi.org/10.3390/ijms26115204) (ziemba2025moleculartargetsin pages 1-2).

Mechanistic framework: regulation, localization, and partners
- Phospho-switch for trafficking: AKT/SGK phosphorylation on FOXO1 T24/S256/S319 recruits 14‑3‑3, masks the NLS and reveals the NES, enabling CRM1 export and cytoplasmic sequestration; dephosphorylation or stress-kinase inputs (JNK/p38/MST1/AMPK) favor nuclear import and transcriptional activation (cheng2024forkheadboxo pages 3-4, santos2023foxofamilyisoforms pages 6-7, rodriguezcolman2024foxotranscriptionfactors pages 2-3).
- Acetylation code: p300/CBP acetylation on FOXO1 K245/K248/K262/K265 dampens DNA binding/altered cofactor recruitment, while sirtuin deacetylation (e.g., SIRT family) re-sensitizes FOXOs and influences target selection (santos2023foxofamilyisoforms pages 6-7, asadi2025foxosandtheir pages 2-4).
- Ubiquitin-state control: Monoubiquitylation favors nuclear import and transcriptional competence, polyubiquitylation targets FOXO for proteasomal turnover; MDM2/SKP2 and USP7 participate in FOXO ubiquitin cycling (rodriguezcolman2024foxotranscriptionfactors pages 2-3, asadi2025foxosandtheir pages 2-4).
- Cofactor partnerships: CR3/CR2 interfaces recruit coactivators (CBP/p300, Mediator), engage β‑catenin to relieve autoinhibition, and cooperate with tissue-specific factors to specify transcriptional outcomes (rodriguezcolman2024foxotranscriptionfactors pages 2-3, cheng2024forkheadboxo pages 3-4).

Notes on scope and limitations
- RNF213-mediated K63-linked FOXO1 ubiquitination and several endothelial/metabolic primary studies from late 2024–2025 fall outside the directly citable context here. Where mechanistic components (e.g., K63 Ub and nuclear import) are discussed broadly for FOXOs, we have cited integrative 2023–2024 reviews (rodriguezcolman2024foxotranscriptionfactors pages 2-3, asadi2025foxosandtheir pages 2-4). For fusion-positive ARMS, the 2025 narrative synthesis aggregates 2017–2024 evidence (ziemba2025moleculartargetsin pages 45-47, ziemba2025moleculartargetsin pages 1-2), including super-enhancer biology and indirect targeting strategies; readers should consult the referenced URLs for detailed 2023–2024 primary citations.

References with URLs and dates
- Santos BF et al. FOXO family isoforms. Cell Death & Disease. Oct 2023. https://doi.org/10.1038/s41419-023-06177-1 (santos2023foxofamilyisoforms pages 4-6, santos2023foxofamilyisoforms pages 6-7, santos2023foxofamilyisoforms pages 12-13)
- Cheng M et al. Forkhead box O proteins: steering the course of stem cell fate. Cell Regeneration. Mar 2024. https://doi.org/10.1186/s13619-024-00190-1 (cheng2024forkheadboxo pages 3-4, cheng2024forkheadboxo pages 1-3)
- Rodriguez-Colman MJ, Dansen TB, Burgering BMT. FOXO transcription factors as mediators of stress adaptation. Nat Rev Mol Cell Biol. Sep 2024. https://doi.org/10.1038/s41580-023-00649-0 (rodriguezcolman2024foxotranscriptionfactors pages 2-3)
- Doan AE et al. FOXO1 is a master regulator of memory programming in CAR T cells. Nature. Online Apr 10, 2024. https://doi.org/10.1038/s41586-024-07300-8 (doan2024foxo1isa pages 1-2)
- Mackall CL et al. FOXO1 is a master regulator of CAR T memory programming. Research Square. Nov 2023. https://doi.org/10.21203/rs.3.rs-2802998/v1 (mackall2023foxo1isa pages 6-8)
- Ziemba B, Lukow K. Molecular targets in alveolar rhabdomyosarcoma: progress and pitfalls. Int J Mol Sci. May 2025. https://doi.org/10.3390/ijms26115204 (ziemba2025moleculartargetsin pages 45-47, ziemba2025moleculartargetsin pages 2-4, ziemba2025moleculartargetsin pages 48-50, ziemba2025moleculartargetsin pages 1-2, ziemba2025moleculartargetsin pages 4-6)
- Sankhe CS, Hall L, Kendall GC. Fusion oncogenes in rhabdomyosarcoma: mechanisms and therapeutic implications. Frontiers in Oncology. Jun 2025. https://doi.org/10.3389/fonc.2025.1570070 (sankhe2025fusiononcogenesin pages 2-4, sankhe2025fusiononcogenesin pages 1-2)
- Asadi Y et al. FOXOs and their roles in acute and chronic neurological disorders. Front Mol Biosci. Apr 2025. https://doi.org/10.3389/fmolb.2025.1538472 (asadi2025foxosandtheir pages 1-2, asadi2025foxosandtheir pages 2-4, asadi2025foxosandtheir pages 9-10)

Conclusion
Human FOXO1 (Q12778) is a stress- and nutrient-responsive transcription factor whose activity is set by a combinatorial PTM code (phosphorylation, acetylation, ubiquitylation) and nuclear shuttling via 14‑3‑3/CRM1 and importins. Recent high-impact work established FOXO1 as a tractable lever to enhance human CAR T memory, persistence, and antitumor efficacy, positioning FOXO1 modulation for near-term translational applications. In parallel, consolidated evidence underscores FOXO1’s central roles in hepatic gluconeogenesis and endothelial stress responses, and documents that PAX3/7–FOXO1 fusions drive ARMS via enhancer reprogramming with actionable cofactor dependencies. Together, these advances provide precise mechanistic targets and implementation paths—from T cell engineering knobs to fusion-positive sarcoma vulnerabilities—for FOXO1-centered interventions (doan2024foxo1isa pages 1-2, mackall2023foxo1isa pages 6-8, rodriguezcolman2024foxotranscriptionfactors pages 2-3, santos2023foxofamilyisoforms pages 12-13, ziemba2025moleculartargetsin pages 2-4).

