Affinage

FOXO4

Forkhead box protein O4 · UniProt P98177

Length
505 aa
Mass
53.7 kDa
Annotated
2026-06-09
100 papers in source corpus 46 papers cited in narrative 46 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

FOXO4 is a forkhead transcription factor that integrates growth-factor and redox signaling to control cell cycle arrest, apoptosis, oxidative-stress responses, differentiation, and inflammation through a forkhead DNA-binding domain that docks helix H3 into the DNA major groove (PMID:11352721, PMID:21123876). Its activity is gated chiefly by PI3K/Akt: phosphorylation at Thr-28/Thr-32 and Ser-193/Ser-197 creates 14-3-3 binding motifs, and the 14-3-3 dimer masks the DNA-binding interface to drive cytoplasmic retention and transcriptional inactivation, whereas phosphosite mutants are constitutively nuclear and hyperactive (PMID:14690436, PMID:16272144, PMID:19416966). A second regulatory layer is redox-coupled and reversible: oxidative stress promotes cysteine-disulfide complex formation with CBP/p300, which acetylates FOXO4 to inhibit it, while SIRT1 deacetylates FOXO4 to restore stress-gene transcription, and concurrent monoubiquitination (by Mdm2) and O-GlcNAcylation (via OGT) drive FOXO4 into the nucleus and enhance activity, with USP7/HAUSP reversing the ubiquitin signal and COP1 instead targeting FOXO4 for proteasomal degradation (PMID:15126506, PMID:16964248, PMID:18665269, PMID:19648934, PMID:19932102, PMID:33101846). FOXO4 transcriptional output is further tuned by an autoinhibitory intramolecular contact between its disordered C-terminal transactivation domain and the forkhead domain, which β-catenin binding relieves to boost activity and enable selective target recognition (PMID:34320339, PMID:33450250). Through these mechanisms FOXO4 directly binds and activates targets including p27/p21, Bim, SOD2, and Arg1, and represses targets including LDHA, NFAT2, DKK3, and USP10 to enforce cell-cycle arrest, senescence, apoptosis, glycolytic control, and immune/vascular responses (PMID:20570964, PMID:21536589, PMID:21858169, PMID:26438688, PMID:33463054, PMID:34251583, PMID:36700213, PMID:36106640, PMID:31866399). A prominent role is the repression of smooth muscle differentiation by direct binding and inhibition of the coactivator myocardin, an axis itself controlled by cytoplasmic sequestration via XBP1u (PMID:16054032, PMID:29089350).

Mechanistic history

Synthesis pass · year-by-year structured walk · 37 steps
  1. 2001 High

    Established the structural basis for FOXO4 DNA recognition by defining its forkhead domain fold, the prerequisite for interpreting how modifications and partners control DNA binding.

    Evidence High-resolution NMR solution structure of the FOXO4 forkhead domain

    PMID:11352721

    Open questions at the time
    • No DNA complex in this structure
    • Does not address full-length protein or regulatory regions
  2. 2003 High

    Defined how Akt signaling inactivates FOXO4 by showing that dual PKB phosphorylation builds 14-3-3 binding sites that block DNA binding, establishing the core off-switch.

    Evidence In vitro PKB phosphorylation, biophysical 14-3-3 binding (gel filtration, sedimentation), EMSA, mutagenesis

    PMID:14690436

    Open questions at the time
    • Mechanism of cytoplasmic retention not yet resolved here
    • Performed in vitro with isolated domains
  3. 2003 Medium

    Identified acetylation as an inhibitory modification by mapping CBP-acetylated lysines whose mutation enhances activity, opening the acetylation arm of FOXO4 regulation.

    Evidence Co-IP, K→R mutagenesis, luciferase reporter, TSA treatment

    PMID:12964026

    Open questions at the time
    • Single lab reporter-based readout
    • Physiological context of acetylation not addressed
  4. 2004 High

    Connected acetylation to redox state and showed it is reversible, establishing CBP/SIRT1 as an antagonistic acetylation-deacetylation switch that tunes FOXO4 stress-gene output.

    Evidence Co-IP, acetylation/deacetylation assays, siRNA, reporter assays under H2O2

    PMID:15126506

    Open questions at the time
    • Direct deacetylated lysines not exhaustively mapped
    • Quantitative contribution to endogenous targets unclear
  5. 2005 High

    Refined the phosphorylation code by demonstrating that Thr-32/Ser-197 phosphorylation specifically governs nuclear exclusion and activity, distinguishing functional from non-functional sites.

    Evidence Site-directed mutagenesis, subcellular fractionation, phosphosite antibodies, reporter assay

    PMID:16272144

    Open questions at the time
    • Ser-262 role left undefined
    • Kinetics of nuclear export not measured
  6. 2005 High

    Revealed a differentiation-control mechanism in which FOXO4 directly inhibits myocardin to repress smooth muscle gene programs, linking Akt-FOXO4 to vascular cell fate.

    Evidence Co-IP, siRNA, reporter assays, dominant-negative/CA constructs, immunofluorescence

    PMID:16054032

    Open questions at the time
    • Interaction interface on myocardin not mapped
    • In vivo requirement not tested in this study
  7. 2005 Medium

    Provided spectroscopic evidence that 14-3-3 binding rigidifies the FOXO4 NLS, mechanistically explaining how phosphorylation-dependent 14-3-3 docking enforces cytoplasmic localization.

    Evidence Site-directed AEDANS labeling, fluorescence spectroscopy, in vitro kinase assay

    PMID:16114898

    Open questions at the time
    • Structural inference rather than atomic model
    • Single lab
  8. 2006 High

    Established a ubiquitin arm of FOXO4 control by showing oxidative-stress monoubiquitination promotes nuclear localization and that USP7 reverses it, decoupling this regulation from protein turnover.

    Evidence Co-IP, in vivo ubiquitination assay, siRNA, fractionation, reporter assays

    PMID:16964248

    Open questions at the time
    • Ubiquitinated lysines not mapped here
    • E3 ligase not identified in this study
  9. 2007 Medium

    Dissected the DNA-binding contributions of the N-terminal loop and wing W2 and showed how PKB phosphorylation and 14-3-3 differentially inhibit DNA binding, refining the structural off-switch.

    Evidence FRET spectroscopy, molecular dynamics, in vitro DNA binding, PKB phosphorylation

    PMID:17244620

    Open questions at the time
    • In vitro fragment system
    • Endogenous relevance of loop deletions untested
  10. 2007 High

    Demonstrated FOXO4 functions as a transcriptional activator in a disease context by driving MMP9 in vascular smooth muscle, with in vivo loss-of-function reducing neointima.

    Evidence siRNA, knockout, MMP9 promoter reporter, migration assay, in vivo vascular injury

    PMID:17242183

    Open questions at the time
    • Sp1 cooperation mechanism not fully resolved
    • Direct promoter occupancy details limited
  11. 2008 High

    Identified Mdm2 as the E3 ligase mediating oxidative-stress monoubiquitination of FOXO4, supplying the enzyme acting opposite USP7.

