Affinage

FOXO1

Forkhead box protein O1 · UniProt Q12778

Length
655 aa
Mass
69.7 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOXO1 is a forkhead transcription factor that serves as a central nuclear effector translating insulin and growth-factor signaling into transcriptional programs governing metabolism, stress resistance, immune-cell function, vascular development, and tissue differentiation (PMID:10358075, PMID:11696581). Its activity is gated principally by AKT/PKB, which directly phosphorylates FOXO1 at Thr-24, Ser-256, and Ser-319 downstream of PI3K to drive nuclear exclusion (PMID:10358075); CK1 phosphorylation at Ser-322/325 within the multisite phosphorylation domain is additionally required for IGF-1/insulin-induced nuclear export (PMID:14710188), while PI3K-independent inputs from Pak1 and the TAK1-NLK pathway also promote cytoplasmic localization and repress its transactivation (PMID:12560069, PMID:20061393). A reciprocal layer of acetylation control tunes FOXO1: CBP acetylation of Lys-242/245/262 reduces DNA-binding affinity and sensitizes FOXO1 to AKT phosphorylation (PMID:16076959), whereas the PML-SIRT1 complex and deacetylase regulation direct FOXO1 between protective and proapoptotic programs and protect it from degradation (PMID:16154098, PMID:21196578). FOXO1 protein abundance and dephosphorylation are further set by the SCP4/CTDSPL2 nuclear phosphatase and by the DDB1-CUL4A ligase acting through the CRY1 repressor (PMID:28790135, PMID:28851713). In the nucleus FOXO1 binds defined target promoters to execute lineage-specific programs: gluconeogenic genes G6Pase and PEPCK in liver to mediate insulin suppression of glucose production (PMID:11696581, PMID:34208360), pro-apoptotic and DNA-repair genes such as caspase-3 and GADD45α (PMID:16157701, PMID:21196578), and immune, vascular, and differentiation genes including CCR7, ICAM-1, CXCR2, CD11b, CXCR4, VEGFA, RUNX2, and IL9/IRF4 across dendritic cells, neutrophils, lymphatic endothelium, keratinocytes, osteoblasts, and T cells (PMID:21281751, PMID:25786691, PMID:28928749, PMID:29574902, PMID:29339772, PMID:31852686). The chromosomal PAX3-FOXO1 fusion reprograms the enhancer landscape of alveolar rhabdomyosarcoma by establishing BRD4-dependent super-enhancers and master-TF autoregulatory loops (PMID:28446439).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 High

    Established the core regulatory logic: FOXO1 is a direct physiological AKT substrate, defining how insulin/growth-factor signaling switches it off.

    Evidence In vitro kinase assays with site-directed mutagenesis and PI3K/MEK/mTOR inhibitor dissection in 293 cells

    PMID:10358075

    Open questions at the time
    • Did not establish the in vivo consequences of phosphorylation on target gene programs
    • Subcellular trafficking mechanism not resolved at this stage
  2. 2001 High

    Placed FOXO1 as a required transcriptional mediator of insulin's suppression of hepatic gluconeogenic genes, connecting the kinase target to a metabolic output.

    Evidence Adenoviral gain-of-function and dominant-negative loss-of-function in primary hepatocytes and kidney cells

    PMID:11696581

    Open questions at the time
    • Direct promoter occupancy at G6Pase/PEPCK not shown here
    • Cofactor requirements unresolved
  3. 2003 Medium

    Revealed phosphorylation-independent nuclear entry and a PI3K-independent kinase input, expanding FOXO1 regulation beyond the AKT axis.

    Evidence Domain mutants in differentiating primary myoblasts (#5) and Pak1 Co-IP/in vitro kinase/reporter assays (#7)

    PMID:12560069 PMID:12606579

    Open questions at the time
    • Pak1 site of phosphorylation not mapped
    • Relationship between phospho-independent nuclear import and known phospho-sites unclear
  4. 2004 High

    Defined CK1 multisite-domain phosphorylation as required for nuclear export and showed FOXO1 is essential for vascular development.

    Evidence CK1 inhibitor (D4476) with site-specific readout in H4IIE cells (#2); Foxo1 knockout mice and ES-derived endothelial VEGF-response assays (#6)

    PMID:14710188 PMID:15184386

    Open questions at the time
    • Direct endothelial FOXO1 transcriptional targets not identified at this stage
    • Hierarchy between AKT and CK1 phosphorylation not fully resolved
  5. 2005 High

    Uncovered acetylation as a parallel control layer that lowers DNA affinity and reroutes FOXO1 between degradation, stress-protective, and apoptotic fates.

    Evidence Acetylation-mimetic/deficient mutants with DNA-binding and kinase assays (#3); FoxO1-PML-SIRT1 Co-IP and transgenic beta-cell models (#4); caspase-3 transcriptional activation in rhabdomyosarcoma cells (#9)

    PMID:16076959 PMID:16154098 PMID:16157701

    Open questions at the time
    • Quantitative interplay between acetylation and individual phospho-sites incomplete
    • Which acetylation states predominate physiologically across tissues unclear
  6. 2006 Medium

    Extended FOXO1 to reproductive tissue programming, showing it sets decidualization-specific gene expression in endometrial stroma.