References

(santos2023foxofamilyisoforms pages 4-6): Bruno F. Santos, Inês Grenho, Paulo J. Martel, Bibiana I. Ferreira, and Wolfgang Link. Foxo family isoforms. Cell Death & Disease, Oct 2023. URL: https://doi.org/10.1038/s41419-023-06177-1, doi:10.1038/s41419-023-06177-1. This article has 88 citations and is from a peer-reviewed journal.
(cheng2024forkheadboxo pages 3-4): Mengdi Cheng, Yujie Nie, Min Song, Fulin Chen, and Yuan Yu. Forkhead box o proteins: steering the course of stem cell fate. Cell Regeneration, Mar 2024. URL: https://doi.org/10.1186/s13619-024-00190-1, doi:10.1186/s13619-024-00190-1. This article has 10 citations.
(rodriguezcolman2024foxotranscriptionfactors pages 2-3): Maria J. Rodriguez-Colman, Tobias B. Dansen, and Boudewijn. M. T. Burgering. Foxo transcription factors as mediators of stress adaptation. Nature Reviews Molecular Cell Biology, 25:46-64, Sep 2024. URL: https://doi.org/10.1038/s41580-023-00649-0, doi:10.1038/s41580-023-00649-0. This article has 143 citations and is from a domain leading peer-reviewed journal.
(santos2023foxofamilyisoforms pages 12-13): Bruno F. Santos, Inês Grenho, Paulo J. Martel, Bibiana I. Ferreira, and Wolfgang Link. Foxo family isoforms. Cell Death & Disease, Oct 2023. URL: https://doi.org/10.1038/s41419-023-06177-1, doi:10.1038/s41419-023-06177-1. This article has 88 citations and is from a peer-reviewed journal.
(santos2023foxofamilyisoforms pages 6-7): Bruno F. Santos, Inês Grenho, Paulo J. Martel, Bibiana I. Ferreira, and Wolfgang Link. Foxo family isoforms. Cell Death & Disease, Oct 2023. URL: https://doi.org/10.1038/s41419-023-06177-1, doi:10.1038/s41419-023-06177-1. This article has 88 citations and is from a peer-reviewed journal.
(asadi2025foxosandtheir pages 2-4): Yasin Asadi, Rozenn K. Moundounga, Anand Chakroborty, Augustina Pokokiri, and Hongmin Wang. Foxos and their roles in acute and chronic neurological disorders. Frontiers in Molecular Biosciences, Apr 2025. URL: https://doi.org/10.3389/fmolb.2025.1538472, doi:10.3389/fmolb.2025.1538472. This article has 5 citations and is from a poor quality or predatory journal.
(doan2024foxo1isa pages 1-2): Alexander E. Doan, Katherine P. Mueller, Andy Y. Chen, Geoffrey T. Rouin, Yingshi Chen, Bence Daniel, John Lattin, Martina Markovska, Brett Mozarsky, Jose Arias-Umana, Robert Hapke, In-Young Jung, Alice Wang, Peng Xu, Dorota Klysz, Gabrielle Zuern, Malek Bashti, Patrick J. Quinn, Zhuang Miao, Katalin Sandor, Wenxi Zhang, Gregory M. Chen, Faith Ryu, Meghan Logun, Junior Hall, Kai Tan, Stephan A. Grupp, Susan E. McClory, Caleb A. Lareau, Joseph A. Fraietta, Elena Sotillo, Ansuman T. Satpathy, Crystal L. Mackall, and Evan W. Weber. Foxo1 is a master regulator of memory programming in car t cells. Nature, 629:211-218, Apr 2024. URL: https://doi.org/10.1038/s41586-024-07300-8, doi:10.1038/s41586-024-07300-8. This article has 162 citations and is from a highest quality peer-reviewed journal.
(mackall2023foxo1isa pages 6-8): Crystal L. Mackall, Alexander E Doan, Katherine P Mueller, Andy Y. Chen, Geoffrey T. Rouin, Bence Daniel, John Lattin, Yingshi Chen, Brett Mozarsky, M. Markovska, Jose Arias-Umana, Robert Hapke, Inyoung Jung, Peng Xu, D. Klysz, Malek Bashti, Patrick Quinn, Katalin D. Sandor, Wenxi Zhang, Junior Hall, Caleb A. Lareau, Stephan A. Grupp, J. Fraietta, E. Sotillo, Ansuman T. Satpathy, and Evan W. Weber. Foxo1 is a master regulator of car t memory programming. Research Square, Nov 2023. URL: https://doi.org/10.21203/rs.3.rs-2802998/v1, doi:10.21203/rs.3.rs-2802998/v1. This article has 10 citations.
(ziemba2025moleculartargetsin pages 2-4): Barbara Ziemba and Klaudia Lukow. Molecular targets in alveolar rhabdomyosarcoma: a narrative review of progress and pitfalls. International Journal of Molecular Sciences, 26:5204, May 2025. URL: https://doi.org/10.3390/ijms26115204, doi:10.3390/ijms26115204. This article has 1 citations and is from a poor quality or predatory journal.
(ziemba2025moleculartargetsin pages 4-6): Barbara Ziemba and Klaudia Lukow. Molecular targets in alveolar rhabdomyosarcoma: a narrative review of progress and pitfalls. International Journal of Molecular Sciences, 26:5204, May 2025. URL: https://doi.org/10.3390/ijms26115204, doi:10.3390/ijms26115204. This article has 1 citations and is from a poor quality or predatory journal.
(ziemba2025moleculartargetsin pages 1-2): Barbara Ziemba and Klaudia Lukow. Molecular targets in alveolar rhabdomyosarcoma: a narrative review of progress and pitfalls. International Journal of Molecular Sciences, 26:5204, May 2025. URL: https://doi.org/10.3390/ijms26115204, doi:10.3390/ijms26115204. This article has 1 citations and is from a poor quality or predatory journal.
(ziemba2025moleculartargetsin pages 48-50): Barbara Ziemba and Klaudia Lukow. Molecular targets in alveolar rhabdomyosarcoma: a narrative review of progress and pitfalls. International Journal of Molecular Sciences, 26:5204, May 2025. URL: https://doi.org/10.3390/ijms26115204, doi:10.3390/ijms26115204. This article has 1 citations and is from a poor quality or predatory journal.
(ziemba2025moleculartargetsin pages 45-47): Barbara Ziemba and Klaudia Lukow. Molecular targets in alveolar rhabdomyosarcoma: a narrative review of progress and pitfalls. International Journal of Molecular Sciences, 26:5204, May 2025. URL: https://doi.org/10.3390/ijms26115204, doi:10.3390/ijms26115204. This article has 1 citations and is from a poor quality or predatory journal.
(cheng2024forkheadboxo pages 1-3): Mengdi Cheng, Yujie Nie, Min Song, Fulin Chen, and Yuan Yu. Forkhead box o proteins: steering the course of stem cell fate. Cell Regeneration, Mar 2024. URL: https://doi.org/10.1186/s13619-024-00190-1, doi:10.1186/s13619-024-00190-1. This article has 10 citations.
(sankhe2025fusiononcogenesin pages 2-4): Chinmay S. Sankhe, Lisa Hall, and Genevieve C. Kendall. Fusion oncogenes in rhabdomyosarcoma: model systems, mechanisms of tumorigenesis, and therapeutic implications. Frontiers in Oncology, Jun 2025. URL: https://doi.org/10.3389/fonc.2025.1570070, doi:10.3389/fonc.2025.1570070. This article has 4 citations and is from a poor quality or predatory journal.
(sankhe2025fusiononcogenesin pages 1-2): Chinmay S. Sankhe, Lisa Hall, and Genevieve C. Kendall. Fusion oncogenes in rhabdomyosarcoma: model systems, mechanisms of tumorigenesis, and therapeutic implications. Frontiers in Oncology, Jun 2025. URL: https://doi.org/10.3389/fonc.2025.1570070, doi:10.3389/fonc.2025.1570070. This article has 4 citations and is from a poor quality or predatory journal.
(asadi2025foxosandtheir pages 1-2): Yasin Asadi, Rozenn K. Moundounga, Anand Chakroborty, Augustina Pokokiri, and Hongmin Wang. Foxos and their roles in acute and chronic neurological disorders. Frontiers in Molecular Biosciences, Apr 2025. URL: https://doi.org/10.3389/fmolb.2025.1538472, doi:10.3389/fmolb.2025.1538472. This article has 5 citations and is from a poor quality or predatory journal.
(asadi2025foxosandtheir pages 9-10): Yasin Asadi, Rozenn K. Moundounga, Anand Chakroborty, Augustina Pokokiri, and Hongmin Wang. Foxos and their roles in acute and chronic neurological disorders. Frontiers in Molecular Biosciences, Apr 2025. URL: https://doi.org/10.3389/fmolb.2025.1538472, doi:10.3389/fmolb.2025.1538472. This article has 5 citations and is from a poor quality or predatory journal.

Citations

santos2023foxofamilyisoforms pages 12-13
rodriguezcolman2024foxotranscriptionfactors pages 2-3
cheng2024forkheadboxo pages 3-4
ziemba2025moleculartargetsin pages 1-2
santos2023foxofamilyisoforms pages 4-6
santos2023foxofamilyisoforms pages 6-7
asadi2025foxosandtheir pages 2-4
ziemba2025moleculartargetsin pages 2-4
ziemba2025moleculartargetsin pages 4-6
ziemba2025moleculartargetsin pages 48-50
ziemba2025moleculartargetsin pages 45-47
cheng2024forkheadboxo pages 1-3
sankhe2025fusiononcogenesin pages 2-4
sankhe2025fusiononcogenesin pages 1-2
asadi2025foxosandtheir pages 1-2
asadi2025foxosandtheir pages 9-10
https://doi.org/10.1038/s41586-024-07300-8
https://doi.org/10.21203/rs.3.rs-2802998/v1
https://doi.org/10.1038/s41419-023-06177-1
https://doi.org/10.1038/s41580-023-00649-0
https://doi.org/10.3390/ijms26115204,
https://doi.org/10.3390/ijms26115204
https://doi.org/10.1186/s13619-024-00190-1
https://doi.org/10.3389/fonc.2025.1570070
https://doi.org/10.3389/fmolb.2025.1538472
https://doi.org/10.1038/s41419-023-06177-1,
https://doi.org/10.1186/s13619-024-00190-1,
https://doi.org/10.1038/s41580-023-00649-0,
https://doi.org/10.3389/fmolb.2025.1538472,
https://doi.org/10.1038/s41586-024-07300-8,
https://doi.org/10.21203/rs.3.rs-2802998/v1,
https://doi.org/10.3389/fonc.2025.1570070,

📄 View Raw YAML

id: Q12778
gene_symbol: FOXO1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >
  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 FOXO1–PGC-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.
existing_annotations:
# ====================
# IBA ANNOTATIONS (Phylogenetically inferred - high confidence baseline)
# ====================
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:18786403
          supporting_text: "Structural basis for DNA recognition by FoxO1 and its
            regulation by posttranslational modification"
        - reference_id: santos2023foxofamilyisoforms
          supporting_text: "FOXO1 is a forkhead box O transcription factor that binds
            DNA via a conserved winged-helix DBD"

        - reference_id: file:human/FOXO1/FOXO1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:11311120
          supporting_text: "Ser(329) phosphorylation also decreases the ability of
            FKHR to stimulate gene transactivation and reduces the proportion of FKHR
            present in the nucleus."
        - reference_id: PMID:12228231
          supporting_text: "Studies with GFP(1) fusion proteins indicate that Ser-256
            phosphorylation is critical for nuclear exclusion of FKHR."

  - term:
      id: GO:0045722
      label: positive regulation of gluconeogenesis
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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 FOXO1–PGC-1alpha
        interaction has been reported as indirect.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:17024043
          supporting_text: "the transcription factor FOXO1 and the transcriptional
            co-activator PGC-1alpha act synergistically to stimulate the expression
            of genes in the gluconeogenesis pathway"
        - reference_id: santos2023foxofamilyisoforms
          supporting_text: "hepatic FOXO1 (with FOXO3/4) controls gluconeogenic programs"

  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >
        As a transcription factor, FOXO1 regulates transcription by RNA polymerase
        II. This is the fundamental
        biological process in which FOXO1 participates.
      action: ACCEPT
      reason: >
        Core biological process annotation for a transcription factor. FOXO1 is established
        to regulate both
        activation and repression of Pol II-transcribed genes.
      supported_by:
        - reference_id: rodriguezcolman2024foxotranscriptionfactors
          supporting_text: "FOXO transcription factors as mediators of stress adaptation"

  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:18786403
          supporting_text: "Structural basis for DNA recognition by FoxO1"
        - reference_id: cheng2024forkheadboxo
          supporting_text: "FOXO proteins recognize the DAF-16 family binding element
            (DBE; 5'-TTGTTTAC-3') with high affinity"

  - term:
      id: GO:0008286
      label: insulin receptor signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10358076
          supporting_text: "Phosphorylation of serine 256 by protein kinase B disrupts
            transactivation by FKHR and mediates effects of insulin"
        - reference_id: santos2023foxofamilyisoforms
          supporting_text: "AKT/PKB phosphorylation at conserved FOXO1 residues Thr24,
            Ser256, and Ser319 creates 14-3-3 docking sites"

# ====================
# IEA ANNOTATIONS (Electronically inferred - require careful assessment)
# ====================
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: UniProt:Q12778
          supporting_text: "Acts as an inhibitor of glucose sensing in pancreatic
            beta cells by acting as a transcription repressor and suppressing expression
            of PDX1 (By similarity)."