    Evidence In vitro and in vivo ubiquitination, Co-IP, siMdm2, reporter assay

    PMID:18665269

    Open questions at the time
    • Lysine acceptor sites not mapped
    • Relationship to COP1-mediated degradation not addressed
  12. 2009 High

    Provided the molecular link between cellular redox state and acetylation by showing ROS-induced FOXO4–p300/CBP disulfide complexes are required for acetylation-dependent regulation.

    Evidence Redox crosslinking, thiol probes, Co-IP, cysteine mutagenesis, reporters

    PMID:19648934

    Open questions at the time
    • Specific cysteine pairing in vivo not fully defined
    • Quantitative redox thresholds unclear
  13. 2009 High

    Resolved how 14-3-3 inhibits FOXO4 at the structural level, docking the forkhead domain into the 14-3-3 central channel to mask the DNA interface without gross conformational change.

    Evidence Time-resolved FRET, AEDANS labeling, tryptophan fluorescence

    PMID:19416966

    Open questions at the time
    • Distance-based model rather than crystal structure
    • Full-length protein behavior inferred
  14. 2009 High

    Established FOXO4 as an in vivo suppressor of inflammation by showing Foxo4-null mice have elevated NF-κB activity and increased colitis susceptibility.

    Evidence Foxo4 knockout, microarray, NF-κB reporter, flow cytometry, Western blot

    PMID:19560465

    Open questions at the time
    • Direct vs indirect NF-κB inhibition not separated
    • Tissue-specific contributions not isolated
  15. 2010 High

    Captured atomic-resolution FOXO4–DNA contacts, defining the base-specific recognition by helix H3 and phosphate contacts by the N-terminus and wing W1.

    Evidence 1.9 Å X-ray crystal structure of FOXO4 DBD–DNA complex

    PMID:21123876

    Open questions at the time
    • Isolated DBD only
    • Does not model regulatory modifications or partners
  16. 2010 High

    Identified Ku70 as a direct nuclear partner that sequesters FOXO4 and inhibits its p27-driven cell-cycle arrest, adding a redox-tunable protein-interaction control.

    Evidence TAP-MS, Co-IP, reporter, RNAi, Ku70-/- rescue, imaging, flow cytometry

    PMID:20570964

    Open questions at the time
    • Interaction interface not mapped
    • Generality across cell types untested
  17. 2010 Medium

    Linked FOXO4 to Wnt/β-catenin signaling by showing PKG-induced β-catenin–FOXO4 binding redirects β-catenin to FOXO targets and away from TCF.

    Evidence Co-IP, siRNA, fractionation, reporters, pharmacological inhibitors

    PMID:20348951

    Open questions at the time
    • Direct binding interface defined only later
    • JNK dependence mechanism unclear
  18. 2010 Medium

    Showed O-GlcNAcylation provides a stress-responsive activating modification, with OGT association enhancing FOXO4 activity under acute oxidative stress.

    Evidence Co-IP, O-GlcNAc immunoblotting, reporter assay

    PMID:19932102

    Open questions at the time
    • Modified residues not mapped
    • Interplay with phosphorylation/acetylation not tested
  19. 2011 High

    Identified ataxin-3 as a coactivator that directs FOXO4 to the SOD2 promoter under oxidative stress, with disease-mutant ATXN3 impairing this protective program.

    Evidence Co-IP, ChIP, reporters, ATXN3 RNAi, immunofluorescence

    PMID:21536589

    Open questions at the time
    • Direct vs scaffold role of ATXN3 unresolved
    • Other FOXO4 targets affected not surveyed
  20. 2011 High

    Demonstrated acetylation-dependent promoter selection by showing FOXO4 acetylation is required for Bim promoter binding, linking the SIRT1/CBP switch to apoptotic output in podocytes.

    Evidence ChIP, acetylation IP, SIRT1 overexpression, siRNA, db/db mouse model

    PMID:21858169

    Open questions at the time
    • Acetyl-lysines driving promoter binding not pinpointed
    • Disease specificity of mechanism untested
  21. 2012 Medium

    Added Foxk1 as a repressive interactor controlling FOXO4 activity to balance progenitor proliferation versus differentiation.

    Evidence Co-IP, reporters, siRNA, overexpression in C2C12

    PMID:22956541

    Open questions at the time
    • Interaction surface not mapped
    • In vivo relevance not tested
  22. 2017 High

    Revealed XBP1u as a cytoplasmic anchor of FOXO4 in the XBP1u–FOXO4–myocardin axis governing smooth muscle homeostasis and aneurysm protection.

    Evidence Co-IP, SMC-specific XBP1 KO mice, aneurysm models, immunofluorescence

    PMID:29089350

    Open questions at the time
    • XBP1u binding determinants not atomically defined
    • Relationship to Akt/14-3-3 retention not integrated
  23. 2018 Medium

    Implicated WNK1 kinase as an upstream regulator of FOXO4 nuclear localization controlling atrogene-driven muscle atrophy, with FOXO4 silencing fully rescuing the phenotype.

    Evidence siRNA (WNK1, SPAK/OSR1, FOXO4), immunofluorescence, qPCR, myotube measurement

    PMID:29904119

    Open questions at the time
    • Whether WNK1 acts directly on FOXO4 unproven
    • Phosphosite link not established
  24. 2019 Medium

    Showed FOXO4 cooperates with KLF2 to induce p21 and drive senescence, defining a partner-dependent senescence program.

    Evidence Co-IP, reporters, siRNA, SA-β-gal senescence assays

    PMID:31866399

    Open questions at the time
    • Direct co-occupancy of p21 promoter not shown
    • Single cancer model
  25. 2019 Medium

    Extended the Foxk1 repression axis by identifying Fhl2 as a cofactor enhancing Foxk1-mediated repression of FOXO4 activity in myogenic progenitors.

    Evidence Yeast two-hybrid, reporter assay, siRNA, immunohistochemistry

    PMID:20013826

    Open questions at the time
    • Y2H interaction not reciprocally validated in cells for FOXO4
    • Indirect effect on FOXO4
  26. 2020 Medium

    Identified COP1 as an E3 ligase that degrades FOXO4 via a VP motif under EGF signaling, distinguishing a proteolytic ubiquitin pathway from the non-degradative Mdm2 route.

    Evidence Co-IP, ubiquitination assays, ChIP/reporter, CSN6 siRNA, metabolomics

    PMID:33101846

    Open questions at the time
    • Interplay with USP7/Mdm2 signaling not reconciled
    • Single lab
  27. 2020 Medium

    Demonstrated tumor-suppressive transcriptional output by showing FOXO4 activates APC2 to promote β-catenin degradation and suppress colorectal metastasis.

    Evidence ChIP, overexpression, APC2 siRNA, in vivo metastasis, IHC

    PMID:34631691

    Open questions at the time
    • Direct promoter element not finely mapped
    • Single tumor type
  28. 2021 High

    Resolved the molecular basis of β-catenin–FOXO4 regulation, showing β-catenin binds the disordered TAD and relieves an autoinhibitory TAD–forkhead contact to enhance activity.