    Evidence siRNA knockdown, overexpression, and PRL promoter reporter in human endometrial stromal cells

    PMID:16690806

    Open questions at the time
    • Direct binding to most regulated genes not shown beyond PRL
    • Upstream signal controlling FOXO1 in decidualization not defined
  7. 2010 Medium

    Identified the TAK1-NLK pathway as a PI3K/AKT-independent route that phosphorylates the transactivation domain to exclude FOXO1 from the nucleus, with evolutionary conservation.

    Evidence NLK-FOXO1 Co-IP, in vitro kinase assay, siRNA knockdown with target-gene and PARP-cleavage readouts; conservation in Drosophila

    PMID:20061393

    Open questions at the time
    • Precise transactivation-domain residues not individually mapped
    • Physiological contexts engaging TAK1-NLK vs AKT not delineated
  8. 2011 Medium

    Demonstrated direct promoter binding driving lineage differentiation, linking FOXO1 to skeletal programs and stress-response transcription.

    Evidence ChIP at the RUNX2 promoter with RNAi and differentiation assays in osteoblast precursors (#11); nuclear translocation and GADD45α/PUMA SIRT1-dependent switching in beta cells (#10)

    PMID:21196578 PMID:21281751

    Open questions at the time
    • Cofactors directing FOXO1 to protective vs apoptotic promoters not fully defined
    • SIRT1-dependent target selectivity mechanism incomplete
  9. 2015 Medium

    Established FOXO1 as a direct transcriptional driver of innate immune-cell trafficking and effector function via defined promoter targets.

    Evidence Conditional knockouts with ChIP and rescue at CCR7/ICAM-1 in dendritic cells (#13) and NFATc1 regulation in osteoclasts (#12)

    PMID:25694609 PMID:25786691

    Open questions at the time
    • Signal-to-FOXO1 coupling (MAPK) not mechanistically resolved at the phospho-site level
    • Whether the same FOXO1 cofactors operate across immune lineages unknown
  10. 2017 Medium

    Defined the upstream stability and dephosphorylation machinery setting nuclear FOXO1 levels and showed the oncogenic fusion reprograms enhancers, plus extended FOXO1 to neutrophil function.

    Evidence Hepatocyte Ddb1 KO with CRY1 epistasis (#15); SCP4 in vitro dephosphorylation and KO mice (#16); CXCR2/CD11b ChIP and conditional KO in neutrophils (#14); PAX3-FOXO1 ChIP-seq and BET-inhibitor dependence (#24)

    PMID:28446439 PMID:28790135 PMID:28851713 PMID:28928749

    Open questions at the time
    • Direct SCP4 dephosphorylation sites on FOXO1 not enumerated
    • How PAX3-FOXO1 differs mechanistically from wild-type FOXO1 occupancy incompletely defined
  11. 2018 Medium

    Broadened FOXO1 to angiogenic, T-cell, and reproductive epithelial programs through direct target genes and reciprocal hormonal regulation.

    Evidence Keratinocyte KO and VEGFA transcription assays in wound models (#18); ChIP at Il9/Irf4 with conditional KO in CD4+ T cells (#19); uterine Foxo1 KO with PGR reciprocal regulation (#17)

    PMID:29339772 PMID:29574902 PMID:30452456

    Open questions at the time
    • Mechanism of PGR-FOXO1 mutual inhibition not molecularly defined
    • Cofactor partners at IL9/IRF4 promoters unknown
  12. 2020 Medium

    Confirmed FOXO1 control of lymphatic development through direct CXCR4 regulation and showed acetylation control of FOXO1 by an S100A11-HDAC6 axis in hepatic lipid metabolism.

    Evidence Endothelial KO with microarray and migration assays at CXCR4 (#20); S100A11-HDAC6 Co-IP with FOXO1-acetylation epistasis in hepatocytes/mice (#21)

    PMID:31852686 PMID:33075563

    Open questions at the time
    • Direct FOXO1 occupancy at autophagy/lipogenic targets in the S100A11 axis not mapped
    • Quantitative link between HDAC6-dependent FOXO1 acetylation and specific genes incomplete
  13. 2022 Medium

    Established FOXO1 as a determinant of macrophage polarization and metabolic inflammation, antagonizing Stat6 and intestinal homeostasis programs.

    Evidence Myeloid conditional KO with M1/M2 polarization and NASH models (#23); intestinal epithelial KO with goblet-cell autophagy/mucus assays (#22)

    PMID:34287641 PMID:35700043

    Open questions at the time
    • Molecular basis of FOXO1-Stat6 counteraction not resolved
    • Direct FOXO1 targets governing goblet-cell autophagy not identified
  14. 2023 Low

    Extended direct FOXO1 promoter control to adipocyte lipid-handling genes in a non-human model.