  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      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.
      action: ACCEPT
      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.

  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      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.
      action: ACCEPT
      reason: >
        Correct general annotation. FOXO1 is a transcription factor that binds DNA
        and regulates gene expression.

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >
        Duplicate of IBA annotation for nucleus. FOXO1 localizes to nucleus where
        it functions.
      action: ACCEPT
      reason: >
        Correct cellular component annotation. Nuclear localization is well-established
        for FOXO1.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >
        FOXO1 is present in the nucleoplasm where it functions as a transcription
        factor. More specific
        than nucleus.
      action: ACCEPT
      reason: >
        Correct subcellular localization. FOXO1 functions in the nucleoplasm to regulate
        gene transcription.

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      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.
      action: ACCEPT
      reason: >
        Correct - cytoplasmic localization is a key aspect of FOXO1 regulation. AKT
        phosphorylation promotes
        nuclear export and cytoplasmic sequestration.
      supported_by:
        - reference_id: PMID:11237865
          supporting_text: "insulin-like growth factor (IGF)-1 and serum-induced nuclear
            exclusion of FKHR[S256A] depends on the degree of overexpression of this
            mutant."

  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >
        General term for transcription regulation. FOXO1 regulates transcription of
        its target genes.
      action: ACCEPT
      reason: >
        Correct general annotation for a transcription factor.

  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:20543840
          supporting_text: "Cytosolic FoxO1 is essential for the induction of autophagy"

  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:31063815
          supporting_text: "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."

  - term:
      id: GO:0008013
      label: beta-catenin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >
        FOXO1 interacts with beta-catenin. This interaction has functional consequences
        for FOXO1-dependent
        transcription and may relieve autoinhibition of the DNA-binding domain.
      action: ACCEPT
      reason: >
        Beta-catenin binding is documented and functionally relevant. IDA evidence
        also exists for this
        interaction (PMID:15905404).
      supported_by:
        - reference_id: PMID:15905404
          supporting_text: "Functional interaction between beta-catenin and FOXO in
            oxidative stress signaling"
        - reference_id: rodriguezcolman2024foxotranscriptionfactors
          supporting_text: "β-catenin can relieve autoinhibition of the DBD"

  - term:
      id: GO:0030154
      label: cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.

  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >
        FOXO1 binds DNA in a sequence-specific manner, recognizing IRE and DBE consensus
        sequences.
      action: ACCEPT
      reason: >
        Core molecular function - sequence-specific DNA binding is fundamental to
        FOXO1's transcription
        factor activity.

# ====================
# IPI ANNOTATIONS - protein binding (require assessment of functional relevance)
# ====================
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11237865
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:11237865
          supporting_text: "Thr-24 phosphorylation alone is critical for interaction
            with 14-3-3 proteins"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11353774
    review:
      summary: >
        Reference describes FOXO1 functioning as a nuclear receptor coactivator/corepressor.
      action: MODIFY
      reason: >
        "Protein binding" is uninformative. The interaction with nuclear receptors
        could be more
        specifically annotated as nuclear receptor coactivator activity or similar.
      proposed_replacement_terms:
        - id: GO:0030374
          label: nuclear receptor transcription coactivator activity

      supported_by:
        - reference_id: PMID:11353774
          supporting_text: 2001 May 15. Forkhead homologue in rhabdomyosarcoma 
            functions as a bifunctional nuclear receptor-interacting protein 
            with both coactivator and corepressor functions.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15084259
    review:
      summary: >
        Reference describes integration of Smad and forkhead pathways - FOXO1 interacts
        with Smad proteins.
      action: MODIFY
      reason: >
        Smad binding would be more informative than generic protein binding.
      proposed_replacement_terms:
        - id: GO:0070412
          label: R-SMAD binding

      supported_by:
        - reference_id: PMID:15084259
          supporting_text: Integration of Smad and forkhead pathways in the 
            control of neuroepithelial and glioblastoma cell proliferation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15220471
    review:
      summary: >
        Reference documents FOXO1 interaction with SIRT1. SIRT1 deacetylates FOXO1
        and potentiates its
        transcriptional activity.
      action: MODIFY
      reason: >
        The SIRT1 interaction is functionally important. A more specific term would
        be informative.
      proposed_replacement_terms:
        - id: GO:0042802
          label: identical protein binding
      supported_by:
        - reference_id: PMID:15220471
          supporting_text: "Silent information regulator 2 potentiates Foxo1-mediated
            transcription through its deacetylase activity"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15692560
    review:
      summary: >
        Reference describes FOXO1 interaction with FHL2 and SIRT1-mediated deacetylation.
      action: MODIFY
      reason: >
        Generic protein binding annotation should be made more specific.
      proposed_replacement_terms:
        - id: GO:0042802
          label: identical protein binding

      supported_by:
        - reference_id: PMID:15692560
          supporting_text: Suppression of FOXO1 activity by FHL2 through 
            SIRT1-mediated deacetylation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18235501
    review:
      summary: >
        Reference documents DBC1 as a negative regulator of SIRT1, affecting FOXO1
        indirectly.
      action: ACCEPT
      reason: >
        The interaction data is valid even if the generic term is uninformative.

      supported_by:
        - reference_id: PMID:18235501
          supporting_text: DBC1 is a negative regulator of SIRT1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18408765
    review:
      summary: >
        Reference describes CDK1 phosphorylation and inhibition of FOXO1.
      action: MODIFY
      reason: >
        Could be more specifically annotated as kinase binding or protein serine/threonine
        kinase activity.
      proposed_replacement_terms:
        - id: GO:0030332
          label: cyclin binding

      supported_by:
        - reference_id: PMID:18408765
          supporting_text: CDK1 promotes cell proliferation and survival via 
            phosphorylation and inhibition of FOXO1 transcription factor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18786403
    review:
      summary: >
        Reference is the structural study of FOXO1 DNA binding domain and its regulation
        by PTMs.
      action: ACCEPT
      reason: >
        Valid protein binding evidence from structural study.

      supported_by:
        - reference_id: PMID:18786403
          supporting_text: Structural basis for DNA recognition by FoxO1 and its
            regulation by posttranslational modification.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24419615
    review:
      summary: >
        Reference describes crystallization of FOXO1/ETS1 DNA-binding complex.
      action: ACCEPT
      reason: >
        Valid protein-protein interaction evidence.

      supported_by:
        - reference_id: PMID:24419615
          supporting_text: Crystallization and preliminary X-ray analysis of a 
            complex of the FOXO1 and Ets1 DNA-binding domains and DNA.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24983498
    review:
      summary: >
        Reference describes FOXO1 interaction with SET/TAF-Ibeta (INHAT subunit).
      action: ACCEPT
      reason: >
        Valid interaction data.

      supported_by:
        - reference_id: PMID:24983498
          supporting_text: Epub 2014 Jun 28. Inhibition of FoxO1 acetylation by 
            INHAT subunit SET/TAF-Iβ induces p21 transcription.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25241761
    review:
      summary: >
        Large-scale proximity ligation assay study of protein-protein interactions.
      action: ACCEPT
      reason: >
        High-throughput interaction data, acceptable as supporting evidence.

      supported_by:
        - reference_id: PMID:25241761
          supporting_text: Oct 9. Using an in situ proximity ligation assay to 
            systematically profile endogenous protein-protein interactions in a 
            pathway network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25609649
    review:
      summary: >
        Proteomic study of chromatin-associated transcription factor complexes.
      action: ACCEPT
      reason: >
        Valid high-throughput interaction data.

      supported_by:
        - reference_id: PMID:25609649
          supporting_text: Proteomic analyses reveal distinct 
            chromatin-associated and soluble transcription factor complexes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: >
        Large-scale human interactome mapping study.
      action: ACCEPT
      reason: >
        Valid high-throughput interaction data.

      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Architecture of the human interactome defines protein
            communities and disease networks.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >
        Dual proteome-scale network study of human interactome.
      action: ACCEPT
      reason: >
        Valid high-throughput interaction data.

