Affinage

FOXO3

Forkhead box protein O3 · UniProt O43524

Length
673 aa
Mass
71.3 kDa
Annotated
2026-06-09
100 papers in source corpus 33 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOXO3 (FKHRL1/FOXO3a) is a forkhead transcription factor that integrates growth-factor, metabolic, and stress signals to determine cell fate between survival, quiescence, autophagy, and apoptosis (PMID:11694570, PMID:19896443). Its activity is governed by phosphorylation-driven nuclear-cytoplasmic shuttling: downstream of PI3K, Akt phosphorylates Ser-253 and SGK1 phosphorylates Ser-315, with both kinases targeting Thr-32, and concerted phosphorylation of all three sites drives nuclear exclusion and transcriptional silencing (PMID:11154281). This module is engaged by diverse upstream inputs including TGF-β, neurotrophin/TrkA signaling, and thrombopoietin, each acting through PI3K/Akt to retain FOXO3a in the cytoplasm (PMID:11694570, PMID:11953455, PMID:11278373), and by p53-induced SGK1 during DNA damage (PMID:15383658). Layered onto phosphorylation, FOXO3a activity is tuned by acetylation—p300 acetylates FoxO3 to drive cytosolic relocalization and proteasomal degradation, while SIRT1 deacetylation enhances its activity—and by prolyl hydroxylation that targets it for degradation under normoxia (PMID:22094330, PMID:39266959, PMID:30912765). When active in the nucleus, FOXO3a executes apoptosis through the mitochondrial pathway by transactivating the BH3-only proteins Bim and Noxa and repressing Survivin (PMID:16888645, PMID:19211844), and enforces cell-cycle arrest via p27Kip1 (PMID:17894357). Beyond apoptosis, FOXO3a binds promoters of an antioxidant, metabolic, and autophagy program: it transactivates SIRT6 to suppress the Warburg effect (PMID:32124950, PMID:31004738), drives Keap1 transcription to constrain Nrf2 (PMID:26857210), activates BNIP3, PARKIN, and PERK to control mitophagy and the unfolded-protein response (PMID:27694219, PMID:36539848, PMID:31312024), and represses SLC7A11 to limit ferroptosis (PMID:37267686). FOXO3 also coordinates the DNA-damage response by binding the ATM FAT domain and the ATM-Chk2-p53 complex to promote checkpoint activation, repair, and apoptosis (PMID:18344987, PMID:22893124). Its own expression and localization are regulated by transcriptional activators (TEAD1, WTIP), m6A methylation (METTL14), nuclear-retention partners (SNAI2), and cytoplasmic-sequestering partners (REP1) (PMID:21211055, PMID:34930905, PMID:37935312, PMID:35271390, PMID:28055019), and FOXO3 maintains the neural stem cell pool by enforcing quiescence and controlling oxygen metabolism (PMID:19896443).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Established the core regulatory logic of FOXO3a: how survival kinases inactivate it through site-specific phosphorylation.

    Evidence In vitro kinase assays with site-directed mutagenesis of Thr-32/Ser-253/Ser-315 and reporter/survival assays in cells

    PMID:11154281

    Open questions at the time
    • Did not resolve which phosphatase reverses inactivation
    • In vivo physiological relevance of distinct Akt vs SGK1 site usage not established
  2. 2001 High

    Showed the phosphorylation switch is engaged by physiological extracellular cues, linking FOXO3a to TGF-β and thrombopoietin signaling and identifying its transactivation domain as required for apoptosis.

    Evidence Triple Akt-site mutant, dominant-negative Akt and PI3K inhibitor in mammary epithelial cells; inducible constitutively active allele in TPO-dependent megakaryocytic cells

    PMID:11278373 PMID:11694570

    Open questions at the time
    • Direct target genes mediating arrest/apoptosis in these contexts not defined
    • Megakaryocyte study is Medium confidence with limited methods
  3. 2002 Medium

    Extended PI3K/Akt-mediated FOXO3a inactivation to neurotrophin-driven neuronal survival.

    Evidence Kinase inhibitors, constitutively active/dominant-negative Akt, in vitro kinase assay, TrkA vs p75 cell comparison in PC12 cells

    PMID:11953455

    Open questions at the time
    • Downstream survival targets not identified
    • Single cell-line model
  4. 2004 Medium

    Revealed an Akt-independent route to FOXO3a inactivation during DNA damage, mediated by p53-induced SGK1.

    Evidence siRNA knockdown of SGK1, pharmacological inhibitors, localization and phosphorylation assays in p53-deficient cells

    PMID:15383658

    Open questions at the time
    • Reconciliation with FOXO3a's pro-apoptotic role in DNA damage not fully resolved
    • Specific phosphosites engaged by p53/SGK1 not mapped
  5. 2006 High

    Defined the molecular effectors of FOXO3a-driven apoptosis, establishing it as a transcriptional trigger of the mitochondrial death pathway.

    Evidence 4-OHT-regulated FKHRL1(A3)ER transgene, RNAi of Noxa/Bim, dnFADD, Bcl2 overexpression, cytochrome c and caspase assays; promoter binding to G6Pase IRSs

    PMID:16840535 PMID:16888645

    Open questions at the time
    • Direct vs indirect transactivation of all BH3-only genes not fully dissected
    • Metabolic G6Pase study is Medium confidence
  6. 2008 High

    Identified a non-transcriptional, protein-protein function for FOXO3a in the DNA-damage response via direct ATM activation.