    Evidence ChIP and FOXO response-element mutagenesis at CD36/STEAP4 with RNAi in bovine adipocytes

    PMID:37506793

    Open questions at the time
    • Single lab in a bovine model, no independent replication
    • Conservation of these targets in human adipocytes untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple, often competing post-translational inputs (AKT, CK1, Pak1, TAK1-NLK, PKA, acetylation, SCP4, ubiquitin ligases) are integrated to select among FOXO1's many tissue-specific transcriptional programs remains unresolved.
  • No unified model linking specific phospho/acetyl states to specific target-gene selection
  • Cofactor combinatorics directing cell-type-specific promoter choice undefined
  • Structural basis for DNA-binding modulation by combined modifications not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 7
Localization
GO:0005634 nucleus 7 GO:0005829 cytosol 4
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1430728 Metabolism 5 R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 2
Partners
AKT1CBPCK1NLKPAK1PMLSCP4SIRT1
Complex memberships
FoxO1-PML-SIRT1 complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PKBα (AKT) directly phosphorylates FOXO1 (FKHR) at Thr-24, Ser-256, and Ser-319 in vitro and in cells; these sites match canonical PKB consensus sequences. IGF-1-stimulated phosphorylation at all three sites was abolished by wortmannin (PI3K inhibitor) but not by MEK or mTOR inhibitors, establishing FOXO1 as a direct physiological substrate of PKB downstream of PI3K. In vitro kinase assay, site-directed mutagenesis, cotransfection with PKB/PDK1, IGF-1 stimulation with pharmacological inhibitors in 293 cells The Journal of biological chemistry High 10358075
2001 FOXO1 confers insulin sensitivity onto glucose-6-phosphatase (G6P) expression in liver/kidney cells. Adenoviral transduction of Foxo1 restored insulin inhibition of dex/cAMP-induced G6p expression; dominant-negative Foxo1 partially inhibited dex/cAMP-induced G6p and Pepck expression, placing FOXO1 as a required transcriptional mediator of insulin's suppression of hepatic gluconeogenic genes. Recombinant adenovirus transduction, dominant-negative mutant expression, primary hepatocyte and kidney cell culture models The Journal of clinical investigation High 11696581
2004 CK1 phosphorylates FOXO1a at Ser-322 and Ser-325 within its multisite phosphorylation domain (MPD) in hepatoma cells. The cell-permeant CK1 inhibitor D4476 specifically blocked phosphorylation at these two sites and prevented accelerated nuclear exclusion of FOXO1a in response to IGF-1 and insulin, demonstrating that CK1-mediated MPD phosphorylation is required for nuclear export. In vitro kinase assay, pharmacological inhibition (D4476) in H4IIE cells, site-specific phosphorylation analysis EMBO reports High 14710188
2005 CBP-mediated acetylation of FOXO1 at Lys-242, Lys-245, and Lys-262 reduces its DNA-binding affinity. Additionally, acetylation increases phosphorylation of FOXO1 at Ser-253 via the PI3K-PKB pathway; DNA binding by FOXO1 inhibits PKB-dependent phosphorylation in vitro, whereas acetylation-mimicking mutants are efficiently phosphorylated even in the presence of target DNA. Thus acetylation regulates FOXO1 by reducing DNA affinity and increasing susceptibility to PKB phosphorylation. In vitro kinase assay, acetylation-deficient and acetylation-mimicking mutants, gel retardation/DNA-binding assays, cotransfection experiments Proceedings of the National Academy of Sciences of the United States of America High 16076959
2005 FoxO1 forms a complex with PML (promyelocytic leukemia protein) and SIRT1 to activate transcription of NeuroD and MafA in pancreatic beta cells, protecting against oxidative stress. Acetylation-defective and acetylation-mimicking FoxO1 mutants demonstrated that acetylation targets FoxO1 to PML and prevents ubiquitin-dependent degradation; hyperglycemia suppresses MafA expression and this is prevented by constitutively nuclear FoxO1 transgene. Co-immunoprecipitation (FoxO1-PML-SIRT1 complex), acetylation mutants, adenoviral/transgenic mouse models, in vivo hyperglycemia model Cell metabolism High 16154098