      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35271311
    review:
      summary: >
        OpenCell study using endogenous tagging for cellular organization mapping.
      action: ACCEPT
      reason: >
        Valid high-throughput interaction and localization data.

      supported_by:
        - reference_id: PMID:35271311
          supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography
            of human cellular organization.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35512704
    review:
      summary: >
        Study of mutation-directed neo-protein-protein interactions in cancer.
      action: ACCEPT
      reason: >
        Valid interaction data.

      supported_by:
        - reference_id: PMID:35512704
          supporting_text: 2022 May 4. Systematic discovery of mutation-directed
            neo-protein-protein interactions in cancer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:36931259
    review:
      summary: >
        Study describing 14-3-3 proteins as central chaperones with FOXO1 as a client.
      action: MODIFY
      reason: >
        This specifically documents 14-3-3 binding which should be annotated more
        specifically.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding

# ====================
# IEA (Ensembl Compara) ANNOTATIONS
# ====================
      supported_by:
        - reference_id: PMID:36931259
          supporting_text: A central chaperone-like role for 14-3-3 proteins in 
            human cells.
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 associates with chromatin when functioning as a transcription factor.
        Recent evidence
        suggests FOXOs can act as pioneer factors to open condensed chromatin.
      action: ACCEPT
      reason: >
        FOXO1 binds to chromatin at target gene promoters. This is consistent with
        its transcription
        factor function.
      supported_by:
        - reference_id: rodriguezcolman2024foxotranscriptionfactors
          supporting_text: "FOXO family members can act as pioneer factors to open
            condensed chromatin"

  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        Duplicate of IBA annotation. FOXO1 binds to specific cis-regulatory sequences.
      action: ACCEPT
      reason: >
        Core molecular function annotation.

  - term:
      id: GO:0001227
      label: DNA-binding transcription repressor activity, RNA polymerase 
        II-specific
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 can function as a transcriptional repressor for certain genes (e.g.,
        PDX1, PPARG).
      action: ACCEPT
      reason: >
        Valid molecular function - FOXO1 has documented repressor activity for specific
        target genes.
      supported_by:
        - reference_id: UniProt:Q12778
          supporting_text: "Acts as an inhibitor of glucose sensing in pancreatic
            beta cells by acting as a transcription repressor and suppressing expression
            of PDX1 (By similarity)."

  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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 FOXO1–PGC-1alpha interaction reported.
      action: ACCEPT
      reason: >
        Core molecular function - FOXO1 is primarily a transcriptional activator.
      supported_by:
        - reference_id: PMID:17024043
          supporting_text: "FOXO1 and the transcriptional co-activator PGC-1alpha
            act synergistically to stimulate the expression of genes in the gluconeogenesis
            pathway"

  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        Duplicate annotation. FOXO1 regulates Pol II-mediated transcription.
      action: ACCEPT
      reason: >
        Core biological process for a transcription factor.

  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: KEEP_AS_NON_CORE
      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).
      supported_by:
        - reference_id: santos2023foxofamilyisoforms
          supporting_text: "FOXO1 activates genes involved in DNA repair and stress
            resistance"

  - term:
      id: GO:0008286
      label: insulin receptor signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        Duplicate of IBA annotation. FOXO1 is a key component of insulin signaling.
      action: ACCEPT
      reason: >
        Core biological process - FOXO1 is the main transcriptional target of insulin-PI3K-AKT
        signaling.

  - term:
      id: GO:0031490
      label: chromatin DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 binds to DNA within chromatin context at target gene promoters and enhancers.
      action: ACCEPT
      reason: >
        Specific subtype of DNA binding that accurately describes how FOXO1 functions
        in the cell.

  - term:
      id: GO:0032869
      label: cellular response to insulin stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 mediates cellular responses to insulin - it is phosphorylated and inactivated
        by the
        insulin-stimulated PI3K-AKT pathway.
      action: ACCEPT
      reason: >
        Core function - FOXO1's regulation by insulin is central to its role in metabolic
        homeostasis.
      supported_by:
        - reference_id: PMID:10358076
          supporting_text: "Insulin disrupts IRS-dependent transactivation by FKHR"

  - term:
      id: GO:0034599
      label: cellular response to oxidative stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 is activated by and mediates cellular responses to oxidative stress.
        Oxidative stress
        promotes FOXO1 nuclear localization and transcriptional activation of antioxidant
        genes.
      action: ACCEPT
      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."
      supported_by:
        - reference_id: rodriguezcolman2024foxotranscriptionfactors
          supporting_text: "FOXO transcription factors as mediators of stress adaptation"

  - term:
      id: GO:0045599
      label: negative regulation of fat cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 inhibits adipogenesis by repressing PPARG expression. This is a documented
        function
        in adipocyte biology.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: UniProt:Q12778
          supporting_text: "Regulates the expression of adipogenic genes such as PPARG
            during preadipocyte differentiation"

  - term:
      id: GO:0045722
      label: positive regulation of gluconeogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        Duplicate of IBA annotation. Core function of FOXO1.
      action: ACCEPT
      reason: >
        Core function - regulation of gluconeogenesis is FOXO1's primary evolved metabolic
        role.

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 activates transcription of target genes. This is its primary molecular
        activity.
      action: ACCEPT
      reason: >
        Core biological process - FOXO1 is primarily a transcriptional activator.

  - term:
      id: GO:0046676
      label: negative regulation of insulin secretion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 can negatively regulate insulin secretion in pancreatic beta cells through
        suppression of PDX1 expression.
      action: KEEP_AS_NON_CORE
      reason: >
        This is a tissue-specific function in beta cells, not the core evolved function.
        Valid but non-core.
      supported_by:
        - reference_id: UniProt:Q12778
          supporting_text: "Acts as an inhibitor of glucose sensing in pancreatic
            beta cells"

  - term:
      id: GO:0051721
      label: protein phosphatase 2A binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 interacts with PP2A (via PPP2R1A subunit). PP2A dephosphorylates FOXO1
        at T24 and S256,
        promoting nuclear import.
      action: ACCEPT
      reason: >
        Valid molecular function - PP2A interaction is important for FOXO1 regulation.
      supported_by:
        - reference_id: UniProt:Q12778
          supporting_text: "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"

  - term:
      id: GO:0070542
      label: response to fatty acid
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 responds to fatty acids and regulates lipid metabolism genes. In chondrogenic
        commitment, FOXO1 responds to low lipid levels.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: UniProt:Q12778
          supporting_text: "key regulator of chondrogenic commitment of skeletal progenitor
            cells in response to lipid availability"

  - term:
      id: GO:0071732
      label: cellular response to nitric oxide
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 mediates cellular responses to nitric oxide, including transcriptional
        activation
        of DNA repair genes in beta cells.
      action: KEEP_AS_NON_CORE
      reason: >
        Valid stress response function but represents one of many stress stimuli that
        activate FOXO1
        rather than a core evolved function.
      supported_by:
        - reference_id: UniProt:Q12778
          supporting_text: "Regulates the transcriptional activity of GADD45A and
            repair of nitric oxide-damaged DNA in beta-cells"

  - term:
      id: GO:1990841
      label: promoter-specific chromatin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >
        FOXO1 binds to chromatin at specific promoters of target genes.
      action: ACCEPT
      reason: >
        Accurate molecular function describing how FOXO1 engages chromatin at target
        gene promoters.

# ====================
# IDA (Direct assay) ANNOTATIONS - highest confidence
# ====================
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >
        Immunofluorescence data showing FOXO1 in nucleoplasm.
      action: ACCEPT
      reason: >
        Direct experimental evidence for nucleoplasm localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >
        Immunofluorescence data showing FOXO1 in cytosol.
      action: ACCEPT
      reason: >
        Direct experimental evidence. Cytosolic localization is the inactive, phosphorylated
        state.

  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    evidence_type: IDA
    original_reference_id: PMID:28851713
    review:
      summary: >
        SCP4 dephosphorylates FOXO1, promoting gluconeogenesis. This demonstrates
        FOXO1's
        transcriptional activator function.
      action: ACCEPT
      reason: >
        Core molecular function with direct experimental evidence.

      supported_by:
        - reference_id: PMID:28851713
          supporting_text: SCP4 Promotes Gluconeogenesis Through FoxO1/3a 
            Dephosphorylation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28851713
    review:
      summary: >
        FOXO1 interaction with SCP4 phosphatase.
      action: ACCEPT
      reason: >
        Valid protein-protein interaction.

      supported_by:
        - reference_id: PMID:28851713
          supporting_text: SCP4 Promotes Gluconeogenesis Through FoxO1/3a 
            Dephosphorylation.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:28851713
    review:
      summary: >
        Direct assay showing nuclear localization.
      action: ACCEPT
      reason: >
        Direct experimental evidence for nuclear localization.

      supported_by:
        - reference_id: PMID:28851713
          supporting_text: SCP4 Promotes Gluconeogenesis Through FoxO1/3a 
            Dephosphorylation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19483080
    review:
      summary: >
        FOXO1 interaction with STUB1/CHIP E3 ligase.
      action: MODIFY
      reason: >
        Could be more specifically annotated as ubiquitin ligase binding.
      proposed_replacement_terms:
        - id: GO:0031625
          label: ubiquitin protein ligase binding

      supported_by:
        - reference_id: PMID:19483080
          supporting_text: 2009 May 29. C terminus of Hsc70-interacting protein 
            promotes smooth muscle cell proliferation and survival through 
            ubiquitin-mediated degradation of FoxO1.
  - term:
      id: GO:0034393
      label: positive regulation of smooth muscle cell apoptotic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        FOXO1 promotes apoptosis in smooth muscle cells through transcriptional activation
        of
        pro-apoptotic genes.
      action: KEEP_AS_NON_CORE
      reason: >
        Tissue-specific function. FOXO1 can promote apoptosis but this is a downstream
        effect
        rather than core function. Valid but non-core.
      supported_by:
        - reference_id: PMID:19483080
          supporting_text: "overexpression of CHIP repressed FoxO1-mediated transactivation
            and its proapoptotic function following tumor necrosis factor-alpha treatment."

  - term:
      id: GO:0060260
      label: regulation of transcription initiation by RNA polymerase II
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        FOXO1 regulates transcription initiation at target gene promoters.
      action: ACCEPT
      reason: >
        Appropriate biological process term for a transcription factor.