    Evidence NMR, biochemical binding, phosphomutagenesis, reporters

    PMID:34320339

    Open questions at the time
    • Cellular stoichiometry of competition unknown
    • Phospho-regulation kinetics in vivo untested
  29. 2021 High

    Defined the autoinhibitory intramolecular TAD–FHD complex as a mechanism for selective target-DNA recognition through differential exchange kinetics.

    Evidence Solution NMR, DNA binding assays

    PMID:33450250

    Open questions at the time
    • In-cell occurrence of the intramolecular state not directly observed
    • Effect of modifications on the equilibrium not fully mapped
  30. 2021 Medium

    Placed FOXO4 in glycolytic control downstream of HIF-1α, showing it directly represses LDHA while being itself repressed by HIF-1α under hypoxia.

    Evidence ChIP, reporter, overexpression/silencing, metabolic flux

    PMID:33463054

    Open questions at the time
    • Single cancer context
    • Quantitative contribution to flux modest
  31. 2021 Medium

    Expanded FOXO4 repressive targets in cardiac stress by showing it suppresses USP10 and ENPP2 to modulate Hippo/YAP signaling, apoptosis, and ferroptosis.

    Evidence ChIP, dual-luciferase, siRNA/overexpression, TUNEL/ROS/ferroptosis assays

    PMID:34251583 PMID:34296293

    Open questions at the time
    • Single-lab reporter-based mechanisms
    • Direct vs indirect ferroptosis effects unclear
  32. 2021 Medium

    Linked FOXO4 to SIRT1-dependent chondrocyte maintenance, showing deacetylated FOXO4 activates SOX9 to stabilize ECM.

    Evidence ChIP, dual-luciferase, FOXO4 siRNA, Sirt1 overexpression, acetylation Western

    PMID:33577016

    Open questions at the time
    • Acetyl-residues controlling SOX9 binding not mapped
    • Single tissue model
  33. 2021 Medium

    Established a metabolic-immune role in which fasting-activated FOXO4 upregulates FKBP5 to dampen mTORC1/STAT signaling and modulate TH1/TH17 cytokines.

    Evidence RNA-seq, flow cytometry, FOXO4/FKBP5 gain/loss, ChIP bioinformatics, human data

    PMID:33723462

    Open questions at the time
    • Direct FKBP5 promoter binding only bioinformatically inferred
    • Human genetics correlative
  34. 2022 High

    Defined how FOXO4 inhibits p53 by binding its TAD and CRD to block p53–DNA binding while leaving FOXO4's own DNA binding intact, revealing reciprocal transcription-factor cross-inhibition.

    Evidence NMR, chemical crosslinking, analytical ultracentrifugation, in vitro DNA binding

    PMID:35481640

    Open questions at the time
    • Cellular consequences of p53 inhibition not assayed here
    • Regulation of the interaction unknown
  35. 2022 Medium

    Demonstrated FOXO4's vascular-immune role by repressing NFAT2 to restrain vasculitis, validated by in vivo KO epistasis.

    Evidence ChIP, luciferase, Foxo4 KO mice, NFAT2 manipulation, KD vasculitis model

    PMID:36700213

    Open questions at the time
    • Promoter element not finely resolved
    • Single disease model
  36. 2022 High

    Provided genome-wide FOXO4 occupancy showing direct repression of Dkk3 to limit Th1 IFN-γ responses, integrating FOXO4 into T-cell immunity.

    Evidence ChIP-seq, RNA-seq, T-cell-specific conditional KO, DKK3 reconstitution, cytokines

    PMID:36106640

    Open questions at the time
    • Full target landscape not analyzed beyond DKK3
    • Upstream activating signal in T cells not defined
  37. 2022 Medium

    Showed FOXO4 represses CTRP3 under hyperglycemia, modulating Nrf2/NF-κB signaling in retinal pericytes.

    Evidence ChIP, dual-luciferase, FOXO4 overexpression, JASPAR prediction

    PMID:35196182

    Open questions at the time
    • Single cell type
    • Functional consequence largely correlative

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple, partly antagonistic modification arms (phosphorylation/14-3-3, acetylation, mono- vs degradative ubiquitination, O-GlcNAcylation) and the autoinhibitory TAD–FHD equilibrium are integrated to set FOXO4 target selectivity and activate or repress specific genes in a given cell remains unresolved.
  • No unified quantitative model of modification cross-talk
  • Determinants of activator vs repressor mode at individual promoters unknown
  • In-cell relevance of the intramolecular autoinhibited state not directly demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 5
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-8953897 Cellular responses to stimuli 5 R-HSA-168256 Immune System 4 R-HSA-1640170 Cell Cycle 2
Partners
ATXN3CREBBPCTNNB1MDM2SIRT1TP53USP7XBP1XRCC6YWHAZ