2003 FOXO1 (FKHR) regulates myotube fusion of differentiating primary myoblasts. FOXO1 translocates to the nucleus by a phosphorylation-independent mechanism upon serum starvation-induced differentiation. A dominant-active non-phosphorylatable FOXO1 mutant dramatically augments myotube fusion rate, while a dominant-negative FOXO1 mutant blocks myotube formation, establishing FOXO1 as a regulator of the myogenic fusion step. Dominant-active and dominant-negative FOXO1 mutants, primary myoblast culture, serum starvation differentiation model, nuclear localization assays The EMBO journal High 12606579
2004 Foxo1-deficient mice die at ~E11 due to defects in vascular development. Foxo1-deficient endothelial cells derived from ES cells showed markedly abnormal morphological responses to VEGF compared to wild-type, establishing that Foxo1 is essential for proper endothelial cell response to VEGF and normal vascular development. Foxo1 knockout mouse generation, ES cell in vitro differentiation to endothelial cells, VEGF stimulation assay The Journal of biological chemistry High 15184386
2003 PAX1-activated kinase-1 (Pak1) directly interacts with FOXO1 (FKHR) and phosphorylates it in a PI3K-independent, estrogen-dependent manner, causing perinuclear cytoplasmic localization and impairing FOXO1-dependent transcription from the Fas ligand promoter (FRE). Dominant-negative Pak1 restored FOXO1 transcriptional activity. Co-immunoprecipitation (Pak1-FKHR interaction), in vitro kinase assay, luciferase reporter assay, dominant-negative Pak1 expression, subcellular localization FEBS letters Medium 12560069
2010 The TAK1-NLK kinase pathway phosphorylates FOXO1 at Pro-directed Ser/Thr residues in its transactivation domain. NLK binds FOXO1, and TAK1-NLK-mediated phosphorylation inhibits FOXO1 transcriptional activity and causes nuclear exclusion independently of PI3K/Akt. Knockdown of TAK1-NLK dephosphorylates FOXO1, promotes nuclear translocation, and increases FOXO target gene mRNA and PARP cleavage. The NLK-FOXO1 interaction is evolutionarily conserved in Drosophila. Co-immunoprecipitation (NLK-FOXO1), in vitro kinase assay, siRNA knockdown, subcellular localization, reporter assay The Journal of biological chemistry Medium 20061393
2005 FOXO1a is absent from primary alveolar rhabdomyosarcoma (ARMS) tumors and ARMS-derived cell lines. Restoration of FOXO1a expression in ARMS cells induces cell cycle arrest and apoptosis by directly activating caspase-3 transcription. This effect is selective: enforced FOXO1a expression in embryonal RMS (ERMS) cells had no effect. Adenoviral FOXO1a expression in tumor cell lines, immunohistochemistry of primary tumors, reporter and RT-PCR for caspase-3, comparison of ARMS vs ERMS cell lines The Journal of cell biology Medium 16157701
2011 FoxO1 translocates to the nucleus in response to nitric oxide in pancreatic beta cells and stimulates GADD45α expression, promoting DNA repair. SIRT1 regulates FoxO1-dependent gene expression: SIRT1 inhibition shifts FoxO1 from a protective (GADD45α/DNA repair) to a proapoptotic program (PUMA mRNA accumulation, caspase-3 cleavage). Subcellular fractionation/localization, siRNA knockdown, pharmacological SIRT1 inhibition, RT-PCR, caspase cleavage assay in beta cells The Journal of biological chemistry Medium 21196578
2011 FOXO1 directly binds the RUNX2 promoter (demonstrated by ChIP) in osteoblast precursors and is required for osteoblast differentiation: FOXO1 knockdown reduced RUNX2 DNA-binding activity, alkaline phosphatase activity, and expression of osteoblast marker genes, and decreased mineralizing nodule formation. RNAi knockdown, chromatin immunoprecipitation (ChIP) for FOXO1 at RUNX2 promoter, alkaline phosphatase assay, mineralization assay in MC3T3-E1 cells Bone Medium 21281751
2015 FOXO1 mediates RANKL-induced osteoclast formation by regulating NFATc1 nuclear localization and expression, and downstream effectors including DC-STAMP, ATP6vod2, cathepsin K, and integrin αv. Lineage-specific FOXO1 deletion (LyzM.Cre+FOXO1L/L) reduced osteoclast formation and activity by ~50% in vivo and in vitro; FOXO1 deletion also reduced M-CSF-induced RANK expression and osteoclast precursor migration. Lineage-specific FOXO1 conditional knockout (LyzM.Cre+FOXO1L/L), siRNA knockdown in RAW264.7, NFATc1 localization assay, in vivo and in vitro osteoclast differentiation assays Journal of immunology Medium 25694609