# ====================
# TAS (Traceable Author Statement) - Reactome ANNOTATIONS
# ====================
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5692779
    review:
      summary: >
        MAPKAPK5 phosphorylates FOXO1 in nucleoplasm.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway annotation.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5692785
    review:
      summary: >
        Phosphorylated FOXO1 binds RAG gene in nucleoplasm.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway annotation.

  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    evidence_type: IDA
    original_reference_id: PMID:17024043
    review:
      summary: >
        PMID:17024043 is a comment re-evaluating the FOXO1–PGC-1alpha model and does
        not provide
        direct experimental evidence for FOXO1 transcriptional activation.
      action: MARK_AS_OVER_ANNOTATED
      reason: >
        The abstract reports FOXO1 is neither required nor sufficient for PGC-1alpha-driven
        G6Pase
        reporter activation and that the FOXO1–PGC-1alpha interaction is indirect,
        so this PMID
        alone is not strong IDA support for transcription activator activity.
      supported_by:
        - reference_id: PMID:17024043
          supporting_text: "FOXO1 is neither required nor sufficient for the stimulation
            of G6Pase-luciferase fusion gene expression by PGC-1alpha"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:25009184
    review:
      summary: >
        p53 and SIRT6 cooperate to regulate FOXO1 nuclear localization and gluconeogenesis.
      action: ACCEPT
      reason: >
        Direct experimental evidence for nuclear localization.

      supported_by:
        - reference_id: PMID:25009184
          supporting_text: Tumor suppressor p53 cooperates with SIRT6 to 
            regulate gluconeogenesis by promoting FoxO1 nuclear exclusion.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:25009184
    review:
      summary: >
        SIRT6-mediated deacetylation promotes FOXO1 cytoplasmic translocation.
      action: ACCEPT
      reason: >
        Direct experimental evidence showing cytoplasmic localization after SIRT6
        deacetylation.
      supported_by:
        - reference_id: PMID:25009184
          supporting_text: "whose interaction with FoxO1 leads to FoxO1 deacetylation
            and export to the cytoplasm."

  - term:
      id: GO:0045722
      label: positive regulation of gluconeogenesis
    evidence_type: IDA
    original_reference_id: PMID:17024043
    review:
      summary: >
        PMID:17024043 re-evaluates the FOXO1–PGC-1alpha connection and reports FOXO1
        is not required
        or sufficient for PGC-1alpha-driven G6Pase reporter activation.
      action: MARK_AS_OVER_ANNOTATED
      reason: >
        This comment does not provide direct evidence that FOXO1 positively regulates
        gluconeogenesis;
        it instead reports an indirect FOXO1–PGC-1alpha interaction and lack of requirement
        for FOXO1
        in PGC-1alpha-driven G6Pase reporter activity.
      supported_by:
        - reference_id: PMID:17024043
          supporting_text: "FOXO1 is neither required nor sufficient for the stimulation
            of G6Pase-luciferase fusion gene expression by PGC-1alpha"

  - term:
      id: GO:0045722
      label: positive regulation of gluconeogenesis
    evidence_type: IDA
    original_reference_id: PMID:25009184
    review:
      summary: >
        SIRT6 inhibits FOXO1-mediated gluconeogenesis by promoting nuclear exclusion.
      action: ACCEPT
      reason: >
        Additional evidence for FOXO1's core gluconeogenic function.

      supported_by:
        - reference_id: PMID:25009184
          supporting_text: Tumor suppressor p53 cooperates with SIRT6 to 
            regulate gluconeogenesis by promoting FoxO1 nuclear exclusion.
  - term:
      id: GO:0046676
      label: negative regulation of insulin secretion
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        FOXO1 inhibits insulin secretion in beta cells.
      action: KEEP_AS_NON_CORE
      reason: >
        Tissue-specific function in pancreatic beta cells, not core evolved function.

  - term:
      id: GO:0003676
      label: nucleic acid binding
    evidence_type: EXP
    original_reference_id: PMID:18786403
    review:
      summary: >
        Structural study demonstrating FOXO1's DNA binding activity.
      action: ACCEPT
      reason: >
        General term but supported by structural evidence. More specific terms also
        present.

      supported_by:
        - reference_id: PMID:18786403
          supporting_text: Structural basis for DNA recognition by FoxO1 and its
            regulation by posttranslational modification.
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: IDA
    original_reference_id: PMID:17024043
    review:
      summary: >
        PMID:17024043 discusses FOXO1 in the context of gluconeogenic gene regulation
        but provides
        limited direct evidence for transcription factor activity.
      action: MARK_AS_OVER_ANNOTATED
      reason: >
        This comment focuses on re-evaluating the FOXO1–PGC-1alpha relationship and
        reports an
        indirect interaction; it is not primary experimental evidence of FOXO1 transcription
        factor
        activity.

      supported_by:
        - reference_id: PMID:17024043
          supporting_text: 'Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection.'
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: IMP
    original_reference_id: PMID:31063815
    review:
      summary: >
        Cyclophilin A-FOXO1 signaling in endothelial cell apoptosis demonstrates FOXO1's
        transcription factor activity.
      action: ACCEPT
      reason: >
        Mutant phenotype evidence for transcription factor function.

      supported_by:
        - reference_id: PMID:31063815
          supporting_text: May 4. Cyclophilin A-FoxO1 signaling pathway in 
            endothelial cell apoptosis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31063815
    review:
      summary: >
        FOXO1 interacts with cyclophilin A (PPIA).
      action: ACCEPT
      reason: >
        Valid protein-protein interaction.

      supported_by:
        - reference_id: PMID:31063815
          supporting_text: May 4. Cyclophilin A-FoxO1 signaling pathway in 
            endothelial cell apoptosis.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:31063815
    review:
      summary: >
        Nuclear localization demonstrated in endothelial cell study.
      action: ACCEPT
      reason: >
        Direct experimental evidence.

      supported_by:
        - reference_id: PMID:31063815
          supporting_text: May 4. Cyclophilin A-FoxO1 signaling pathway in 
            endothelial cell apoptosis.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:31063815
    review:
      summary: >
        Cytoplasmic localization in endothelial cells.
      action: ACCEPT
      reason: >
        Direct experimental evidence.

      supported_by:
        - reference_id: PMID:31063815
          supporting_text: May 4. Cyclophilin A-FoxO1 signaling pathway in 
            endothelial cell apoptosis.
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:31063815
    review:
      summary: >
        FOXO1 regulates endothelial cell apoptosis through transcription of BCL2L11.
      action: KEEP_AS_NON_CORE
      reason: >
        Valid annotation showing FOXO1's role in apoptosis, but this is a downstream
        effect
        of transcriptional regulation rather than core function.
      supported_by:
        - reference_id: PMID:31063815
          supporting_text: "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."

  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        Sequence similarity-based evidence for transcriptional activator function.
      action: ACCEPT
      reason: >
        Core function supported by multiple evidence types.

  - term:
      id: GO:0070542
      label: response to fatty acid
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        FOXO1 responds to fatty acid levels.
      action: KEEP_AS_NON_CORE
      reason: >
        Context-specific response, not core function.

  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: ISA
    original_reference_id: GO_REF:0000113
    review:
      summary: >
        TFClass database annotation for chromatin association.
      action: ACCEPT
      reason: >
        Valid cellular component annotation.

  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    evidence_type: ISA
    original_reference_id: GO_REF:0000113
    review:
      summary: >
        TFClass database annotation for Pol II transcription factor activity.
      action: ACCEPT
      reason: >
        Core molecular function.

  - term:
      id: GO:1903243
      label: negative regulation of cardiac muscle hypertrophy in response to 
        stress
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        FOXO1 can inhibit cardiac hypertrophy.
      action: KEEP_AS_NON_CORE
      reason: >
        Tissue-specific function in heart. Valid but not core function.
      supported_by:
        - reference_id: UniProt:Q12778
          supporting_text: "Mediates the function of MLIP in cardiomyocytes hypertrophy
            and cardiac remodeling"

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:27577745
    review:
      summary: >
        MARCH1 study showing FOXO1's transcriptional activation function.
      action: ACCEPT
      reason: >
        Core biological process.

      supported_by:
        - reference_id: PMID:27577745
          supporting_text: MARCH1 regulates insulin sensitivity by controlling 
            cell surface insulin receptor levels.
  - term:
      id: GO:0008013
      label: beta-catenin binding
    evidence_type: IDA
    original_reference_id: PMID:15905404
    review:
      summary: >
        Direct evidence for FOXO1-beta-catenin interaction in oxidative stress signaling.
      action: ACCEPT
      reason: >
        Direct experimental evidence for specific protein-protein interaction.
      supported_by:
        - reference_id: PMID:15905404
          supporting_text: "Functional interaction between beta-catenin and FOXO in
            oxidative stress signaling"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20543840
    review:
      summary: >
        FOXO1 interacts with ATG7 in cytoplasm for autophagy induction.
      action: ACCEPT
      reason: >
        Valid protein-protein interaction data.

      supported_by:
        - reference_id: PMID:20543840
          supporting_text: Cytosolic FoxO1 is essential for the induction of 
            autophagy and tumour suppressor activity.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:20543840
    review:
      summary: >
        Nuclear localization in autophagy study.
      action: ACCEPT
      reason: >
        Direct experimental evidence.

      supported_by:
        - reference_id: PMID:20543840
          supporting_text: Cytosolic FoxO1 is essential for the induction of 
            autophagy and tumour suppressor activity.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:20543840
    review:
      summary: >
        Cytoplasmic localization important for autophagy function.
      action: ACCEPT
      reason: >
        Direct experimental evidence.

      supported_by:
        - reference_id: PMID:20543840
          supporting_text: Cytosolic FoxO1 is essential for the induction of 
            autophagy and tumour suppressor activity.
  - term:
      id: GO:0009267
      label: cellular response to starvation
    evidence_type: IDA
    original_reference_id: PMID:20543840
    review:
      summary: >
        FOXO1 mediates cellular response to starvation/nutrient deprivation.
      action: ACCEPT
      reason: >
        Core function - FOXO1 is activated by starvation to promote gluconeogenesis
        and autophagy.
      supported_by:
        - reference_id: PMID:20543840
          supporting_text: "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."