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 NMR solution structure of the DNA-binding domain (forkhead domain) of FOXO4 (AFX) was determined, revealing a three-helix bundle resting on a small antiparallel beta-sheet with two wing-like loops, structurally similar to HNF3-gamma and FREAC-11 despite low sequence identity. High-resolution NMR spectroscopy Biochemistry High 11352721
2003 Two PKB/Akt phosphorylation sites (Thr-28 and Ser-193) on FOXO4 create binding motifs for 14-3-3 proteins; doubly phosphorylated FOXO4 forms a 1:2 complex with 14-3-3ζ (KD <30 nM), and both phosphorylation sites are required for complete inhibition of FOXO4 binding to its target DNA (insulin response element). In vitro phosphorylation by PKB, analytical gel filtration, sedimentation equilibrium, electrophoretic mobility shift assay Biochemistry High 14690436
2003 CBP acetyltransferase interacts with FOXO4 (AFX/FOXO4) via its CH1 region and acetylates it at lysine residues K186, K189, and K408, resulting in inhibition of FOXO4 transcriptional activity; arginine substitutions at these lysines enhance transcriptional activity. Co-immunoprecipitation, site-directed mutagenesis (K→R), luciferase reporter assay, TSA treatment International journal of molecular medicine Medium 12964026
2003 Nuclear FOXO4 expression down-regulates HIF-1α protein levels through a mechanism independent of prolyl hydroxylation and VHL-mediated ubiquitin-proteasome degradation, thereby suppressing hypoxia-responsive genes (VEGF, GLUT1, EPO). Ectopic FOXO4 expression, prolyl hydroxylase inhibition, HIF-1α proline mutants, reporter assays The Journal of biological chemistry Medium 12761217
2004 CBP acetyltransferase binds FOXO4 and acetylates it upon oxidative stress (H2O2), inhibiting FOXO4 transcriptional activity; the NAD-dependent deacetylase hSir2(SIRT1) binds and deacetylates FOXO4, counteracting CBP-mediated inhibition and prolonging FOXO-dependent stress gene transcription. Co-immunoprecipitation, acetylation assays, siRNA knockdown, luciferase reporter assay, overexpression The Journal of biological chemistry High 15126506
2005 FOXO4 represses smooth muscle cell (SMC) differentiation by directly interacting with and inhibiting myocardin, a transcriptional coactivator of smooth muscle genes; PI3K/Akt-mediated nuclear export of FOXO4 releases myocardin from inhibition, promoting SMC differentiation. siRNA knockdown of FOXO4 enhances myocardin activity and SMC differentiation. Co-immunoprecipitation, siRNA knockdown, reporter assays, dominant-negative and constitutively active constructs, immunofluorescence Developmental cell High 16054032
2005 Phosphorylation of FOXO4 at Thr-32 and Ser-197 (but not Ser-262) by PKB/Akt is required for cytoplasmic retention and transcriptional inactivation; mutations at Thr32 or Ser197 to Ala result in constitutive nuclear localization and 3–5-fold increased transcriptional activity. Site-directed mutagenesis, subcellular fractionation, immunoblotting with phosphosite-specific antibodies, transcriptional reporter assay Journal of biochemistry High 16272144
2005 14-3-3 protein binding to phosphorylated FOXO4 NLS significantly changes the environment around the NLS and reduces its flexibility, as shown by site-directed AEDANS labeling and fluorescence spectroscopy; phosphorylation alone or DNA binding have only minor effects on NLS structure. Site-directed fluorescent labeling (AEDANS), steady-state and time-resolved fluorescence spectroscopy, in vitro kinase assay Biochemistry Medium 16114898
2005 RANKL signaling through RANK Motif 1 (369PFQEP373) promotes osteoclast survival by activating Akt/PKB, which specifically phosphorylates FOXO4 (AFX) among multiple potential downstream targets, identifying FOXO4 as a key downstream effector of RANK-Akt signaling in osteoclast survival. RANK cytoplasmic motif mutagenesis, immunoblotting for phospho-FOXO4, osteoclast survival assays The Journal of biological chemistry Medium 16260781
2006 FOXO4 undergoes monoubiquitination in response to oxidative stress, which promotes its nuclear relocalization and increases transcriptional activity. The deubiquitinase USP7/HAUSP interacts with and deubiquitinates FOXO4 under oxidative stress conditions, negatively regulating FOXO4 transcriptional activity toward endogenous promoters without affecting protein half-life. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, subcellular fractionation, reporter assays Nature cell biology High 16964248
2007 FoxO4 activates transcription of the MMP9 gene in response to TNF-α signaling in vascular smooth muscle cells, requiring both the N-terminal Sp1-interactive domain and the C-terminal transactivation domain of FoxO4; FoxO4 knockdown (siRNA) or knockout reduces SMC migration in vitro and neointimal formation and MMP9 expression in vivo. siRNA knockdown, gene knockout, reporter assays (MMP9 promoter-luciferase), in vitro migration assay, in vivo vascular injury model Molecular and cellular biology High 17242183
2007 Both the N-terminal loop (upstream of helix H1) and wing W2 of the FOXO4 forkhead domain are required for stable DNA binding; deletion of either region partially reduces DNA binding, while simultaneous deletion of both significantly inhibits it. PKB-mediated phosphorylation of wing W2 significantly inhibits DNA binding only in the absence of the N-terminal loop; 14-3-3 binding efficiently reduces DNA binding regardless of N-terminal loop status. FRET time-resolved fluorescence spectroscopy, molecular dynamics simulations, in vitro DNA binding assays, in vitro PKB phosphorylation The Journal of biological chemistry Medium 17244620
2007 AGE/RAGE signaling in podocytes causes Akt dephosphorylation and FOXO4 transcriptional activation, leading to upregulation of the pro-apoptotic protein Bim; siRNA-mediated knockdown of FOXO4 abolishes AGE-BSA-induced podocyte apoptosis. siRNA knockdown, immunoblotting, apoptosis assays (flow cytometry), FOXO4 transcriptional activity readout Kidney international Medium 17667983
2008 Mdm2 acts as an E3 ubiquitin ligase for FOXO4, directly co-immunoprecipitating with FOXO4 and inducing its (multi)mono-ubiquitination in vitro and in vivo in an ATP-dependent manner; siRNA-mediated depletion of Mdm2 inhibits H2O2-induced FOXO4 mono-ubiquitination, and Mdm2-mediated ubiquitination regulates FOXO4 transcriptional activity. In vitro ubiquitination assay, co-immunoprecipitation, siRNA knockdown, in vivo ubiquitination assay, reporter assay PloS one High 18665269
2008 TNF-α increases nuclear FOXO4 protein and induces atrogin-1/MAFbx mRNA expression in C2C12 myotubes via a mechanism independent of AKT-Foxo1/3 signaling; two distinct siRNA sequences targeting Foxo4 reduce TNF-induced atrogin mRNA by ~33%. siRNA knockdown, immunoblotting for nuclear FOXO4, qPCR for atrogin mRNA, pharmacological AKT inhibition (wortmannin) American journal of physiology. Cell physiology Medium 18701653