2015 FOXO1 directly binds the CCR7 and ICAM-1 promoters in dendritic cells (demonstrated by ChIP), stimulates their transcriptional activity, and is required for DC phagocytosis, chemotaxis, and DC–lymphocyte binding. Bacteria induce FOXO1 nuclear localization through the MAPK pathway. Rescue of FOXO1-deleted DCs with ICAM-1 or both CCR7+ICAM-1 restored phagocytosis, chemotaxis, and lymph node homing respectively. Conditional FOXO1 knockout (CD11c.Cre+FOXO1L/L), ChIP assay at CCR7 and ICAM-1 promoters, luciferase reporter, rescue transfection, in vivo DC homing assay Journal of immunology Medium 25786691
2017 FOXO1 directly binds the promoter regions of CXCR2 and CD11b in neutrophils (ChIP), and its expression is required for CXCR2 and CD11b induction by bacteria. Lineage-specific FOXO1 deletion (LyzM.Cre+FOXO1L/L) impaired neutrophil mobilization from bone marrow, recruitment to infection sites, bacterial clearance, chemotaxis, and killing. Bacteria-induced nuclear FOXO1 localization required TLR2/TLR4 signaling and was reduced by ROS/NOS inhibitors and deacetylase inhibitors. Conditional FOXO1 knockout, ChIP assay, in vivo bacterial challenge model, in vitro chemotaxis and bacterial killing assays, pharmacological inhibition Frontiers in immunology Medium 28928749
2017 The DDB1-CUL4A ubiquitin E3 ligase promotes FOXO1-driven hepatic gluconeogenesis by degrading the circadian protein CRY1, a known FOXO1 repressor. In the absence of CRY1, insulin fails to reduce nuclear FOXO1 or suppress gluconeogenic gene expression. Hepatocyte-specific Ddb1 deletion reduces FOXO1 protein expression and impairs gluconeogenesis in mice. Hepatocyte-specific Ddb1 KO, liver-specific Cry1 knockdown and overexpression, FOXO1 protein stability assays, gluconeogenesis assays in vivo Diabetes Medium 28790135
2017 SCP4/CTDSPL2 is a nuclear phosphatase that directly dephosphorylates FoxO1 and FoxO3a, promoting their transcriptional activity and hepatic gluconeogenesis (PEPCK1 and G6PC expression). SCP4 gene ablation causes neonatal hypoglycemia in mice; SCP4 expression is induced by glucose deprivation and is elevated in obese mice. SCP4 gain- and loss-of-function, in vitro dephosphorylation assay, SCP4 knockout mice, glucose production assay, gene expression analysis Diabetes Medium 28851713
2018 FOXO1 is required for uterine epithelial integrity and progesterone receptor (PGR) regulation during the implantation window. Uterine ablation of Foxo1 (PgrCre model) causes infertility due to altered epithelial polarity and apoptosis; PGR is constitutively retained in the uterine epithelium when FOXO1 is absent. Constitutive epithelial PGR during the receptive period inhibits nuclear FOXO1, revealing a reciprocal regulatory relationship between PGR and FOXO1. Conditional uterine Foxo1 knockout (PgrCre), transcriptome analysis, immunohistochemistry, in vitro cell culture PLoS genetics Medium 30452456
2018 FOXO1 directly regulates VEGFA transcription in keratinocytes. Keratinocyte-specific deletion of Foxo1 reduces VEGFA expression in wounds, leading to reduced endothelial cell proliferation and angiogenesis. A FOXO1 inhibitor applied locally in a porcine wound model reduced angiogenesis. Keratinocyte-specific conditional Foxo1 KO, in vitro VEGFA transcription assay, murine and porcine wound healing models The Journal of pathology Medium 29574902
2018 Foxo1 promotes Th9 cell differentiation and IL-9 expression. ChIP and luciferase assays demonstrated direct Foxo1 binding to Il9 and Irf4 promoters with transactivation. Pharmacological or genetic disruption of Foxo1 in CD4+ T cells reduced IL-9 and upregulated IL-17A and IFNγ. ChIP assay, luciferase reporter assay, Foxo1 pharmacological inhibitor (AS1842856), conditional Foxo1 knockout in CD4+ T cells, adoptive transfer model Scientific reports Medium 29339772