  - term:
      id: GO:0010508
      label: positive regulation of autophagy
    evidence_type: IMP
    original_reference_id: PMID:20543840
    review:
      summary: >
        FOXO1 promotes autophagy through both transcriptional and non-transcriptional
        mechanisms.
      action: KEEP_AS_NON_CORE
      reason: >
        Valid but represents a downstream stress response rather than core function.
        The core
        function is metabolic regulation.
      supported_by:
        - reference_id: PMID:20543840
          supporting_text: "Cytosolic FoxO1 is essential for the induction of autophagy"

  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IPI
    original_reference_id: PMID:20543840
    review:
      summary: >
        FOXO1 interacts with ubiquitin E3 ligases including STUB1/CHIP.
      action: ACCEPT
      reason: >
        Valid molecular function relevant to FOXO1 regulation.

      supported_by:
        - reference_id: PMID:20543840
          supporting_text: Cytosolic FoxO1 is essential for the induction of 
            autophagy and tumour suppressor activity.
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:20543840
    review:
      summary: >
        FOXO1 promotes apoptosis under stress conditions.
      action: KEEP_AS_NON_CORE
      reason: >
        Valid but downstream effect of FOXO1's transcriptional activity rather than
        core function.
      supported_by:
        - reference_id: PMID:20543840
          supporting_text: "Cytosolic FoxO1 is essential for the induction of autophagy
            and tumour suppressor activity."

  - term:
      id: GO:0045732
      label: positive regulation of protein catabolic process
    evidence_type: IMP
    original_reference_id: PMID:20543840
    review:
      summary: >
        FOXO1 promotes protein catabolism through autophagy induction.
      action: KEEP_AS_NON_CORE
      reason: >
        Downstream effect of autophagy induction, not core function.

      supported_by:
        - reference_id: PMID:20543840
          supporting_text: Cytosolic FoxO1 is essential for the induction of 
            autophagy and tumour suppressor activity.
  - term:
      id: GO:0071455
      label: cellular response to hyperoxia
    evidence_type: IDA
    original_reference_id: PMID:20543840
    review:
      summary: >
        FOXO1 responds to oxidative stress including hyperoxia.
      action: ACCEPT
      reason: >
        Part of FOXO1's stress response function.

      supported_by:
        - reference_id: PMID:20543840
          supporting_text: Cytosolic FoxO1 is essential for the induction of 
            autophagy and tumour suppressor activity.
  - term:
      id: GO:0032869
      label: cellular response to insulin stimulus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        Duplicate annotation for insulin response.
      action: ACCEPT
      reason: >
        Core function.

  - term:
      id: GO:0045599
      label: negative regulation of fat cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        FOXO1 inhibits adipogenesis.
      action: KEEP_AS_NON_CORE
      reason: >
        Tissue-specific function, not core.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-211178
    review:
      summary: >
        Phosphorylated FOXO1 is excluded from nucleus and found in cytosol.
      action: ACCEPT
      reason: >
        Valid localization annotation.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9614414
    review:
      summary: >
        AKT-phosphorylated FOXO translocates to cytosol.
      action: ACCEPT
      reason: >
        Valid localization.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9614423
    review:
      summary: >
        14-3-3 binds phosphorylated FOXO1 in cytosol.
      action: ACCEPT
      reason: >
        Valid localization.

  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        Some evidence for mitochondrial localization of FOXO1.
      action: UNDECIDED
      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.

      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:18680538
    review:
      summary: >
        Nuclear localization evidence.
      action: ACCEPT
      reason: >
        Direct evidence for nuclear localization.

# Multiple Reactome TAS annotations for nucleoplasm - consolidate review
      supported_by:
        - reference_id: PMID:18680538
          supporting_text: GAS6-induced signaling in human endothelial cells is 
            mediated by FOXO1a.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-199299
    review:
      summary: >
        AKT phosphorylates FOXO transcription factors in nucleoplasm.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-211164
    review:
      summary: >
        AKT phosphorylates FOXO1A in nucleoplasm.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-211178
    review:
      summary: >
        Phosphorylated FOXO1A is excluded from the nucleus.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2399992
    review:
      summary: >
        AKT1 E17K mutant phosphorylates FOXO transcription factors.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6790036
    review:
      summary: >
        STAT3-upregulated nuclear proteins including FOXO.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9614414
    review:
      summary: >
        AKT-phosphorylated FOXOs translocate to cytosol.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9614662
    review:
      summary: >
        FOXO1 binds FASLG gene promoter.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9617840
    review:
      summary: >
        FOXO1 binds CDKN1A gene promoter.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9617996
    review:
      summary: >
        FOXO1 binds SMAD2/3:SMAD4 complex.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9622980
    review:
      summary: >
        FOXO1 binds NPY gene promoter.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9623415
    review:
      summary: >
        FOXO1 binds IGFBP1 gene promoter.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9624976
    review:
      summary: >
        FOXO1 binds CAV1 gene promoter.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9625091
    review:
      summary: >
        FOXO1 binds ABCA6 gene promoter.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9626928
    review:
      summary: >
        CREBBP binds FOXO1.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-9620806
    review:
      summary: >
        FOXO1 binds Rbl2 gene.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-9620857
    review:
      summary: >
        FOXO1 binds Ccng2 gene.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-9624599
    review:
      summary: >
        FOXO1 binds Fbxo32 gene promoter.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-9625492
    review:
      summary: >
        FOXO1 and Smad2/3:Smad4 bind Mstn gene promoter.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-9625758
    review:
      summary: >
        FOXO1 and SMAD3 bind Trim63 gene promoter.
      action: ACCEPT
      reason: >
        Supported by Reactome pathway.

  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        FOXO1 participates in DNA damage response.
      action: KEEP_AS_NON_CORE
      reason: >
        Downstream stress response, not core function.

  - term:
      id: GO:0071732
      label: cellular response to nitric oxide
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        FOXO1 responds to nitric oxide.
      action: KEEP_AS_NON_CORE
      reason: >
        Stress response, not core function.

  - term:
      id: GO:0034599
      label: cellular response to oxidative stress
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        FOXO1 responds to oxidative stress.
      action: ACCEPT
      reason: >
        Core function - oxidative stress response is one of FOXO1's primary evolved
        roles.

  - term:
      id: GO:0051721
      label: protein phosphatase 2A binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        PP2A binding for FOXO1 dephosphorylation.
      action: ACCEPT
      reason: >
        Valid molecular function.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15890677
    review:
      summary: >
        FOXO1 interacts with p300 coactivator.
      action: MODIFY
      reason: >
        Should be annotated more specifically.
      proposed_replacement_terms:
        - id: GO:0003713
          label: transcription coactivator activity

      supported_by:
        - reference_id: PMID:15890677
          supporting_text: May 12. The coactivator p300 directly acetylates the 
            forkhead transcription factor Foxo1 and stimulates Foxo1-induced 
            transcription.
  - term:
      id: GO:0001659
      label: temperature homeostasis
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        FOXO1 role in temperature homeostasis through metabolic regulation.
      action: KEEP_AS_NON_CORE
      reason: >
        Downstream physiological effect, not core molecular function.

      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0001678
      label: intracellular glucose homeostasis
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        FOXO1 regulates glucose homeostasis through gluconeogenic gene transcription.
      action: ACCEPT
      reason: >
        Core function - glucose homeostasis is central to FOXO1's evolved role.
      supported_by:
        - reference_id: santos2023foxofamilyisoforms
          supporting_text: "hepatic FOXO1 controls gluconeogenic programs"

        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0003682
      label: chromatin binding
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        FOXO1 binds chromatin at target gene promoters.
      action: ACCEPT
      reason: >
        Valid molecular function for a transcription factor.

      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        Cytosolic localization.
      action: ACCEPT
      reason: >
        Valid cellular component annotation.

      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0006473
      label: protein acetylation
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        FOXO1 is acetylated; its acetylation status regulates activity.
      action: MARK_AS_OVER_ANNOTATED
      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.

      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0009267
      label: cellular response to starvation
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        FOXO1 responds to starvation by promoting gluconeogenesis.
      action: ACCEPT
      reason: >
        Core function - starvation response through gluconeogenesis is central to
        FOXO1.

      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0045444
      label: fat cell differentiation
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        FOXO1 regulates adipogenesis.
      action: KEEP_AS_NON_CORE
      reason: >
        Tissue-specific function, not core. FOXO1 inhibits rather than promotes this
        process.

      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        FOXO1 can repress transcription of certain genes.
      action: ACCEPT
      reason: >
        Valid biological process - FOXO1 acts as repressor for some targets.

      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0070417
      label: cellular response to cold
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        FOXO1 role in cold response through metabolic adaptation.
      action: KEEP_AS_NON_CORE
      reason: >
        Downstream physiological effect, not core molecular function.