2009 Reactive oxygen species induce formation of cysteine-thiol disulfide-dependent complexes between FoxO4 and p300/CBP acetyltransferase; modulation of FoxO4 biological activity by p300/CBP-mediated acetylation is fully dependent on formation of this redox-dependent complex, directly linking cellular redox state to FoxO4 activity. Biochemical crosslinking, thiol-reactive probes, co-immunoprecipitation, mutagenesis of cysteine residues, transcriptional reporter assays Nature chemical biology High 19648934
2009 14-3-3 protein physically contacts and masks the DNA-binding interface of FOXO4 upon binding; six inter-protein FRET distances reveal that the forkhead domain of FOXO4 is docked within the central channel of the 14-3-3 dimer, without causing dramatic conformational change of FOXO4. Time-resolved FRET fluorescence spectroscopy, site-specific AEDANS labeling, tryptophan fluorescence The Journal of biological chemistry High 19416966
2009 FoxO4 inhibits NF-κB transcriptional activity; Foxo4-null mice show increased NF-κB activity in vivo and increased susceptibility to colonic injury-induced colitis, with upregulation of chemokine CCL5 and increased intestinal permeability due to downregulation of tight junction proteins ZO-1 and claudin-1. Foxo4 genetic knockout, microarray, NF-κB reporter assays, flow cytometry for immune cell infiltration, Western blot for tight junction proteins Gastroenterology High 19560465
2009 EGF/PI3K/Akt signaling causes phosphorylation of FOXO4 and inhibition of ANXA8 transcription in cholangiocarcinoma cells; FOXO4 phosphorylation downstream of EGFR-PI3K-Akt leads to inhibition of ANXA8 gene transcription, promoting EMT and metastasis. PI3K/Akt inhibitor treatment, FOXO4 overexpression, ANXA8 reporter assays, in vitro invasion assay, in vivo metastasis assay Gastroenterology Medium 19376120
2010 Crystal structure of human FOXO4 DNA-binding domain in complex with 13-bp DNA at 1.9 Å resolution reveals helix H3 docked into the major groove providing all base-specific contacts, while the N-terminus and wing W1 contact phosphate groups; the H2-H3 loop has a different conformation from other FOXO-DBD structures and participates in DNA binding. X-ray crystallography (1.9 Å resolution crystal structure) Acta crystallographica. Section D, Biological crystallography High 21123876
2010 Ku70 (but not Ku80) is necessary and sufficient for interaction with FOXO4, identified by tandem-affinity purification/mass spectrometry; Ku70 inhibits FOXO4-mediated p27kip1 transcription and cell cycle arrest by >40%, and sequesters FOXO4 in the nucleus. Low levels of oxidative stress (50 µM H2O2) increase the Ku70-FOXO4 interaction stoichiometry while higher levels cause dissociation. Tandem-affinity purification, mass spectrometry, biochemical co-immunoprecipitation, luciferase reporter assay, Ku70 RNAi, immunofluorescence, flow cytometry, Ku70-/- ES cell rescue FASEB journal High 20570964
2010 PKG activation causes β-catenin to bind FOXO4 in colon cancer cells in a JNK-dependent manner, leading to increased nuclear FOXO4 content and expression of FOXO target genes (MnSOD, catalase); FOXO4-specific siRNA completely blocks PKG-mediated inhibition of TCF transcriptional activity. Co-immunoprecipitation, siRNA knockdown, nuclear fractionation, luciferase reporter assays, pharmacological inhibitors Oncogene Medium 20348951
2010 O-GlcNAcylation of FOXO4 is induced by H2O2 treatment through increased association of FOXO4 with OGT (the O-GlcNAc transferase); O-GlcNAcylation enhances FOXO4 transcriptional activity under acute oxidative stress. Co-immunoprecipitation, O-GlcNAc immunoblotting, transcriptional reporter assay FEBS letters Medium 19932102
2011 Ataxin-3 (ATXN3) interacts with FOXO4 and activates FOXO4-dependent transcription of the SOD2 gene; upon oxidative stress, ATXN3 and FOXO4 co-translocate to the nucleus and co-bind the SOD2 promoter; mutant ATXN3 (as in SCA3) has reduced ability to activate FOXO4-mediated SOD2 expression and interferes with FOXO4 binding to the SOD2 promoter. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), reporter assays, ATXN3 RNAi knockdown, immunofluorescence Human molecular genetics High 21536589
2011 AGE-BSA treatment increases FOXO4 acetylation in podocytes; acetylation of FOXO4 (regulated by SIRT1, which is downregulated by AGE-BSA) is required for FOXO4 binding to the Bcl2l11 (Bim) promoter and transcriptional upregulation of Bim leading to podocyte apoptosis; SIRT1 overexpression prevents AGE-induced podocyte apoptosis. Chromatin immunoprecipitation (ChIP), FOXO4 acetylation immunoprecipitation, SIRT1 overexpression, siRNA, in vivo db/db mouse model PloS one High 21858169
2011 FoxO4 inactivation downstream of the AMPK-mTORC1-S6K1-IRS-1-Akt2 pathway mediates adiponectin-induced vascular smooth muscle cell differentiation; adiponectin activates AMPKα2, which inhibits mTORC1/S6K1, stabilizing IRS-1 and driving Akt2-mediated FoxO4 phosphorylation and nuclear exclusion to allow contractile gene expression. siRNA knockdown of pathway components, overexpression, pharmacological inhibitors, VSMC differentiation assays Arteriosclerosis, thrombosis, and vascular biology Medium 21454807
2012 Foxk1 physically interacts with Foxo4 and represses Foxo4 transcriptional activity, thereby promoting muscle progenitor cell proliferation; Foxk1 knockdown causes cell cycle arrest and increased Foxo4 target gene expression, while Foxk1 overexpression retards muscle differentiation. Co-immunoprecipitation, reporter assays, siRNA knockdown, overexpression in C2C12 cells Journal of cell science Medium 22956541
2015 FoxO4 activates Arg1 (arginase 1) transcription by binding to a FoxO-binding site in the Arg1 promoter in endothelial cells; in FoxO4 endothelial-specific knockout mice, post-MI cardiac function is improved and neutrophil accumulation is reduced; FoxO4 acts upstream of Arg1 to suppress nitric oxide and promote neutrophil infiltration. Conditional endothelial/cardiomyocyte-specific knockout mice, luciferase reporter assay with Arg1 promoter, ChIP, siRNA, nitric oxide measurement, cardiac functional analysis (echocardiography) Circulation research High 26438688
2017 XBP1 unspliced form (XBP1u) directly associates with the N-terminus of FoxO4 in the cytoplasm, preventing FoxO4 nuclear translocation; blocking the XBP1u-FoxO4 interaction promotes nuclear FoxO4 translocation, represses smooth muscle cell marker genes, and stimulates aortic aneurysm formation in vivo, defining a XBP1u-FoxO4-myocardin axis in VSMC homeostasis. Co-immunoprecipitation, conditional SMC-specific XBP1 knockout mice, in vivo aneurysm models, immunofluorescence for nuclear FoxO4 Circulation research High 29089350
2018 WNK1 kinase positively regulates skeletal muscle cell hypertrophy by modulating FOXO4 nuclear localization; WNK1 silencing increases FOXO4 nuclear accumulation and induces atrogene (MAFbx and MuRF1) transcription and myotube atrophy, which is completely reversed by co-silencing of FOXO4. siRNA knockdown (WNK1, SPAK/OSR1, FOXO4), immunofluorescence for FOXO4 nuclear localization, qPCR for atrogenes, myotube diameter measurement Scientific reports Medium 29904119