    Evidence Domain-mapped Co-IP (FOXO3a C-terminus to ATM FAT domain), siRNA, foci immunofluorescence, checkpoint and repair assays

    PMID:18344987

    Open questions at the time
    • Structural basis of the FOXO3a-FAT interface not determined
    • How phosphorylation status of FOXO3a gates this interaction unclear
  7. 2008 High

    Resolved how FOXO3a enforces quiescence and survival in proliferating cells, distinguishing late vs early cell-cycle control and defining its stem-cell role.

    Evidence Adenoviral overexpression with p27Kip1/p21 promoter-luciferase in muscle precursors; FoxO3 knockout mice with neurosphere, multipotency, and expression profiling

    PMID:17894357 PMID:19896443

    Open questions at the time
    • Direct FOXO3 occupancy of p27Kip1 promoter not shown by ChIP in muscle study (Medium)
    • NSC quiescence gene program members only partially defined
  8. 2009 High

    Showed FOXO3a sensitizes cells to genotoxic therapy by repressing the anti-apoptotic node Survivin.

    Evidence Conditional FKHRL1(A3)ER allele, Survivin shRNA and transgenic rescue, mitochondrial readouts, DNA-damaging drug sensitivity

    PMID:19211844

    Open questions at the time
    • Direct binding of FOXO3a to BIRC5/Survivin regulatory regions not mapped
    • Generality across tumor types untested
  9. 2011 High

    Established acetylation by p300 as a degradation/relocalization switch and identified TEAD1 as an upstream transcriptional activator of FoxO3a in muscle.

    Evidence Co-IP (FoxO3-p300), acetylation-mimic/resistant mutants (Lys-262) in denervation model; ChIP/EMSA/luciferase for TEAD1 at the FoxO3a M-CAT element

    PMID:21211055 PMID:22094330

    Open questions at the time
    • Deacetylases acting on these lysines in muscle not identified in this study
    • TEAD1 study is Medium confidence and muscle-restricted
  10. 2012 High

    Placed FOXO3 inside the ATM-Chk2-p53 DNA-damage complex as an essential bidirectional partner and defined a FOXO3-ATM-CREB axis controlling caspase-8.

    Evidence Reciprocal Co-IP of the four-protein complex, siRNA epistasis, foci and apoptosis assays; conditional FOXO3 transgene with ATM/CREB inhibition and bisulfite methylation analysis

    PMID:22493319 PMID:22893124

    Open questions at the time
    • Stoichiometry and assembly order of the FOXO3-ATM-Chk2-p53 complex unresolved
    • caspase-8 axis study is Medium confidence
  11. 2016 High

    Defined FOXO3 as a transcriptional governor of redox balance through direct Keap1 activation and BNIP3-driven mitochondrial fate.

    Evidence ChIP, siRNA, luciferase and xenograft for the FoxO3-Keap1-Nrf2 axis; dominant-negative FOXO3a (AAV9) with BNIP3 manipulation and cardiac functional readouts

    PMID:26857210 PMID:27694219

    Open questions at the time
    • Interplay between FOXO3-driven Keap1 (anti-Nrf2) and FOXO3's own antioxidant role not integrated
    • Tissue-specific weighting of these outputs unclear
  12. 2019 High

    Identified prolyl hydroxylation as an oxygen-sensing degradation switch and established direct FOXO3 transactivation of metabolic/stress targets SIRT6 and PERK.

    Evidence Tubule-specific FoxO3 and HIF-1α conditional KO with prolyl hydroxylation assays and renal injury models; ChIP/luciferase/triple-KO MEF validation for SIRT6 and PERK targets; NMR-validated small molecules targeting the FOXO3 DNA-binding domain

    PMID:30912765 PMID:31004738 PMID:31312024 PMID:31789593 PMID:32124950

    Open questions at the time
    • The PHD enzyme(s) and hydroxylated proline residues not all individually mapped
    • Druggability shown in cells but not in vivo efficacy
  13. 2010 High

    Confirmed direct FOXO3a transactivation of SIRT6 to suppress aerobic glycolysis across multiple cancer types.

    Evidence ChIP, luciferase, knockdown/overexpression epistasis with glycolysis assays and xenografts in melanoma and glioblastoma

    PMID:31004738 PMID:32124950

    Open questions at the time
    • Whether the FOXO3-SIRT6 axis operates in non-transformed metabolic tissues untested
  14. 2022 High

    Expanded FOXO3's transcriptional output to autophagy/mitophagy and revealed positive feedback loops and partner-controlled localization that amplify or constrain its activity.

    Evidence ChIP and feedback dissection for COPS3 and the SNAI2-FOXO3 feed-forward loop (with CRM1 export assays, conserved in Drosophila); Co-IP for SIRT1 (BNIP3/PINK1-Parkin) and REP1 (cytoplasmic sequestration); ChIP/luciferase for PARKIN with transgenic cardiac rescue

    PMID:28055019 PMID:35271390 PMID:36451342 PMID:36539848 PMID:39266959

    Open questions at the time
    • Several partner interactions rest on single-lab Co-IP (Medium)
    • Hierarchy among competing nuclear-retention and export factors unresolved
  15. 2023 Medium

    Showed FOXO3a controls non-canonical outputs—ferroptosis suppression via SLC7A11 repression, selective circRNA biogenesis (circSPON1), and its own m6A-dependent stability.