      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0097009
      label: energy homeostasis
    evidence_type: ISS
    original_reference_id: PMID:22510882
    review:
      summary: >
        FOXO1 regulates energy homeostasis through metabolic gene transcription.
      action: ACCEPT
      reason: >
        Core function - energy/metabolic homeostasis is central to FOXO1.

      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:11237865
    review:
      summary: >
        Cytoplasmic localization with 14-3-3 binding.
      action: ACCEPT
      reason: >
        Direct experimental evidence.

      supported_by:
        - reference_id: PMID:11237865
          supporting_text: Roles of the forkhead in rhabdomyosarcoma (FKHR) 
            phosphorylation sites in regulating 14-3-3 binding, transactivation 
            and nuclear targetting.
  - term:
      id: GO:0008286
      label: insulin receptor signaling pathway
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >
        FOXO1 in insulin signaling.
      action: ACCEPT
      reason: >
        Core function.

  - term:
      id: GO:0032873
      label: negative regulation of stress-activated MAPK cascade
    evidence_type: IDA
    original_reference_id: PMID:19696738
    review:
      summary: >
        FoxM1 paper - may be mislabeled for FOXO1.
      action: UNDECIDED
      reason: >
        The cited reference PMID:19696738 is about FoxM1, not FOXO1. This may be an
        annotation
        error. Need verification.

      supported_by:
        - reference_id: PMID:19696738
          supporting_text: FoxM1, a critical regulator of oxidative stress 
            during oncogenesis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17030088
    review:
      summary: >
        FOXO1 interacts with APPL1, APPL2, AKT2 in FSH receptor complex.
      action: ACCEPT
      reason: >
        Valid protein-protein interaction data.

      supported_by:
        - reference_id: PMID:17030088
          supporting_text: Epub 2006 Oct 9. APPL1, APPL2, Akt2 and FOXO1a 
            interact with FSHR in a potential signaling complex.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:11311120
    review:
      summary: >
        DYRK1A phosphorylation study showing nuclear FOXO1.
      action: ACCEPT
      reason: >
        Direct experimental evidence.
      supported_by:
        - reference_id: PMID:11311120
          supporting_text: "Ser(329) phosphorylation also decreases the ability of
            FKHR to stimulate gene transactivation and reduces the proportion of FKHR
            present in the nucleus."

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:12228231
    review:
      summary: >
        Phosphorylation study showing nuclear localization.
      action: ACCEPT
      reason: >
        Direct experimental evidence.

      supported_by:
        - reference_id: PMID:12228231
          supporting_text: 2002 Sep 12. Phosphorylation of serine 256 suppresses
            transactivation by FKHR (FOXO1) by multiple mechanisms.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:11311120
    review:
      summary: >
        Cytoplasmic localization after phosphorylation.
      action: ACCEPT
      reason: >
        Direct experimental evidence.

      supported_by:
        - reference_id: PMID:11311120
          supporting_text: The kinase DYRK1A phosphorylates the transcription 
            factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation 
            site.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:12228231
    review:
      summary: >
        Cytoplasmic localization after insulin stimulation.
      action: ACCEPT
      reason: >
        Direct experimental evidence.

      supported_by:
        - reference_id: PMID:12228231
          supporting_text: 2002 Sep 12. Phosphorylation of serine 256 suppresses
            transactivation by FKHR (FOXO1) by multiple mechanisms.
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IDA
    original_reference_id: PMID:10871843
    review:
      summary: >
        PAX3/FKHR fusion study - shows FOXO1 can have anti-apoptotic effects in certain
        contexts.
      action: UNDECIDED
      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.

      supported_by:
        - reference_id: PMID:10871843
          supporting_text: Transcriptional modulation of the anti-apoptotic 
            protein BCL-XL by the paired box transcription factors PAX3 and 
            PAX3/FKHR.
  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IDA
    original_reference_id: PMID:12228231
    review:
      summary: >
        Direct evidence for sequence-specific DNA binding from phosphorylation study.
      action: ACCEPT
      reason: >
        Core molecular function with direct evidence.
      supported_by:
        - reference_id: PMID:12228231
          supporting_text: "Phosphorylation of serine 256 suppresses transactivation
            by FKHR (FOXO1) by multiple mechanisms."

  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:10871843
    review:
      summary: >
        PAX3/FKHR study showing transcriptional activation.
      action: ACCEPT
      reason: >
        Direct evidence for transcriptional activation function.

      supported_by:
        - reference_id: PMID:10871843
          supporting_text: Transcriptional modulation of the anti-apoptotic 
            protein BCL-XL by the paired box transcription factors PAX3 and 
            PAX3/FKHR.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:12228231
    review:
      summary: >
        Evidence for FOXO1 transcriptional activation function.
      action: ACCEPT
      reason: >
        Core biological process.

      supported_by:
        - reference_id: PMID:12228231
          supporting_text: 2002 Sep 12. Phosphorylation of serine 256 suppresses
            transactivation by FKHR (FOXO1) by multiple mechanisms.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:7862145
    review:
      summary: >
        Early PAX3-FKHR fusion study showing transcriptional activation.
      action: ACCEPT
      reason: >
        Early evidence for FOXO1's transactivation domain function.

      supported_by:
        - reference_id: PMID:7862145
          supporting_text: The PAX3-FKHR fusion protein created by the t(2;13) 
            translocation in alveolar rhabdomyosarcomas is a more potent 
            transcriptional activator than PAX3.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:10871843
    review:
      summary: >
        Evidence for Pol II-mediated transcription activation.
      action: ACCEPT
      reason: >
        Core biological process.

      supported_by:
        - reference_id: PMID:10871843
          supporting_text: Transcriptional modulation of the anti-apoptotic 
            protein BCL-XL by the paired box transcription factors PAX3 and 
            PAX3/FKHR.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:12228231
    review:
      summary: >
        Evidence for Pol II-mediated transcription activation.
      action: ACCEPT
      reason: >
        Core biological process.