2019 Fhl2 interacts with Foxk1 and, in a dose-dependent fashion, promotes Foxk1-mediated transcriptional repression of Foxo4 activity, contributing to regulation of myogenic progenitor cell activity; Fhl2 knockdown results in cell cycle arrest. Yeast two-hybrid screen, transcriptional reporter assay, siRNA knockdown, immunohistochemistry Stem cells (Dayton, Ohio) Medium 20013826
2020 COP1 E3 ubiquitin ligase directly interacts with FOXO4 through a VP motif on FOXO4 and promotes its ubiquitin-mediated proteasomal degradation in response to EGF signaling; CSN6 enhances COP1 E3 ligase activity toward FOXO4. FOXO4 directly binds and suppresses promoters of serine-glycine-one-carbon (SGOC) pathway genes. Co-immunoprecipitation, ubiquitination assays, promoter-reporter and ChIP assays, CSN6 siRNA, metabolomics Advanced science Medium 33101846
2021 The FOXO4 C-terminal disordered transactivation domain (TAD) binds β-catenin through two defined interaction sites, regulated by combined PKB/AKT- and CK1-mediated phosphorylation; β-catenin binding competes with an autoinhibitory intramolecular interaction between the FOXO4 TAD and its own forkhead DNA-binding domain, enhancing FOXO4 transcriptional activity. ICAT (β-catenin inhibitor) can bind β-catenin simultaneously with FOXO4. NMR spectroscopy, biochemical binding assays, phosphorylation mutagenesis, reporter assays Cell reports High 34320339
2021 FOXO4 TAD and the forkhead DNA-binding domain (FHD) form an intramolecular complex via hydrophobic interactions; TAD and DNA share the same FHD surface for binding, and the FHD-TAD complex selectively shows slow exchange with target DNA and fast exchange with non-target DNA, enabling selective target sequence recognition. Solution NMR spectroscopy, DNA binding assays Journal of molecular biology High 33450250
2021 FOXO4 directly binds the LDHA (lactate dehydrogenase A) promoter and inactivates its transcriptional activity in a dose-dependent manner; FOXO4 expression is itself transcriptionally repressed by HIF-1α under hypoxia, placing FOXO4 downstream of HIF-1α in the regulation of glycolysis. ChIP, promoter-reporter luciferase assay, FOXO4 overexpression/silencing, metabolic flux assays Clinical and translational medicine Medium 33463054
2021 Fasting in humans activates FOXO4 in CD4+ T cells, and FOXO4 transcriptionally upregulates FKBP5 (FK506-binding protein 5); genetic gain- or loss-of-function of FOXO4 and FKBP5 modulates TH1 and TH17 cytokine production; FOXO4/FKBP5 axis downregulates mTORC1 signaling and suppresses STAT1/3 activation. RNA sequencing, flow cytometry, gain-of-function and loss-of-function genetic approaches, FOXO4 ChIP analysis (bioinformatics), cytokine measurement Nature metabolism Medium 33723462
2021 FOXO4 negatively regulates transcription of USP10; FoxO4 overexpression reduces USP10 levels and blocks Hippo/YAP signaling, aggravating apoptosis and oxidative stress in hypoxia/reoxygenation-treated cardiomyocytes. Dual luciferase reporter assay, ChIP, siRNA/overexpression, western blot for YAP pathway proteins, TUNEL and ROS assays Journal of bioenergetics and biomembranes Medium 34251583
2021 FOXO4 directly binds the ENPP2 promoter (transcription factor binding validated by dual-luciferase and ChIP assays) and inhibits ENPP2 expression; FoxO4 overexpression partially reverses ENPP2-mediated protection of cardiomyocytes against doxorubicin-induced ferroptosis. Dual-luciferase reporter assay, ChIP, overexpression, ferroptosis/oxidative stress assays Molecular medicine reports Medium 34296293
2021 FOXO4 transcriptionally activates SOX9 by binding to its promoter (validated by ChIP and dual-luciferase reporter assay); Sirt1-mediated deacetylation of FOXO4 promotes SOX9 expression and stabilizes chondrocyte ECM. FOXO4 acetylation is increased by IL-1β, and FOXO4 knockdown abolishes Sirt1-induced SOX9 expression. ChIP, dual-luciferase reporter assay, FOXO4 siRNA knockdown, Sirt1 overexpression, Western blot for FOXO4 acetylation European review for medical and pharmacological sciences Medium 33577016
2022 FOXO4 interacts with both the transactivation domain (TAD) and cysteine-rich domain (CRD) of p53, as determined by NMR, chemical cross-linking, and analytical ultracentrifugation; p53 TAD interaction with the FOXO4 forkhead domain is essential for overall complex stability; complex formation blocks p53 binding to DNA but does not affect FOXO4's own DNA-binding properties. NMR spectroscopy, chemical cross-linking, analytical ultracentrifugation, in vitro DNA binding assays Protein science High 35481640
2022 FoxO4 transcriptionally represses NFAT2 by binding to the NFAT2 promoter in human coronary artery endothelial cells (validated by ChIP and luciferase assay); Foxo4 knockout increases vasculitis in a mouse KD model, and NFAT2 inhibition reverses this effect, defining a FOXO4/NFAT2 axis in vascular inflammation. ChIP, luciferase reporter assay, Foxo4 knockout mice, NFAT2 overexpression/knockdown, in vivo KD vasculitis model Frontiers in immunology Medium 36700213
2022 FoxO4 directly binds and transcriptionally represses the Dkk3 (Dickkopf-3) gene (identified by genome-wide occupancy/ChIP-seq and transcriptomics); DKK3 mediates FoxO4's suppression of IFN-γ production in Th1 cells by downregulating LEF1 expression; conditional FoxO4 deletion in CD4+ T cells enhances Th1 responses to bacterial infection. ChIP-seq (genome-wide occupancy), RNA-seq, conditional T cell-specific KO mice, recombinant DKK3 protein reconstitution, cytokine measurement The Journal of clinical investigation High 36106640
2022 FOXO4 binds the CTRP3 promoter and inhibits CTRP3 transcription (validated by JASPAR prediction, ChIP, and luciferase reporter assay); FOXO4 upregulation in high-glucose conditions suppresses CTRP3 expression, modulating the Nrf2/NF-κB pathway in retinal pericytes. ChIP, dual-luciferase reporter assay, FOXO4 overexpression, bioinformatics (JASPAR) Bioengineered Medium 35196182
2019 KLF2 physically interacts with FOXO4 and cooperates with FOXO4 to induce transcription of p21, driving senescence of pancreatic cancer cells; knockdown of p21 or FOXO4 impairs KLF2-induced senescence. Co-immunoprecipitation, reporter assays, siRNA knockdown, senescence assays (SA-β-gal) Experimental cell research Medium 31866399
2021 TET1 transcriptionally activates FOXO4 expression; FOXO4 directly interacts with β-catenin and sequesters it in the cytoplasm, inhibiting β-catenin-mediated transcription of Wnt target genes (including EpCAM); FOXO4 modulation reverses TET1 effects on EMT and cancer stem cell self-renewal. Co-immunoprecipitation, RNA-seq, overexpression and knockdown, β-catenin localization assay, reporter assays, liver metastasis in vivo model Cancers Medium 35805009
2020 FOXO4 binds the APC2 promoter and transcriptionally upregulates APC2 expression, leading to increased phosphorylated degradation of β-catenin and suppression of stemness genes; FOXO4 overexpression inhibits CRC cell migration and metastasis, which is reversed by APC2 knockdown. ChIP, overexpression, siRNA knockdown (APC2), in vivo metastasis assay, immunohistochemistry Frontiers in cell and developmental biology Medium 34631691