    Evidence ChIP and FOXO3a KO with AMPK/ferroptosis readouts (SLC7A11); ChIP plus selective circRNA expression and Co-IP (circSPON1-Smad3); m6A-seq/meRIP and mRNA stability assays (METTL14)

    PMID:37267686 PMID:37416778 PMID:37935312

    Open questions at the time
    • Mechanism of FOXO3 selectivity for circRNA over mRNA at SPON1 not defined
    • All three findings are single-lab Medium-confidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many competing post-translational modifications, partner interactions, and feedback loops are integrated to set FOXO3 nuclear residence and target-gene selection in a given cell state remains unresolved.
  • No quantitative model linking PTM combinations to specific target-gene programs
  • Structural basis for FOXO3 partner discrimination unknown
  • Mechanism of promoter selectivity (apoptosis vs autophagy vs metabolic targets) undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 8 GO:0140110 transcription regulator activity 8
Localization
GO:0005634 nucleus 6 GO:0005654 nucleoplasm 3 GO:0005829 cytosol 3
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-9612973 Autophagy 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-73894 DNA Repair 2
Partners
AKT1ATMEP300REP1SGK1SIRT1SNAI2WTIP
Complex memberships
ATM-Chk2-p53 complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SGK1 phosphorylates FOXO3a (FKHRL1) at Ser-315 (with preference over Akt), while Akt preferentially phosphorylates Ser-253; both kinases phosphorylate Thr-32. Phosphorylation of all three sites by SGK1 and Akt in concert suppresses FOXO3a-dependent transcription, leading to nuclear exclusion and inhibition of cell cycle arrest and apoptosis. SGK1 acts downstream of PI3K, like Akt, and promotes cell survival in part through this mechanism. In vitro kinase assays, site-directed mutagenesis of phosphorylation sites, overexpression and dominant-negative constructs, transcriptional reporter assays, cell survival assays Molecular and cellular biology High 11154281
2001 TGF-β induces phosphorylation and cytoplasmic retention of FOXO3a (FKHRL1) in mammary epithelial cells via PI3K/Akt. A triple Akt-site mutant of FKHRL1 (TM-FKHRL1) that cannot be phosphorylated by Akt fails to translocate to the cytoplasm in response to TGF-β, and dominant-negative Akt blocks TGF-β-induced FKHRL1 nuclear exclusion, phosphorylation, and transcriptional suppression. FKHRL1-driven apoptosis requires its transactivation domain. Triple phosphosite mutant transfection, dominant-negative Akt, PI3K inhibitor (LY294002), nuclear exclusion assays, transcriptional reporter assays, apoptosis assays Molecular biology of the cell High 11694570
2001 FOXO3a (FKHRL1) is expressed in human megakaryocytes and is phosphorylated by thrombopoietin (TPO) downstream of PI3K/Akt. Induced expression of constitutively active FKHRL1 causes G0/G1 cell cycle arrest in TPO-dependent megakaryocytic cells, identifying FKHRL1 as a downstream regulator of cell cycle in megakaryocytopoiesis. Tetracycline-inducible expression system, cell cycle analysis (flow cytometry), PI3K/Akt phosphorylation assays The Journal of biological chemistry Medium 11278373
2002 NGF rapidly induces phosphorylation of FKHRL1 (FOXO3a) in PC12 cells via TrkA receptor and PI3K/Akt kinase (but not MAP kinase or S6p70 kinase). Constitutively active Akt and in vitro kinase assays confirmed Akt as the mediating kinase. This phosphorylation contributes to neurotrophin-mediated cell survival. Kinase inhibitors, constitutively active and dominant-negative Akt transfection, in vitro kinase assay, TrkA-expressing vs p75-expressing cell comparison, survival assays with PI3K inhibitor Journal of neurochemistry Medium 11953455
2004 In response to DNA damage, p53 activation leads to FOXO3a (FKHRL1) phosphorylation and cytoplasmic translocation via SGK1, which is induced by p53 in an ERK1/2-dependent post-translational manner. AKT is dispensable for this p53-dependent suppression of FKHRL1; siRNA knockdown of SGK1 significantly decreases FKHRL1 phosphorylation after DNA damage. siRNA knockdown of SGK1, pharmacological inhibitors, subcellular localization assays, Western blotting for phosphorylation, genetic analysis in p53-deficient cells Proceedings of the National Academy of Sciences of the United States of America Medium 15383658
2006 FOXO3a (FKHRL1) induces apoptosis in neuroblastoma cells through the mitochondrial pathway by transcriptionally activating the BH3-only proteins Noxa and Bim, which together are critical for cytochrome c release and caspase-dependent apoptosis. RNAi knockdown of either Noxa or Bim reduces FOXO3a-induced cell death. The death-receptor pathway (TRAIL/dnFADD) is not required, whereas Bcl2 overexpression protects, confirming the Bcl2-rheostat model. 4-OH-tamoxifen-regulated FKHRL1(A3)ERtm transgene, RNAi knockdown of Noxa and Bim, dominant-negative FADD expression, Bcl2 overexpression, cytochrome c release assay, caspase activity Cell death and differentiation High 16888645