2020 FOXO1 regulates developmental dermal lymphangiogenesis by directly upregulating CXCR4 in lymphatic endothelial cells (LECs). Endothelial cell-specific FOXO1 deletion caused disconnected, dilated lymphatic vessels. CXCR4 was the most downregulated gene in FOXO1-deficient LECs by microarray; FOXO1 suppression impaired LEC migration toward CXCL12 (the CXCR4 ligand) and dysregulated proliferation. Endothelial cell-specific FOXO1 conditional KO, DNA microarray, in vitro LEC migration assay, immunostaining Development Medium 31852686
2020 S100A11 promotes hepatic steatosis through a S100A11-HDAC6-FOXO1 axis: S100A11 interacts with HDAC6 to inhibit its deacetylase activity, leading to increased FOXO1 acetylation and activation of autophagy and lipogenesis programs. Co-immunoprecipitation confirmed S100A11-HDAC6 interaction; HDAC6 inhibition phenocopied S100A11 overexpression; FOXO1 inhibition reversed the lipogenic effects. Co-immunoprecipitation (S100A11-HDAC6), HDAC6 inhibitor, FOXO1 inhibitor, adenoviral overexpression in mice, in vitro hepatocyte models Cellular and molecular gastroenterology and hepatology Medium 33075563
2021 Foxo1 regulates mucus secretion by intestinal goblet cells and is required for gut homeostasis. Loss of Foxo1 in intestinal epithelial cells (IECs) causes defects in goblet cell autophagy and mucus secretion, leading to dysbiosis, altered tight junction organization, and enhanced susceptibility to intestinal inflammation. Intestinal epithelial cell-specific Foxo1 KO, goblet cell autophagy and mucus secretion assays, microbiome analysis, gut permeability assays The Journal of experimental medicine Medium 34287641
2022 FoxO1 in myeloid cells promotes M1 macrophage polarization and hepatic inflammation by counteracting Stat6 signaling. Myeloid-specific FoxO1 knockout (LyzM.Cre+FOXO1L/L) skewed macrophages from M1 to M2 phenotype, reduced hepatic macrophage infiltration, improved insulin sensitivity, and protected mice from NASH on a high-fat diet. Myeloid cell conditional FoxO1 KO (LyzM.Cre), macrophage polarization assays, NASH diet model, mechanistic Stat6 interaction studies The Journal of clinical investigation Medium 35700043
2017 PAX3-FOXO1 reprograms the cis-regulatory landscape in alveolar rhabdomyosarcoma by inducing de novo super enhancers and setting up autoregulatory loops with master transcription factors (MYOG, MYOD, MYCN). PAX3-FOXO1 recruits and requires BRD4 at super enhancers, creating a dependence on BET bromodomain function. ChIP-seq, enhancer mapping, BRD4 co-occupancy assays, BET inhibitor treatment, gene expression analysis in cell lines and primary tumors Cancer discovery Medium 28446439
2006 FOXO1a differentially regulates decidualization-specific genes: overexpression increases IGFBP1, DCN, and PRL (with reporter data confirming direct FOXO1A effect on PRL promoter), while decreasing TIMP3 and CNR1. siRNA knockdown of FOXO1A decreased IGFBP1 and DCN but increased CNR1, TIMP3, and PRL. FOXO1A overexpression also induced an epithelioid morphological change in stromal fibroblasts. FOXO1A siRNA knockdown, FOXO1A overexpression, luciferase reporter assay (PRL promoter), real-time PCR in human endometrial stromal cells Endocrinology Medium 16690806
2021 Metformin inhibits hepatic glucose production through a Foxo1-dependent mechanism by suppressing the PKA→Foxo1-S273 phosphorylation signaling pathway. Foxo1-S273D or S273A mutations abolished metformin's suppressive effect on glucagon- or fasting-induced hepatic glucose production in cells and mice. Foxo1 S273D/A mutant mice and cells, glucagon-stimulated glucose production assays, PKA activity assays, high-fat diet mouse model Biomolecules Medium 34208360
2023 FOXO1 directly binds the promoter regions of CD36 and STEAP4 genes in bovine adipocytes (demonstrated by ChIP and site-directed mutagenesis of FOXO response elements), regulating their transcriptional activity and thereby controlling bovine adipocyte lipogenesis through AMPK and PI3K/AKT pathways. ChIP assay, site-directed mutagenesis of promoter elements, FOXO1 RNAi, transcriptomic and metabolomic analyses International journal of biological macromolecules Low 37506793

