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: PMID:37891184
      supporting_text: "FOXO1 is a forkhead box O transcription factor that binds
        DNA via a conserved winged-helix DBD"

      full_text_unavailable: true
    - 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: PMID:37891184
      supporting_text: "hepatic FOXO1 (with FOXO3/4) controls gluconeogenic programs"

      full_text_unavailable: true
- 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: PMID:37710009
      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: PMID:38466341
      supporting_text: "FOXO proteins recognize the DAF-16 family binding element
        (DBE; 5'-TTGTTTAC-3') with high affinity"

      full_text_unavailable: true
- 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: PMID:37891184
      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)
# ====================
      full_text_unavailable: true
- 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: PMID:37710009
      supporting_text: "β-catenin can relieve autoinhibition of the DBD"

      full_text_unavailable: true
- 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: PMID:37710009
      supporting_text: "FOXO family members can act as pioneer factors to open condensed
        chromatin"

      full_text_unavailable: true
- 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: PMID:37891184
      supporting_text: "FOXO1 activates genes involved in DNA repair and stress resistance"

      full_text_unavailable: true
- 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: PMID:37710009
      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: PMID:37891184
      supporting_text: "hepatic FOXO1 controls gluconeogenic programs"

      full_text_unavailable: true
    - 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.