2006 FOXO3a (FKHRL1) and FOXO1a bind insulin response sequences (IRSs) in the glucose-6-phosphatase (G6Pase) promoter cooperatively (two adjacent IRSs), and their binding correlates with insulin-mediated inhibition of basal G6Pase transcription. Insulin stimulates nuclear exclusion of FOXO1a/3a in a PI3K-dependent manner in granulosa cells. Gel retardation/binding assays, overexpression experiments, fusion gene transcription assays in multiple promoter contexts, PI3K inhibition Molecular endocrinology (Baltimore, Md.) Medium 16840535
2007 AGE-induced oxidative stress causes phosphorylation of FOXO3a (FKHRL1) in a redox-dependent and p66shc Ser-36-phosphorylation-dependent manner, leading to ~70% downregulation of MnSOD. AGER1 overexpression suppresses these pro-oxidant responses; AGER1 siRNA restores them. PI3K inhibitor (LY-294002) and N-acetylcysteine partially block FKHRL1 phosphorylation-driven MnSOD suppression. p66shc Ser-36 mutants, AGER1 overexpression/siRNA, PI3K inhibitor, antioxidant rescue, Western blotting American journal of physiology. Cell physiology Medium 18032526
2008 FOXO3a interacts with the ATM FAT domain (C-terminal domain of FOXO3a binds FAT domain of ATM) and promotes ATM autophosphorylation at Ser-1981, leading to formation of ATM-pS1981 and γ-H2AX nuclear foci in response to DNA damage. Silencing FOXO3a abrogates ATM foci formation and DNA repair. FOXO3a promotes intra-S and G2/M checkpoints and facilitates DNA repair. Co-immunoprecipitation, domain-mapping, siRNA knockdown, immunofluorescence foci assays, cell cycle checkpoint analysis, DNA repair assays Nature cell biology High 18344987
2008 FoxO3a overexpression in muscle precursor cells (MPCs) impairs proliferation by preferentially inducing p27Kip1 promoter activity and protein expression (but not p21Waf/Cip1, which is decreased). FoxO3a overexpression does not affect retinoblastoma phosphorylation or cyclin D1, indicating it does not impair the early G1/S transition. Adenoviral FoxO3a overexpression, BrdU incorporation assay, promoter-luciferase assays for p27Kip1 and p21Waf/Cip1, Western blotting Muscle & nerve Medium 17894357
2009 FOXO3a (FKHRL1) represses BIRC5/Survivin transcription and protein expression. Conditional FKHRL1 activation sensitizes neuroblastoma cells to DNA-damaging agents (doxorubicin, etoposide). Transgenic Survivin rescues FKHRL1-induced apoptosis and prevents Bim/Bax mitochondrial accumulation, cytochrome c release, and loss of mitochondrial membrane potential. Survivin shRNA accelerates FKHRL1-induced apoptosis. 4-OH-tamoxifen-regulated FKHRL1(A3)ERtm allele, retroviral Survivin shRNA, transgenic Survivin rescue, cytochrome c release, mitochondrial membrane potential assay, drug sensitivity assays Molecular biology of the cell High 19211844
2009 FoxO3 is required for neural stem cell (NSC) pool maintenance. FoxO3-/- adult mice have fewer NSCs in vivo, and NSCs from FoxO3-/- mice show decreased self-renewal and impaired multipotency. FoxO3 regulates a gene expression program in NSCs that preserves quiescence, prevents premature differentiation, and controls oxygen metabolism. FoxO3 knockout mice, neurosphere assays (self-renewal), multipotency assays, gene expression profiling Cell stem cell High 19896443
2011 During denervation-induced muscle atrophy, FoxO3 is progressively acetylated by the histone acetyltransferase p300 (demonstrated by co-immunoprecipitation). Acetylation causes cytosolic relocalization and proteasomal degradation of FoxO3, coinciding with downregulation of its target atrogin-1. Acetylation-mimicking FoxO3 mutants show decreased transcriptional activity and cytosolic localization; Lys-262 is critical for FoxO3 translocation. Acetylation thus negatively modulates FoxO3 activity. Co-immunoprecipitation (FoxO3-p300), acetylation-mimic and acetylation-resistant FoxO3 mutants, denervation mouse model, subcellular fractionation, proteasome inhibition American journal of physiology. Cell physiology High 22094330
2011 TEAD1 directly binds the M-CAT element in the FoxO3a promoter and transcriptionally activates FoxO3a expression in skeletal muscle, as demonstrated by ChIP, EMSA, and luciferase reporter assays. Overexpression and inhibition experiments confirm TEAD1 as a positive regulator of FoxO3a. ChIP-on-chip, independent ChIP-PCR, EMSA, luciferase reporter assays, overexpression and inhibition experiments BMC molecular biology Medium 21211055
2012 FOXO3 interacts with the ATM-Chk2-p53 complex (demonstrated by Co-IP), augments phosphorylation of all complex members, and induces nuclear foci formation upon DNA damage. FOXO3 is essential for DNA damage-induced apoptosis; conversely, FOXO3 requires ATM, Chk2, and phospho-p53 isoforms to trigger apoptosis. FOXO3 also contributes to chromatin retention of phosphorylated p53. Co-immunoprecipitation of FOXO3-ATM-Chk2-p53 complex, siRNA knockdown, nuclear foci immunofluorescence, apoptosis assays Nature communications High 22893124