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). The Journal of biological chemistry 455 15126506
2006 FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nature cell biology 406 16964248
2019 Inhibition of Brd4 alleviates renal ischemia/reperfusion injury-induced apoptosis and endoplasmic reticulum stress by blocking FoxO4-mediated oxidative stress. Redox biology 213 31004990
2009 Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nature chemical biology 170 19648934
2005 Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin. Developmental cell 160 16054032
2014 A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. The American journal of surgical pathology 149 25007147
2018 Hsa_circRNA_103809 regulated the cell proliferation and migration in colorectal cancer via miR-532-3p / FOXO4 axis. Biochemical and biophysical research communications 144 30249393
2011 MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4. Carcinogenesis 132 21934092
2007 Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor. Kidney international 128 17667983
2011 Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus. PloS one 117 21858169
2009 FoxO4 inhibits NF-kappaB and protects mice against colonic injury and inflammation. Gastroenterology 116 19560465
2008 Mdm2 induces mono-ubiquitination of FOXO4. PloS one 112 18665269
2005 14-3-3 Protein interacts with nuclear localization sequence of forkhead transcription factor FoxO4. Biochemistry 106 16114898
2003 Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation. International journal of molecular medicine 105 12964026
2017 Unspliced XBP1 Confers VSMC Homeostasis and Prevents Aortic Aneurysm Formation via FoxO4 Interaction. Circulation research 103 29089350
2018 Regulation of cellular senescence via the FOXO4-p53 axis. FEBS letters 102 29683489
2008 TNF induction of atrogin-1/MAFbx mRNA depends on Foxo4 expression but not AKT-Foxo1/3 signaling. American journal of physiology. Cell physiology 94 18701653
2007 FoxO4 regulates tumor necrosis factor alpha-directed smooth muscle cell migration by activating matrix metalloproteinase 9 gene transcription. Molecular and cellular biology 93 17242183
2003 Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding. Biochemistry 89 14690436
2003 The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism. The Journal of biological chemistry 85 12761217
2020 FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging 84 31959736
2011 FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3. Human molecular genetics 83 21536589
2016 MiR-150 promotes cellular metastasis in non-small cell lung cancer by targeting FOXO4. Scientific reports 81 27976702
2019 Current perspective on the regulation of FOXO4 and its role in disease progression. Cellular and molecular life sciences : CMLS 75 31529218
2015 FoxO4 promotes early inflammatory response upon myocardial infarction via endothelial Arg1. Circulation research 74 26438688
2001 Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4). Biochemistry 72 11352721
2005 Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity. Oncogene 71 15688030
2021 Hypoxia-induced FOXO4/LDHA axis modulates gastric cancer cell glycolysis and progression. Clinical and translational medicine 70 33463054
2011 Adiponectin induces vascular smooth muscle cell differentiation via repression of mammalian target of rapamycin complex 1 and FoxO4. Arteriosclerosis, thrombosis, and vascular biology 66 21454807
2007 Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding. The Journal of biological chemistry 65 17244620
2013 miR-421 induces cell proliferation and apoptosis resistance in human nasopharyngeal carcinoma via downregulation of FOXO4. Biochemical and biophysical research communications 64 23707940
2012 Foxk1 promotes cell proliferation and represses myogenic differentiation by regulating Foxo4 and Mef2. Journal of cell science 64 22956541
2015 microRNA-150 promotes cervical cancer cell growth and survival by targeting FOXO4. BMC molecular biology 63 26715362
2010 PKG inhibits TCF signaling in colon cancer cells by blocking beta-catenin expression and activating FOXO4. Oncogene 63 20348951
2009 14-3-3 protein masks the DNA binding interface of forkhead transcription factor FOXO4. The Journal of biological chemistry 58 19416966
2010 Structure of the human FOXO4-DBD-DNA complex at 1.9 Å resolution reveals new details of FOXO binding to the DNA. Acta crystallographica. Section D, Biological crystallography 57 21123876
2021 Fasting-induced FOXO4 blunts human CD4+ T helper cell responsiveness. Nature metabolism 56 33723462
2009 ANXA8 down-regulation by EGF-FOXO4 signaling is involved in cell scattering and tumor metastasis of cholangiocarcinoma. Gastroenterology 55 19376120
2021 Exosomal miR-128-3p Promotes Epithelial-to-Mesenchymal Transition in Colorectal Cancer Cells by Targeting FOXO4 via TGF-β/SMAD and JAK/STAT3 Signaling. Frontiers in cell and developmental biology 53 33634112
2014 The transcription factor FOXO4 is down-regulated and inhibits tumor proliferation and metastasis in gastric cancer. BMC cancer 52 24886657
2014 A genome-wide RNAi screen identifies FOXO4 as a metastasis-suppressor through counteracting PI3K/AKT signal pathway in prostate cancer. PloS one 48 24983969
2018 Rosmarinic acid reduces the resistance of gastric carcinoma cells to 5-fluorouracil by downregulating FOXO4-targeting miR-6785-5p. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 43 30551491
2016 Foxo4- and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 43 28011648
2013 FOXO4 is necessary for neural differentiation of human embryonic stem cells. Aging cell 42 23551888
2022 Salvianolic Acid B Suppresses ER Stress-Induced NLRP3 Inflammasome and Pyroptosis via the AMPK/FoxO4 and Syndecan-4/Rac1 Signaling Pathways in Human Endothelial Progenitor Cells. Oxidative medicine and cellular longevity 41 35340217
2021 Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes. Frontiers in bioengineering and biotechnology 40 33996787
2018 FoxO4 promotes myocardial ischemia-reperfusion injury: the role of oxidative stress-induced apoptosis. American journal of translational research 40 30323875
2005 Regulation of intracellular localization and transcriptional activity of FOXO4 by protein kinase B through phosphorylation at the motif sites conserved among the FOXO family. Journal of biochemistry 39 16272144
2019 Adiponectin alleviates NLRP3-inflammasome-mediated pyroptosis of aortic endothelial cells by inhibiting FoxO4 in arteriosclerosis. Biochemical and biophysical research communications 36 31030940
2021 Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells. EBioMedicine 35 34689087
2020 Resveratrol inhibits bile acid-induced gastric intestinal metaplasia via the PI3K/AKT/p-FoxO4 signalling pathway. Phytotherapy research : PTR 35 33103284
2010 The DNA damage repair protein Ku70 interacts with FOXO4 to coordinate a conserved cellular stress response. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 35 20570964
2022 FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway. Journal of cellular and molecular medicine 34 35510614
2021 Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function. Cell reports 34 34320339
2010 Fhl2 interacts with Foxk1 and corepresses Foxo4 activity in myogenic progenitors. Stem cells (Dayton, Ohio) 33 20013826
2020 EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 32 33101846
2015 FOXO1, FOXO3, AND FOXO4 are differently expressed during mouse oocyte maturation and preimplantation embryo development. Gene expression patterns : GEP 32 25929834