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. The Journal of biological chemistry 606 10358075
2001 The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. The Journal of clinical investigation 497 11696581
2005 FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell metabolism 496 16154098
2005 Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proceedings of the National Academy of Sciences of the United States of America 423 16076959
2017 The regulation of FOXO1 and its role in disease progression. Life sciences 348 29158051
1998 Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Genomics 300 9479491
2004 Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. The Journal of biological chemistry 286 15184386
2017 PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability. Cancer discovery 262 28446439
2004 D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO reports 230 14710188
2002 Expression of FKHR, FKHRL1, and AFX genes in the rodent ovary: evidence for regulation by IGF-I, estrogen, and the gonadotropins. Molecular endocrinology (Baltimore, Md.) 165 11875118
2003 FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts. The EMBO journal 149 12606579
2008 PAX3-FOXO1 fusion gene in rhabdomyosarcoma. Cancer letters 140 18457914
1996 In vivo amplification of the PAX3-FKHR and PAX7-FKHR fusion genes in alveolar rhabdomyosarcoma. Human molecular genetics 133 8789435
2012 MicroRNA-223 regulates FOXO1 expression and cell proliferation. FEBS letters 132 22569260
2018 FOXO1 regulates uterine epithelial integrity and progesterone receptor expression critical for embryo implantation. PLoS genetics 120 30452456
2012 FoxO1 is crucial for sustaining cardiomyocyte metabolism and cell survival. Cardiovascular research 120 23263330
2000 Forkhead genes in transcriptional silencing, cell morphology and the cell cycle. Overlapping and distinct functions for FKH1 and FKH2 in Saccharomyces cerevisiae. Genetics 112 10747051
2019 Mucosal Immunity and the FOXO1 Transcription Factors. Frontiers in immunology 108 31849924
1996 The hybrid PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma transforms fibroblasts in culture. Proceedings of the National Academy of Sciences of the United States of America 103 8790412
2014 FOXO1, TGF-β regulation and wound healing. International journal of molecular sciences 91 25226535
2007 FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A. Human molecular genetics 90 17993506
2003 Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells. FEBS letters 87 12560069
2007 Effects of PAX3-FKHR on malignant phenotypes in alveolar rhabdomyosarcoma. Biochemical and biophysical research communications 86 18022385
2011 FOXO1 modulates osteoblast differentiation. Bone 82 21281751
2019 Molecular mechanisms of FOXO1 in adipocyte differentiation. Journal of molecular endocrinology 79 30780132
2006 FOXO1A differentially regulates genes of decidualization. Endocrinology 76 16690806
2018 FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds. The Journal of pathology 75 29574902
2009 FoxO1 and hepatic lipid metabolism. Current opinion in lipidology 75 21037971
2020 S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis. Cellular and molecular gastroenterology and hepatology 74 33075563
2021 FOXO1 constrains activation and regulates senescence in CD8 T cells. Cell reports 71 33503413
2011 FoxO1: a molecule for all seasons. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 68 21541992
2006 Correlation between FOXO1a (FKHR) and FOXO3a (FKHRL1) binding and the inhibition of basal glucose-6-phosphatase catalytic subunit gene transcription by insulin. Molecular endocrinology (Baltimore, Md.) 68 16840535
2010 FoxO1 - the key for the pathogenesis and therapy of acne? Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 66 20151947
2006 Forkhead transcription factor FOXO1A is critical for induction of human decidualization. The Journal of endocrinology 66 16614392
2001 PAX3-FKHR induces morphological change and enhances cellular proliferation and invasion in rhabdomyosarcoma. The American journal of pathology 65 11549601
2011 FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide. The Journal of biological chemistry 62 21196578
2022 HB-EGF induces mitochondrial dysfunction via estrogen hypersecretion in granulosa cells dependent on cAMP-PKA-JNK/ERK-Ca2+-FOXO1 pathway. International journal of biological sciences 60 35342363
2020 Adipose Tissue and FoxO1: Bridging Physiology and Mechanisms. Cells 60 32244542
2018 PAR2 promotes M1 macrophage polarization and inflammation via FOXO1 pathway. Journal of cellular biochemistry 60 30552714
2012 The yeast forkhead transcription factors fkh1 and fkh2 regulate lifespan and stress response together with the anaphase-promoting complex. PLoS genetics 59 22438832
2012 Alveolar rhabdomyosarcoma-associated proteins PAX3/FOXO1A and PAX7/FOXO1A suppress the transcriptional activity of MyoD-target genes in muscle stem cells. Oncogene 59 22710712
2005 Cell-type-specific regulation of distinct sets of gene targets by Pax3 and Pax3/FKHR. Oncogene 55 15688035
2002 Regulation of the forkhead transcription factor FKHR (FOXO1a) by glucose starvation and AICAR, an activator of AMP-activated protein kinase. Endocrinology 55 12130586
2022 Myeloid FoxO1 depletion attenuates hepatic inflammation and prevents nonalcoholic steatohepatitis. The Journal of clinical investigation 54 35700043
2021 Foxo1 controls gut homeostasis and commensalism by regulating mucus secretion. The Journal of experimental medicine 54 34287641
2018 Maintenance of CD4 T cell fitness through regulation of Foxo1. Nature immunology 53 29988091
2012 Regulation of budding yeast mating-type switching donor preference by the FHA domain of Fkh1. PLoS genetics 53 22496671
1995 Structural characterization of the FKHR gene and its rearrangement in alveolar rhabdomyosarcoma. Human molecular genetics 52 8634710