2012 Conditional FOXO3 activation induces caspase-8 expression in neuroblastoma without changing DNA methylation of the caspase-8 gene. Instead, FOXO3 induces phosphorylation of ATM, which then phosphorylates CREB; CREB phosphorylation is critical for FOXO3-mediated caspase-8 expression. The DNA-demethylating drug 5-azadC activates this FOXO3-ATM-CREB pathway to restore caspase-8 expression. Conditional FOXO3 transgene (ERtm), ATM inhibitor/knockdown, CREB inhibition, DNA methylation analysis (bisulfite), caspase-8 expression assays Molecular biology of the cell Medium 22493319
2016 FOXO3a directly binds to the Keap1 promoter and drives basal Keap1 transcription. FoxO3 depletion reduces Keap1, thereby stabilizing and activating Nrf2. This FoxO3-Keap1-Nrf2 axis explains how AKT activation or TNF-α-mediated FoxO3 inactivation leads to Nrf2 induction. In vivo, FoxO3 deficiency potentiates tumor formation and cisplatin resistance in cholangiocarcinoma through Nrf2 activation. ChIP assay (FoxO3 on Keap1 promoter), siRNA knockdown, luciferase reporter, xenograft tumor model, ROS measurement Hepatology (Baltimore, Md.) High 26857210
2016 FOXO3a transcriptionally regulates BNIP3 expression in cardiomyocytes. Increased FOXO3a activity upregulates BNIP3, leading to increased mitochondrial Ca2+, decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis in adult cardiomyocytes. Dominant-negative FOXO3a (AAV9) in a rat HFpEF model decreases BNIP3, reverses adverse remodeling, and improves cardiac function. Dominant-negative FOXO3a adenovirus and AAV9 in vitro/in vivo, BNIP3 knockdown/overexpression, mitochondrial membrane potential assay, Ca2+ imaging, cardiac functional analysis (echocardiography) American journal of physiology. Heart and circulatory physiology High 27694219
2019 FoxO3 is regulated by prolyl hydroxylation: hypoxia inhibits prolyl hydroxylase (PHD)-mediated prolyl hydroxylation of FoxO3, preventing its degradation and leading to FoxO3 accumulation in renal tubular cells. Hypoxia-activated HIF-1α contributes to FoxO3 activation; tubular HIF-1α deletion reduces FoxO3 activation. Tubular FoxO3 deletion during AKI-to-CKD transition worsens structural/functional damage, decreases autophagy, and increases oxidative injury. Tubule-specific conditional FoxO3 knockout and HIF-1α knockout mice, prolyl hydroxylation assays, renal ischemia/reperfusion model, autophagy and oxidative stress markers The Journal of clinical investigation High 30912765
2019 FOXO3 directly transactivates SIRT6 by binding to its promoter region (confirmed by luciferase assay and ChIP). The FOXO3a-SIRT6 axis suppresses aerobic glycolysis (Warburg effect) in melanoma cells. SIRT6 knockdown or overexpression rescues the glycolytic effects of FOXO3a manipulation. ChIP assay, luciferase reporter assay, lentiviral SIRT6 knockdown/overexpression rescue, glycolysis assays (glucose uptake, lactate, Seahorse), mouse xenograft International journal of oncology High 32124950
2019 FOXO3 directly binds the SIRT6 promoter in glioblastoma cells and transcriptionally activates SIRT6, thereby suppressing glycolysis (Warburg effect). FKHRL1 knockdown reduces SIRT6 expression and increases glycolysis; SIRT6 restoration reverses the glycolytic phenotype caused by FKHRL1 knockdown. This axis is confirmed both in vitro and in vivo. Luciferase assay, ChIP assay, siRNA knockdown, SIRT6 overexpression rescue, Seahorse glycolysis assay, xenograft model Cellular signalling High 31004738
2019 Small molecules targeting the FOXO3 DNA-binding domain (DBD) physically interact with it (validated by NMR spectroscopy and docking). Compounds S9 and S9OX interfere with FOXO3 target promoter binding, gene transcription, and modulate the physiological transcriptional program in cancer cells, demonstrating the druggability of the FOXO3-DBD. Pharmacophore-modeling in silico screen, fluorescence polarization binding assay, NMR spectroscopy, docking studies, transcriptional target assays in human cells eLife High 31789593
2019 FOXO3 directly transcribes PERK (eIF2AK3) as established by ChIP, siRNA knockdown, and overexpression assays, as well as validation in Foxo1/3/4-/- MEFs. Drug-resistant breast cancer cells with low FOXO3/PERK expression and high PERK activity are specifically sensitive to PERK inhibition; ectopic FOXO3 reduces this sensitivity. ChIP, siRNA knockdown, FOXO3 overexpression, Foxo1/3/4-/- MEF genetic validation, PERK inhibitor sensitivity assays Oncogene High 31312024
2021 FOXO3a is transcriptionally activated by WTIP, which physically interacts with FOXO3a (Co-IP), promotes its nuclear translocation, and activates its downstream target PUMA, leading to intrinsic apoptosis in AML cells. Co-immunoprecipitation, nuclear translocation assays, luciferase reporter for FOXO3a transcriptional activity, PUMA expression assays, in vitro/in vivo apoptosis assays Cell death & disease Medium 34930905
2022 COPS3 enhances nuclear abundance of FOXO3 and expression of FOXO3-responsive autophagy genes to promote cisplatin resistance in osteosarcoma. In turn, FOXO3 inhibits ubiquitin-mediated degradation of COPS3 and attenuates SKP2-mediated COPS3 inhibition, forming a positive feedback loop. ChIP confirmed FOXO3 occupancy at autophagy gene promoters. ChIP, siRNA/shRNA knockdown, ubiquitination assays, cycloheximide chase, in vitro and xenograft cisplatin sensitivity assays Autophagy Medium 36451342