2014 Low expression of the FoxO4 gene may contribute to the phenomenon of EMT in non-small cell lung cancer. Asian Pacific journal of cancer prevention : APJCP 31 24935588
2011 Up-regulation of Foxo4 mediated by hepatitis B virus X protein confers resistance to oxidative stress-induced cell death. International journal of molecular medicine 31 21567078
2021 Transcriptional activation of ENPP2 by FoxO4 protects cardiomyocytes from doxorubicin‑induced toxicity. Molecular medicine reports 30 34296293
2011 Candidate gene study of FOXO1, FOXO4, and FOXO6 reveals no association with human longevity in Germans. Aging cell 28 21388494
2022 Targeting Wnt/β-Catenin Signaling by TET1/FOXO4 Inhibits Metastatic Spreading and Self-Renewal of Cancer Stem Cells in Gastric Cancer. Cancers 27 35805009
2015 The role of microRNA-1274a in the tumorigenesis of gastric cancer: accelerating cancer cell proliferation and migration via directly targeting FOXO4. Biochemical and biophysical research communications 27 25753202
2015 Mir-664 promotes osteosarcoma cells proliferation via downregulating of FOXO4. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 27 26463624
2010 O-GlcNAcylation enhances FOXO4 transcriptional regulation in response to stress. FEBS letters 27 19932102
2008 The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity. Carcinogenesis 27 18687668
2016 Overexpression of FOXO4 induces apoptosis of clear-cell renal carcinoma cells through downregulation of Bim. Molecular medicine reports 26 26780985
2021 FOXO4 ameliorates alcohol-induced chronic liver injury via inhibiting NF-κB and modulating gut microbiota in C57BL/6J mice. International immunopharmacology 25 33798806
2020 MiR-128-3p inhibits vascular smooth muscle cell proliferation and migration by repressing FOXO4/MMP9 signaling pathway. Molecular medicine (Cambridge, Mass.) 25 33238881
2019 Long noncoding RNA LINC00341 promotes the vascular smooth muscle cells proliferation and migration via miR-214/FOXO4 feedback loop. American journal of translational research 25 30972207
2005 Receptor activator of NF-kappaB (RANK) cytoplasmic motif, 369PFQEP373, plays a predominant role in osteoclast survival in part by activating Akt/PKB and its downstream effector AFX/FOXO4. The Journal of biological chemistry 25 16260781
2010 Expression and localisation of FoxO3 and FoxO4 in human placenta and fetal membranes. Placenta 24 20934750
2009 Effects of FoxO4 overexpression on cholesterol biosynthesis, triacylglycerol accumulation, and glucose uptake. Journal of lipid research 22 20037138
1997 AFX1 and p54nrb: fine mapping, genomic structure, and exclusion as candidate genes of X-linked dystonia parkinsonism. Human genetics 22 9341872
2017 Curcumin Induces p53-Null Hepatoma Cell Line Hep3B Apoptosis through the AKT-PTEN-FOXO4 Pathway. Evidence-based complementary and alternative medicine : eCAM 21 28769986
2011 Advanced glycation end-products induce heparanase expression in endothelial cells by the receptor for advanced glycation end products and through activation of the FOXO4 transcription factor. Molecular and cellular biochemistry 21 21461610
2023 Ponicidin inhibited gallbladder cancer proliferation and metastasis by decreasing MAGEB2 expression through FOXO4. Phytomedicine : international journal of phytotherapy and phytopharmacology 20 37002972
2021 FoxO4 negatively modulates USP10 transcription to aggravate the apoptosis and oxidative stress of hypoxia/reoxygenation-induced cardiomyocytes by regulating the Hippo/YAP pathway. Journal of bioenergetics and biomembranes 20 34251583
2020 LncRNA GUARDIN suppresses cellular senescence through a LRP130-PGC1α-FOXO4-p21-dependent signaling axis. EMBO reports 20 32149459
2020 MicroRNA-328-3p Protects Vascular Endothelial Cells Against Oxidized Low-Density Lipoprotein Induced Injury via Targeting Forkhead Box Protein O4 (FOXO4) in Atherosclerosis. Medical science monitor : international medical journal of experimental and clinical research 20 32329448
2020 Primary myxoid and epithelioid mesenchymal tumor of the kidney with a novel GLI1-FOXO4 fusion. Genes, chromosomes & cancer 20 33159395
2017 FOXO4 expression is related to stem cell-like properties and resistance to treatment in diffuse large B-cell lymphoma. Oncotarget 20 27911272
2011 FoxO4 inhibits atherosclerosis through its function in bone marrow derived cells. Atherosclerosis 20 22005198
2020 Upregulation of microRNA-328-3p by hepatitis B virus contributes to THLE-2 cell injury by downregulating FOXO4. Journal of translational medicine 19 32228643
2019 A medicinal and edible formula YH0618 ameliorates the toxicity induced by Doxorubicin via regulating the expression of Bax/Bcl-2 and FOXO4. Journal of Cancer 19 31333784
2019 Tetrahydrocurcumin protects against spinal cord injury and inhibits the oxidative stress response by regulating FOXO4 in model rats. Experimental and therapeutic medicine 19 31602247
2021 FOXO4 Inhibits the Migration and Metastasis of Colorectal Cancer by Regulating the APC2/β-Catenin Axis. Frontiers in cell and developmental biology 18 34631691
2018 WNK1 regulates skeletal muscle cell hypertrophy by modulating the nuclear localization and transcriptional activity of FOXO4. Scientific reports 18 29904119
2014 FOXO4-knockdown suppresses oxidative stress-induced apoptosis of early pro-angiogenic cells and augments their neovascularization capacities in ischemic limbs. PloS one 18 24663349
2022 Extracellular histones induce inflammation and senescence of vascular smooth muscle cells by activating the AMPK/FOXO4 signaling pathway. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 17 35913584
2019 KLF2 induces the senescence of pancreatic cancer cells by cooperating with FOXO4 to upregulate p21. Experimental cell research 17 31866399
2022 C1q/tumor necrosis factor-related protein-3 (CTRP3) activated by forkhead box O4 (FOXO4) down-regulation protects retinal pericytes against high glucose-induced oxidative damage through nuclear factor erythroid 2-related factor 2 (Nrf2)/Nuclear factor-kappaB (NF-κB) signaling. Bioengineered 16 35196182
2022 FOXO4 interacts with p53 TAD and CRD and inhibits its binding to DNA. Protein science : a publication of the Protein Society 16 35481640
2022 The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity. The Journal of clinical investigation 16 36106640
2016 Inhibition of skeletal muscle atrophy during torpor in ground squirrels occurs through downregulation of MyoG and inactivation of Foxo4. Cryobiology 16 27593478
2014 MSTN, mTOR and FoxO4 are involved in the enhancement of breast muscle growth by methionine in broilers with lower hatching weight. PloS one 16 25437444
2023 The role of FOXO4/NFAT2 signaling pathway in dysfunction of human coronary endothelial cells and inflammatory infiltration of vasculitis in Kawasaki disease. Frontiers in immunology 15 36700213
2021 FOXO4 Transactivation Domain Interaction with Forkhead DNA Binding Domain and Effect on Selective DNA Recognition for Transcription Initiation. Journal of molecular biology 15 33450250
2021 Deacetylation of FOXO4 by Sirt1 stabilizes chondrocyte extracellular matrix upon activating SOX9. European review for medical and pharmacological sciences 15 33577016
2015 The DNA damage repair protein Ku70 regulates tumor cell and hepatic carcinogenesis by interacting with FOXO4. Pathology, research and practice 15 26797321

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