2006 Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection. Nature 51 17024043
2015 FOXO1 regulates dendritic cell activity through ICAM-1 and CCR7. Journal of immunology (Baltimore, Md. : 1950) 50 25786691
2017 SAPHO, autophagy, IL-1, FoxO1, and Propionibacterium (Cutibacterium) acnes. Joint bone spine 49 28499891
2016 FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes. Cell cycle (Georgetown, Tex.) 47 27260854
2010 Regulation of FOXO1 by TAK1-Nemo-like kinase pathway. The Journal of biological chemistry 46 20061393
2017 PAX3-FOXO1: Zooming in on an "undruggable" target. Seminars in cancer biology 45 29146205
2017 FOXO1 Regulates Bacteria-Induced Neutrophil Activity. Frontiers in immunology 43 28928749
2014 Fkh1 and Fkh2 bind multiple chromosomal elements in the S. cerevisiae genome with distinct specificities and cell cycle dynamics. PloS one 43 24504085
2018 Nuclear FOXO1 promotes lymphomagenesis in germinal center B cells. Blood 42 30333121
2002 Effect of multiple phosphorylation events on the transcription factors FKHR, FKHRL1 and AFX. Biochemical Society transactions 41 12196101
2010 FOXO1A is a target for HER2-overexpressing breast tumors. Cancer research 40 20551062
2016 Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase. Genome research 38 26728715
2015 FOXO1 inhibits osteoclastogenesis partially by antagnozing MYC. Scientific reports 37 26568463
2022 Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma. Science translational medicine 36 35857643
2020 The role and molecular mechanism of FoxO1 in mediating cardiac hypertrophy. ESC heart failure 35 33089967
2017 A FOXO1-induced oncogenic network defines the AML1-ETO preleukemic program. Blood 35 28710059
2023 FOXO1 regulates the formation of bovine fat by targeting CD36 and STEAP4. International journal of biological macromolecules 32 37506793
2018 Trichostatin A activates FOXO1 and induces autophagy in osteosarcoma. Archives of medical science : AMS 31 30697272
2016 PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1. Cancer research 31 27864345
2015 FOXO1 mediates RANKL-induced osteoclast formation and activity. Journal of immunology (Baltimore, Md. : 1950) 31 25694609
2018 Foxo1 Promotes Th9 Cell Differentiation and Airway Allergy. Scientific reports 30 29339772
2021 Galanin promotes autophagy and alleviates apoptosis in the hypertrophied heart through FoxO1 pathway. Redox biology 29 33493902
2007 PAX3 and PAX3-FKHR promote rhabdomyosarcoma cell survival through downregulation of PTEN. Cancer letters 29 17350164
2023 Suppression of FOXO1 attenuates inflamm-aging and improves liver function during aging. Aging cell 28 37602516
2017 DDB1-Mediated CRY1 Degradation Promotes FOXO1-Driven Gluconeogenesis in Liver. Diabetes 28 28790135
2018 FoxO1 enhances differentiation and apoptosis in human primary keratinocytes. Experimental dermatology 27 30144329
2007 Forkhead protein FKHR and its phosphorylated form p-FKHR in human prostate cancer. Human pathology 27 17597184
2021 FOXF1 is required for the oncogenic properties of PAX3-FOXO1 in rhabdomyosarcoma. Oncogene 25 33627785
2020 FOXO1 regulates developmental lymphangiogenesis by upregulating CXCR4 in the mouse-tail dermis. Development (Cambridge, England) 25 31852686
2016 FoxO1 Inhibitors: The Future Medicine for Metabolic Disorders? Current diabetes reviews 25 26239835
2009 Atrial natriuretic peptide promotes pancreatic islet beta-cell growth and Akt/Foxo1a/cyclin D2 signaling. Endocrinology 25 19837876
2017 SCP4 Promotes Gluconeogenesis Through FoxO1/3a Dephosphorylation. Diabetes 24 28851713
2005 FOXO1a acts as a selective tumor suppressor in alveolar rhabdomyosarcoma. The Journal of cell biology 24 16157701
2009 Localisation and expression of FoxO1 proteins in human gestational tissues. Placenta 23 19150739
2007 CDK2 and FOXO1: a fork in the road for cell fate decisions. Cell cycle (Georgetown, Tex.) 23 17457058
2018 The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia. Cell reports 22 29320745
2018 Autophagy mediators (FOXO1, SESN3 and TSC2) in Lewy body disease and aging. Neuroscience letters 22 29966750
2012 AKT and PAX3-FKHR cooperation enforces myogenic differentiation blockade in alveolar rhabdomyosarcoma cell. Cell cycle (Georgetown, Tex.) 22 22333587
2022 Role of Forkhead Box Protein O1 (FoxO1) in Stroke: A Literature Review. Aging and disease 21 35371601
2022 Divergent transcriptional and transforming properties of PAX3-FOXO1 and PAX7-FOXO1 paralogs. PLoS genetics 21 35604932
2019 Dynamic relocalization of replication origins by Fkh1 requires execution of DDK function and Cdc45 loading at origins. eLife 21 31084713
2017 Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated β Cell Aging in Pancreas-specific SMAD7 Mutant Mice. The Journal of biological chemistry 21 28057752
2017 FOXO1 expression in keratinocytes promotes connective tissue healing. Scientific reports 21 28220813
2013 Fkh1 and Fkh2 associate with Sir2 to control CLB2 transcription under normal and oxidative stress conditions. Frontiers in physiology 21 23874301
2021 Dual regulation of TxNIP by ChREBP and FoxO1 in liver. iScience 20 33748706
2018 GnRH Transactivates Human AMH Receptor Gene via Egr1 and FOXO1 in Gonadotrope Cells. Neuroendocrinology 20 30368511
2013 FOXO1 regulates expression of a microRNA cluster on X chromosome. Aging 20 23748164
2021 Baicalein ameliorates osteoporosis via AKT/FOXO1 signaling. Aging 19 34198266
2021 Metformin Targets Foxo1 to Control Glucose Homeostasis. Biomolecules 19 34208360
2007 Pax3-fkhr and pax7-fkhr fusion genes impact outcome of alveolar rhabdomyosarcoma in children. Fetal and pediatric pathology 19 17613043
2021 The Roles of FOXO1 in Periodontal Homeostasis and Disease. Journal of immunology research 18 33860060
2021 The Fkh1 Forkhead associated domain promotes ORC binding to a subset of DNA replication origins in budding yeast. Nucleic acids research 18 34095951

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