2022 SIRT1 physically interacts with FOXO3 (Co-IP in RL95-2 cells) and deacetylates it. SIRT1-mediated FOXO3 deacetylation enhances FOXO3 activity, promoting BNIP3 transcription and PINK1/Parkin-mediated mitophagy, which drives hormone resistance in endometrial cancer. SIRT1 overexpression promotes cell proliferation, migration, and tumor growth. Co-immunoprecipitation, high-throughput transcriptome sequencing, FOXO3 acetylation assays, ChIP for BNIP3 promoter, PINK1/Parkin pathway assays, mouse tumor model Molecular medicine (Cambridge, Mass.) Medium 39266959
2022 REP1 physically interacts with FOXO3 (identified by yeast two-hybrid and confirmed by Co-IP) and blocks FOXO3 nuclear translocation, thereby suppressing FOXO3-mediated apoptosis in colon cancer cells. REP1 silencing sensitizes cancer cells to serum starvation- and 5-FU-induced apoptosis; REP1 inhibition combined with 5-FU retards tumor growth in xenograft models. Yeast two-hybrid screen, Co-immunoprecipitation, nuclear translocation assays, siRNA knockdown, xenograft tumor model, apoptosis assays Cell death & disease Medium 28055019
2022 FOXO3 transcriptionally activates PARKIN expression (demonstrated by ChIP and luciferase assays). FOXO3a-driven PARKIN upregulation restores mitophagy, thereby suppressing cardiac hypertrophy. Parkin transgenic mice subjected to Ang II show attenuated hypertrophy and improved cardiac function, dependent on FOXO3a-mediated PARKIN transcription. ChIP, luciferase reporter, PARKIN overexpression/knockdown, Parkin transgenic mice, Ang II cardiac hypertrophy model, echocardiography Cell & bioscience Medium 36539848
2022 FOXO3a transcriptional activation by SNAI2 is part of a coherent feed-forward loop: upon energy stress, FOXO3 transcriptionally induces SNAI2, and SNAI2 then interacts with FOXO3 to reinforce expression of autophagy genes. SNAI2 increases FOXO3-DNA binding, abrogating CRM1-dependent FOXO3 nuclear export and promoting nuclear retention of FOXO3. This loop is conserved in Drosophila (dFoxO-Snail). Genome-wide screen in HeLa cells, ChIP, Co-IP (SNAI2-FOXO3), nuclear export assays (CRM1 inhibition), Drosophila genetic epistasis, autophagy reporter assays Proceedings of the National Academy of Sciences of the United States of America High 35271390
2023 FOXO3a directly binds to the SLC7A11 promoter to repress its expression, thereby reducing glutamate excitotoxicity during cerebral ischemia-reperfusion. AMPK activation leads to FOXO3a activation and inhibits mitochondria-associated ferroptosis. Loss of FoxO3a promotes mitochondrial hyperpolarization, oxygen consumption, and lipid peroxide accumulation. ChIP (FOXO3a on SLC7A11 promoter), FOXO3a KO/knockdown, AMPK inhibition, ferroptosis inducers (erastin), mitochondrial membrane potential assays, rat CIR injury model with trifluoperazine Redox biology Medium 37267686
2023 FOXO3 directly binds the SPON1 promoter and selectively drives expression of the circular RNA form (circSPON1) but not SPON1 mRNA. circSPON1 then inhibits fibroblast activation by sequestering Smad3 in the cytoplasm and by sponging miR-942-5p/miR-520f-3p to promote Smad7 expression, thereby attenuating pulmonary fibrosis. ChIP (FOXO3 on SPON1 promoter), selective circRNA/mRNA expression analysis, Co-IP (circSPON1-Smad3), luciferase miRNA sponge assay, HFL1 fibroblast functional assays International journal of biological sciences Medium 37416778
2023 METTL14 regulates FOXO3a expression and mRNA stability in a m6A-dependent manner. Loss of METTL14 decreases FOXO3a, impairing autophagic flux and aggravating inflammation in T cells from ankylosing spondylitis patients. Forced METTL14 expression upregulates FOXO3a, activates autophagy, and alleviates inflammation. m6A sequencing/meRIP, METTL14 knockdown/overexpression, FOXO3a mRNA stability assays, autophagy flux assays, T cell functional assays from patient samples Clinical immunology (Orlando, Fla.) Medium 37935312
2015 FOXO3a mediates dexamethasone-induced cytotoxicity in B-ALL cells: FOXO3a translocates to the nucleus and induces p27Kip1 and Bim. Dexamethasone activates FOXO3a partly through PI3K/Akt suppression. Two specific post-translational modifications are associated with FOXO3a activation by dexamethasone: phosphorylation on Ser-7 (linked to p38/JNK) and acetylation on Lys-242/245 (correlated with SIRT1/2/6 downregulation and CBP/p300 induction). Immunoblot for phospho-Ser7 and acetyl-Lys242/245 FOXO3a, PI3K inhibitor, FOXO3a siRNA knockdown, nuclear translocation assays, p27Kip1 and Bim expression assays Molecular cancer research : MCR Medium 26376801
2010 FOXO3a directly activates SIRT6 transcription: ChIP and luciferase assays demonstrate FOXO3a enrichment at the SIRT6 promoter. The FOXO3a-SIRT6 axis suppresses aerobic glycolysis in melanoma, as SIRT6 knockdown rescues the anti-glycolytic effect of FOXO3a overexpression (replicated across two cancer types: melanoma and glioblastoma, separately confirmed). ChIP, luciferase reporter, knockdown/overexpression epistasis, glycolysis functional assays, mouse xenograft International journal of oncology High 31004738 32124950