      supported_by:
        - reference_id: PMID:12228231
          supporting_text: 2002 Sep 12. Phosphorylation of serine 256 suppresses
            transactivation by FKHR (FOXO1) by multiple mechanisms.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on on
      inter-ontology links
    findings: []
  - id: GO_REF:0000113
    title: Gene Ontology annotation of human sequence-specific DNA binding 
      transcription factors (DbTFs) based on the TFClass database
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10358076
    title: Phosphorylation of serine 256 by protein kinase B disrupts 
      transactivation by FKHR
    findings:
      - statement: FOXO1 binds to IRE consensus sequence and is suppressed by 
          insulin-activated AKT
  - id: PMID:10871843
    title: Transcriptional modulation of the anti-apoptotic protein BCL-XL by 
      the paired box transcription factors PAX3 and PAX3/FKHR.
    findings: []
  - id: PMID:11237865
    title: Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation 
      sites in regulating 14-3-3 binding, transactivation and nuclear 
      targetting.
    findings:
      - statement: AKT phosphorylation of T24/S256/S319 promotes 14-3-3 binding 
          and nuclear export
  - id: PMID:11311120
    title: The kinase DYRK1A phosphorylates the transcription factor FKHR at 
      Ser329 in vitro, a novel in vivo phosphorylation site.
    findings:
      - statement: FOXO1 is largely nuclear in unstimulated cells
  - id: PMID:11353774
    title: Forkhead homologue in rhabdomyosarcoma functions as a bifunctional 
      nuclear receptor-interacting protein with both coactivator and corepressor
      functions.
    findings: []
  - id: PMID:12228231
    title: Phosphorylation of serine 256 suppresses transactivation by FKHR
    findings:
      - statement: Ser256 phosphorylation decreases DNA binding and promotes 
          nuclear exclusion
  - id: PMID:15084259
    title: Integration of Smad and forkhead pathways
    findings: []
  - id: PMID:15220471
    title: Silent information regulator 2 potentiates Foxo1-mediated 
      transcription through its deacetylase activity.
    findings:
      - statement: SIRT1 deacetylates FOXO1 and enhances transcriptional 
          activity
  - id: PMID:15692560
    title: Suppression of FOXO1 activity by FHL2 through SIRT1-mediated 
      deacetylation
    findings: []
  - id: PMID:15890677
    title: The coactivator p300 directly acetylates the forkhead transcription 
      factor Foxo1 and stimulates Foxo1-induced transcription.
    findings:
      - statement: p300/CBP acetylate FOXO1 and modulate its activity
  - id: PMID:15905404
    title: Functional interaction between beta-catenin and FOXO in oxidative 
      stress signaling
    findings:
      - statement: Beta-catenin interacts with FOXO1 and modulates oxidative 
          stress response
  - id: PMID:17024043
    title: "Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection"
    findings:
      - statement: The original model proposed FOXO1 and PGC-1alpha act 
          synergistically to stimulate gluconeogenic gene expression.
        supporting_text: "FOXO1 and the transcriptional co-activator PGC-1alpha act
          synergistically to stimulate the expression of genes in the gluconeogenesis
          pathway"
      - statement: This report finds FOXO1 is neither required nor sufficient 
          for PGC-1alpha-driven activation of G6Pase reporter expression.
        supporting_text: "FOXO1 is neither required nor sufficient for the stimulation
          of G6Pase-luciferase fusion gene expression by PGC-1alpha"
      - statement: The data indicate the FOXO1–PGC-1alpha transcriptional 
          interaction is indirect.
        supporting_text: "the transcriptional interaction between FOXO1 and PGC-1alpha
          is indirect"
  - id: PMID:17030088
    title: APPL1, APPL2, Akt2 and FOXO1a interact with FSHR
    findings: []
  - id: PMID:18235501
    title: DBC1 is a negative regulator of SIRT1
    findings: []
  - id: PMID:18356527
    title: Activation of FOXO1 by Cdk1
    findings:
      - statement: CDK1 phosphorylates FOXO1 at Ser249
  - id: PMID:18408765
    title: CDK1 promotes cell proliferation and survival via phosphorylation and
      inhibition of FOXO1 transcription factor.
    findings: []
  - id: PMID:18680538
    title: GAS6-induced signaling in human endothelial cells is mediated by 
      FOXO1a.
    findings: []
  - id: PMID:18786403
    title: Structural basis for DNA recognition by FoxO1
    findings:
      - statement: X-ray crystallography of FOXO1 DNA-binding domain
  - id: PMID:19483080
    title: C terminus of Hsc70-interacting protein promotes smooth muscle cell 
      proliferation and survival through ubiquitin-mediated degradation of 
      FoxO1.
    findings:
      - statement: STUB1/CHIP ubiquitinates and degrades FOXO1
  - id: PMID:19696738
    title: FoxM1, a critical regulator of oxidative stress during oncogenesis.
    findings: []
  - id: PMID:20543840
    title: Cytosolic FoxO1 is essential for the induction of autophagy and 
      tumour suppressor activity.
    findings:
      - statement: Acetylated cytosolic FOXO1 interacts with ATG7 to promote 
          autophagy
  - id: PMID:22510882
    title: Novel repressor regulates insulin sensitivity through interaction 
      with Foxo1.
    findings: []
  - id: PMID:24419615
    title: Crystallization and preliminary X-ray analysis of a complex of the 
      FOXO1 and Ets1 DNA-binding domains and DNA.
    findings: []
  - id: PMID:24983498
    title: Inhibition of FoxO1 acetylation by INHAT subunit SET/TAF-Iβ induces 
      p21 transcription.
    findings: []
  - id: PMID:25009184
    title: Tumor suppressor p53 cooperates with SIRT6 to regulate 
      gluconeogenesis by promoting FoxO1 nuclear exclusion.
    findings:
      - statement: SIRT6 deacetylates FOXO1 at K423 promoting cytoplasmic 
          translocation
  - id: PMID:25241761
    title: Using an in situ proximity ligation assay to systematically profile 
      endogenous protein-protein interactions in a pathway network.
    findings: []
  - id: PMID:25609649
    title: Proteomic analyses reveal distinct chromatin-associated and soluble 
      transcription factor complexes.
    findings: []
  - id: PMID:27577745
    title: MARCH1 regulates insulin sensitivity by controlling cell surface 
      insulin receptor
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome
    findings: []
  - id: PMID:28851713
    title: SCP4 promotes gluconeogenesis through FoxO1/3a dephosphorylation
    findings: []
  - id: PMID:31063815
    title: Cyclophilin A-FoxO1 signaling pathway in endothelial cell apoptosis.
    findings:
      - statement: PPIA promotes FOXO1 dephosphorylation and nuclear 
          accumulation
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:35271311
    title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
    findings: []
  - id: PMID:35512704
    title: Systematic discovery of mutation-directed neo-protein-protein 
      interactions
    findings: []
  - id: PMID:36931259
    title: A central chaperone-like role for 14-3-3 proteins in human cells.
    findings: []
  - id: PMID:7862145
    title: The PAX3-FKHR fusion protein created by the t(2;13) translocation in 
      alveolar rhabdomyosarcomas is a more potent transcriptional activator than
      PAX3.
    findings: []
  - id: santos2023foxofamilyisoforms
    title: FOXO family isoforms
    findings:
      - statement: FOXO1 is a forkhead box O transcription factor with conserved
          winged-helix DBD
      - statement: AKT phosphorylation creates 14-3-3 binding sites driving 
          nuclear export
  - id: cheng2024forkheadboxo
    title: Forkhead box O proteins - steering the course of stem cell fate
    findings:
      - statement: FOXO proteins recognize DBE (5'-TTGTTTAC-3') with high 
          affinity
  - id: rodriguezcolman2024foxotranscriptionfactors
    title: FOXO transcription factors as mediators of stress adaptation
    findings:
      - statement: FOXOs can act as pioneer factors to open condensed chromatin
      - statement: PTM code determines context-specific genome engagement
  - id: Reactome:R-HSA-199299
    title: AKT phosphorylates FOXO transcription factors
    findings: []
  - id: Reactome:R-HSA-211164
    title: AKT phosphorylates FOXO1A
    findings: []
  - id: Reactome:R-HSA-211178
    title: Phosphorylated FOXO1A is excluded from the nucleus
    findings: []
  - id: Reactome:R-HSA-2399992
    title: AKT1 E17K mutant phosphorylates forkhead box transcription factors
    findings: []
  - id: Reactome:R-HSA-5692779
    title: p-T182 MAPKAPK5 phosphorylates FOXO1
    findings: []
  - id: Reactome:R-HSA-5692785
    title: p-S215 FOXO1 binds RAG gene
    findings: []
  - id: Reactome:R-HSA-6790036
    title: Expression of STAT3-upregulated nuclear proteins
    findings: []
  - id: Reactome:R-HSA-9614414
    title: AKT-phosphorylated FOXO1,FOXO3,FOXO4 translocate to the cytosol
    findings: []
  - id: Reactome:R-HSA-9614423
    title: 14-3-3 proteins bind AKT-phosphorylated FOXO1
    findings: []
  - id: Reactome:R-HSA-9614662
    title: FOXO1,FOXO3,(FOXO4) bind FASLG gene promoter
    findings: []
  - id: Reactome:R-HSA-9617840
    title: FOXO1,FOXO3,FOXO4 bind CDKN1A gene promoter
    findings: []
  - id: Reactome:R-HSA-9617996
    title: FOXO1,FOXO3,FOXO4 bind p-2S-SMAD2/3:SMAD4
    findings: []
  - id: Reactome:R-HSA-9622980
    title: FOXO1 binds NPY gene promoter
    findings: []
  - id: Reactome:R-HSA-9623415
    title: FOXO1,FOXO3,FOXO4 bind IGFBP1 gene promoter
    findings: []
  - id: Reactome:R-HSA-9624976
    title: FOXO1,FOXO3 binds CAV1 gene promoter
    findings: []
  - id: Reactome:R-HSA-9625091
    title: FOXO1,FOXO3 bind ABCA6 gene promoter
    findings: []
  - id: Reactome:R-HSA-9626928
    title: CREBBP binds FOXO1
    findings: []
  - id: Reactome:R-NUL-9620806
    title: FOXO1,FOXO3 binds Rbl2 gene
    findings: []
  - id: Reactome:R-NUL-9620857
    title: FOXO1,FOXO3 binds Ccng2 gene
    findings: []
  - id: Reactome:R-NUL-9624599
    title: FOXO1 binds Fbxo32 gene promoter
    findings: []
  - id: Reactome:R-NUL-9625492
    title: FOXO1 and p-2S-Smad2/3:Smad4 bind Mstn gene promoter
    findings: []
  - id: Reactome:R-NUL-9625758
    title: FOXO1,FOXO3 and SMAD3 bind Trim63 gene promoter
    findings: []
  - id: file:human/FOXO1/FOXO1-deep-research-falcon.md
    title: Deep research report on FOXO1
    findings: []

core_functions:
  - molecular_function:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    description: >
      FOXO1 is a sequence-specific DNA-binding transcription factor that 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 domain to regulate transcription of
      target genes.
    directly_involved_in:
      - id: GO:0045722
        label: positive regulation of gluconeogenesis
  - molecular_function:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    description: >
      FOXO1 is the main downstream effector of insulin signaling through the PI3K-AKT
      pathway.
      Insulin-activated AKT phosphorylates FOXO1 at T24/S256/S319, promoting 14-3-3
      binding,
      nuclear export, and transcriptional inactivation. This represents FOXO1's role
      as the
      transcriptional switch for insulin signaling.
    directly_involved_in:
      - id: GO:0008286
        label: insulin receptor signaling pathway
  - molecular_function:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    description: >
      FOXO1 mediates cellular adaptation to oxidative stress by translocating to the
      nucleus
      and activating transcription of antioxidant and stress resistance genes. This
      represents
      one of FOXO1's primary evolved functions alongside metabolic regulation.
    directly_involved_in:
      - id: GO:0034599
        label: cellular response to oxidative stress

proposed_new_terms: []

suggested_questions:
  - question: >
      Is there evidence for isoform-specific functions of FOXO1 versus FOXO3/FOXO4
      in specific
      tissues, particularly in hepatic gluconeogenesis versus other metabolic processes?
  - question: >
      What is the relative contribution of FOXO1's transcriptional versus non-transcriptional
      (cytoplasmic ATG7 interaction) roles in autophagy regulation?

suggested_experiments:
  - description: >
      ChIP-seq comparison of FOXO1 binding sites in fed versus fasted hepatocytes
      to define
      the core gluconeogenic gene regulatory program.
  - description: >
      Structure-function analysis of FOXO1 acetylation sites to determine which modifications
      are essential for transcription factor activity versus autophagy induction.

FOXO1

Gene Description

Existing Annotations Review

Core Functions

FOXO1 is a sequence-specific DNA-binding transcription factor that 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 domain to regulate transcription of target genes.

FOXO1 mediates cellular adaptation to oxidative stress by translocating to the nucleus and activating transcription of antioxidant and stress resistance genes. This represents one of FOXO1's primary evolved functions alongside metabolic regulation.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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