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic acids research 1370 26861625
2001 Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Molecular and cellular biology 727 11154281
2009 FoxO3 regulates neural stem cell homeostasis. Cell stem cell 476 19896443
2018 Critical role of FOXO3a in carcinogenesis. Molecular cancer 390 30045773
2015 FOXO3: A Major Gene for Human Longevity--A Mini-Review. Gerontology 277 25832544
2014 GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. The journals of gerontology. Series A, Biological sciences and medical sciences 223 25199915
2019 FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response. Cells 188 31546924
1997 AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. Blood 185 9345057
2008 Functional interaction between FOXO3a and ATM regulates DNA damage response. Nature cell biology 169 18344987
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
2001 Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Molecular biology of the cell 152 11694570
2010 The AMPK-FoxO3A axis as a target for cancer treatment. Cell cycle (Georgetown, Tex.) 151 20190568
2019 Reduction of circular RNA Foxo3 promotes prostate cancer progression and chemoresistance to docetaxel. Cancer letters 145 31593800
2006 FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells. Cell death and differentiation 142 16888645
2005 Activation of Akt (PKB) and suppression of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular activation and development. Developmental biology 137 15893970
2017 Phosphorylation and acetylation modifications of FOXO3a: Independently or synergistically? Oncology letters 128 28521392
2014 FoxO3a and disease progression. World journal of biological chemistry 128 25225602
2023 Energy stress modulation of AMPK/FoxO3 signaling inhibits mitochondria-associated ferroptosis. Redox biology 127 37267686
2004 p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. Proceedings of the National Academy of Sciences of the United States of America 111 15383658
2019 FoxO3 activation in hypoxic tubules prevents chronic kidney disease. The Journal of clinical investigation 99 30912765
2013 Mitochondria and FOXO3: breath or die. Frontiers in physiology 95 23801966
2011 Posttranslational modifications control FoxO3 activity during denervation. American journal of physiology. Cell physiology 95 22094330
2007 AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation. American journal of physiology. Cell physiology 94 18032526
2022 Intrapericardial Exosome Therapy Dampens Cardiac Injury via Activating Foxo3. Circulation research 88 36252111
2018 FOXO3 links autophagy to apoptosis. Autophagy 85 29938591
2016 FoxO3 inactivation promotes human cholangiocarcinoma tumorigenesis and chemoresistance through Keap1-Nrf2 signaling. Hepatology (Baltimore, Md.) 84 26857210
2016 FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress. American journal of physiology. Heart and circulatory physiology 83 27694219
2000 Activation of the Akt/FKHRL1 pathway mediates the antiapoptotic effects of erythropoietin in primary human erythroid progenitors. Biochemical and biophysical research communications 81 10944433
2012 FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage. Nature communications 79 22893124
2002 FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling. Journal of neurochemistry 79 11953455
2010 Wnt1, FoxO3a, and NF-kappaB oversee microglial integrity and activation during oxidant stress. Cellular signalling 78 20462515
2012 EGCG inhibits growth of human pancreatic tumors orthotopically implanted in Balb C nude mice through modulation of FKHRL1/FOXO3a and neuropilin. Molecular and cellular biochemistry 72 22971992
2018 Recent advances in understanding the role of FOXO3. F1000Research 70 30228872
2021 Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a. Journal of cachexia, sarcopenia and muscle 68 34725961
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
2022 The COPS3-FOXO3 positive feedback loop regulates autophagy to promote cisplatin resistance in osteosarcoma. Autophagy 66 36451342
2022 RBM47/SNHG5/FOXO3 axis activates autophagy and inhibits cell proliferation in papillary thyroid carcinoma. Cell death & disease 65 35338124
2022 FOXO3a in cancer drug resistance. Cancer letters 65 35545128
2009 Repression of BIRC5/survivin by FOXO3/FKHRL1 sensitizes human neuroblastoma cells to DNA damage-induced apoptosis. Molecular biology of the cell 63 19211844
2003 Renal ischemia/reperfusion and ATP depletion/repletion in LLC-PK(1) cells result in phosphorylation of FKHR and FKHRL1. Kidney international 62 12969136
2016 The FoxO3 gene and cause-specific mortality. Aging cell 61 27071935
2023 FoxO3 and oxidative stress: a multifaceted role in cellular adaptation. Journal of molecular medicine (Berlin, Germany) 60 36598531
2010 Foxo3a expression and acetylation regulate cancer cell growth and sensitivity to cisplatin. Cancer science 57 20210796
2016 FOXO3 is essential for CD44 expression in pancreatic cancer cells. Oncogene 54 27893718
2019 FOXO3 on the Road to Longevity: Lessons From SNPs and Chromatin Hubs. Computational and structural biotechnology journal 49 31303978
2022 Pharmaceutical and nutraceutical activation of FOXO3 for healthy longevity. Ageing research reviews 46 35421606
2006 Adenovirus-mediated gene transfer of FKHRL1 triple mutant efficiently induces apoptosis in melanoma cells. Cancer biology & therapy 45 16861905
2021 Metformin Attenuates ROS via FOXO3 Activation in Immune Cells. Frontiers in immunology 44 33953705
2018 Regulation of glucose uptake and inflammation markers by FOXO1 and FOXO3 in skeletal muscle. Molecular metabolism 44 30502001
2008 FoxO3a preferentially induces p27Kip1 expression while impairing muscle precursor cell-cycle progression. Muscle & nerve 43 17894357
2001 Forkhead family transcription factor FKHRL1 is expressed in human megakaryocytes. Regulation of cell cycling as a downstream molecule of thrombopoietin signaling. The Journal of biological chemistry 42 11278373
2021 FOXO3a and Its Regulators in Prostate Cancer. International journal of molecular sciences 41 34830408
2002 Effect of multiple phosphorylation events on the transcription factors FKHR, FKHRL1 and AFX. Biochemical Society transactions 41 12196101
2020 FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma. International journal of oncology 40 32124950
2024 SIRT1-mediated deacetylation of FOXO3 enhances mitophagy and drives hormone resistance in endometrial cancer. Molecular medicine (Cambridge, Mass.) 37 39266959
2019 Regulation of PERK expression by FOXO3: a vulnerability of drug-resistant cancer cells. Oncogene 37 31312024
2015 MiR-592 represses FOXO3 expression and promotes the proliferation of prostate cancer cells. International journal of clinical and experimental medicine 35 26629010
2003 Nitric oxide suppression triggers apoptosis through the FKHRL1 (FOXO3A)/ROCK kinase pathway in human breast carcinoma cells. Cancer 35 12599246
2021 FOXO3 is a latent tumor suppressor for FOXO3-positive and cytoplasmic-type gastric cancer cells. Oncogene 33 33795838
2014 FOXO3 and related transcription factors in development, aging, and exceptional longevity. The journals of gerontology. Series A, Biological sciences and medical sciences 30 24747665
2023 The forkhead box O3 (FOXO3): a key player in the regulation of ischemia and reperfusion injury. Cellular and molecular life sciences : CMLS 28 36939886
2011 TEAD1-dependent expression of the FoxO3a gene in mouse skeletal muscle. BMC molecular biology 28 21211055
2023 METTL14-m6A-FOXO3a axis regulates autophagy and inflammation in ankylosing spondylitis. Clinical immunology (Orlando, Fla.) 27 37935312
2021 Circular RNA Foxo3: A Promising Cancer-Associated Biomarker. Frontiers in genetics 27 33833780
2018 FoxO3a Regulates Inflammation-induced Autophagy in Odontoblasts. Journal of endodontics 27 29551204
2024 Unveiling the potential of FOXO3 in lung cancer: From molecular insights to therapeutic prospects. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 38843589
2015 FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL. Molecular cancer research : MCR 26 26376801
2019 Transcriptional activation of SIRT6 via FKHRL1/FOXO3a inhibits the Warburg effect in glioblastoma cells. Cellular signalling 25 31004738
2019 Circular RNA circ-FoxO3 Inhibits Myoblast Cells Differentiation. Cells 25 31248210
2022 FOXO3a-dependent PARKIN negatively regulates cardiac hypertrophy by restoring mitophagy. Cell & bioscience 24 36539848
2010 Expression and localisation of FoxO3 and FoxO4 in human placenta and fetal membranes. Placenta 24 20934750
2004 Expression and intracellular localization of FKHRL1 in mammary gland neoplasms. Acta medica Okayama 24 15551757
2018 AMP-activated protein kinase stabilizes FOXO3 in primary myotubes. Biochemical and biophysical research communications 23 29580989
2008 Involvement of FKHRL1 in melanoma cell survival and death. Pigment cell & melanoma research 23 18426407
2023 FOXO3 regulates Smad3 and Smad7 through SPON1 circular RNA to inhibit idiopathic pulmonary fibrosis. International journal of biological sciences 22 37416778
2022 A coherent FOXO3-SNAI2 feed-forward loop in autophagy. Proceedings of the National Academy of Sciences of the United States of America 21 35271390
2022 Soluble RAGE attenuates myocardial I/R injuries via FoxO3-Bnip3 pathway. Cellular and molecular life sciences : CMLS 21 35501612
2020 MiR-155 targeting FoxO3a regulates oral cancer cell proliferation, apoptosis, and DDP resistance through targeting FoxO3a. Cancer biomarkers : section A of Disease markers 21 31771044
2020 Induction of foxo3a protects turtle neurons against oxidative stress. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 21 32044446
2017 REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival. Cell death & disease 21 28055019
2012 FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma. Molecular biology of the cell 21 22493319
2023 Corylifol A ameliorates muscle atrophy by inhibiting TAOK1/p38-MAPK/FoxO3 pathway in cancer cachexia. Journal of cachexia, sarcopenia and muscle 20 37439183
2018 FOXO3 and Exceptional Longevity: Insights From Hydra to Humans. Current topics in developmental biology 20 29433738
2024 Nanoengineered cargo with targeted in vivo Foxo3 gene editing modulated mitophagy of chondrocytes to alleviate osteoarthritis. Acta pharmaceutica Sinica. B 19 40041910
2021 WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia. Cell death & disease 19 34930905
2020 Molecular regulation and function of FoxO3 in chronic kidney disease. Current opinion in nephrology and hypertension 19 32427691
2018 Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer. Frontiers in endocrinology 19 30271381
2012 NAMPT pathway is involved in the FOXO3a-mediated regulation of GADD45A expression. Biochemical and biophysical research communications 19 22430142
2021 Circular RNA Foxo3 enhances progression of ovarian carcinoma cells. Aging 17 34555810
2020 The DNA methylation of FOXO3 and TP53 as a blood biomarker of late-onset asthma. Journal of translational medicine 17 33298101
2016 FoxO3 suppresses Myc-driven lymphomagenesis. Cell death & disease 17 26764572
2021 FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot (Scophthalmus maximus L.). Frontiers in immunology 16 34276667
2020 PTEN and FOXO3 expression in the prenatal and postnatal human ovary. Journal of assisted reproduction and genetics 16 32424736
2019 MeCP2 inhibits cell functionality through FoxO3a and autophagy in endothelial progenitor cells. Aging 16 31477637
2024 Role and regulation of FOXO3a: new insights into breast cancer therapy. Frontiers in pharmacology 15 38505423
2022 The Role of miRNA-182 and FOXO3 Expression in Breast Cancer. Asian Pacific journal of cancer prevention : APJCP 15 36308360
2019 Modulating FOXO3 transcriptional activity by small, DBD-binding molecules. eLife 15 31789593
2018 SP1 upregulated FoxO3a promotes tumor progression in colorectal cancer. Oncology reports 15 29565456
2024 The role of Foxo3a in neuron-mediated cognitive impairment. Frontiers in molecular neuroscience 14 38962803
2019 DNA-PKcs is activated under nutrient starvation and activates Akt, MST1, FoxO3a, and NDR1. Biochemical and biophysical research communications 14 31679687

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