Affinage

WWOX

WW domain-containing oxidoreductase · UniProt Q9NZC7

Length
414 aa
Mass
46.7 kDa
Annotated
2026-06-11
100 papers in source corpus 34 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

WWOX is a stress-responsive adaptor protein that couples cytoplasmic sequestration of transcription factors and signaling effectors to control of apoptosis, genome stability, metabolism, and neural development (PMID:15070730, PMID:25012504, PMID:27869163). Its first WW domain, activated by Tyr33 phosphorylation, binds PPxY-type motifs and forms complexes with transcription factors that WWOX redistributes from nucleus to cytoplasm to quench their activity, including p73, AP-2gamma (suppressing ERBB2 transcription), SMAD3, HIF1alpha, and Dishevelled in Wnt/beta-catenin signaling (PMID:15070730, PMID:15548692, PMID:19465938, PMID:24330518, PMID:25012504, PMID:17704139). The same Tyr33-phosphorylated WW domain assembles pro-apoptotic complexes with JNK1 and Ser46-phosphorylated p53, stabilizing p53 and driving mitochondrial-then-nuclear translocation to execute stress-induced cell death, a function antagonized by the inhibitory partner Zfra (PMID:12514174, PMID:16219768, PMID:14555208, PMID:17567906). Membrane signals feed into this axis: TGF-beta1- and hyaluronan-driven Hyal-2/WWOX/Smad4 complexes relocate to the nucleus to enhance Smad-dependent transcription and death (PMID:19366691, PMID:27845895). WWOX also acts in the nucleus on DNA-break responses, interacting with BRCA1 to bias double-strand-break repair toward NHEJ by suppressing HDR end-resection, and contributing to the ATR single-strand-break checkpoint (PMID:27869163, PMID:26675548). Through interactions with AMPK and HIF1alpha, WWOX restrains a Warburg-like glycolytic shift and maintains mitochondrial oxidative metabolism, and its loss dysregulates HDL/lipid metabolism in liver (PMID:25012504, PMID:30755385, PMID:24871327). A separate C-terminal short-chain-dehydrogenase/reductase (SDR) domain directs Golgi localization and binds Tau (PMID:14526170, PMID:30158849). In vivo, neuronal WWOX loss causes brain hyperexcitability, impaired oligodendrocyte maturation and myelination, and GSK3beta-dependent epilepsy, defining a role in neurodevelopment and brain excitability (PMID:33914858, PMID:32000863), and WWOX-p53 genetic epistasis governs osteogenesis and osteosarcoma suppression (PMID:27550453).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 High

    Establishing that Tyr33 phosphorylation of WWOX's first WW domain is the switch licensing pro-apoptotic partner binding answered how a single protein toggles between adaptor and death-inducing states.

    Evidence Co-IP, yeast two-hybrid, and Tyr33-to-Arg mutagenesis with apoptosis assays linking WWOX to JNK1 and p53

    PMID:12514174 PMID:14555208

    Open questions at the time
    • Identity of the kinase(s) phosphorylating Tyr33 in each stimulus context not fully resolved
    • Mechanism of mitochondrial-to-nuclear translocation not structurally defined
  2. 2003 Medium

    Mapping WWOX to the Golgi and showing SDR-domain dependence of that localization distinguished domain-specific functions and predicted that SDR-lacking splice forms act as dominant negatives.

    Evidence Immunofluorescence/fractionation with domain-deletion constructs and analysis of aberrant splice forms

    PMID:14526170

    Open questions at the time
    • Dominant-negative claim not mechanistically validated
    • Enzymatic substrate of the SDR domain not identified
  3. 2004 High

    Demonstrating that WWOX sequesters transcription factors (p73, AP-2gamma) in the cytoplasm via WW1–PPxY contacts defined its core mechanism of transcriptional suppression.

    Evidence Reciprocal Co-IP, WW domain and PPPY-motif mutagenesis, subcellular localization, and reporter assays

    PMID:15070730 PMID:15548692

    Open questions at the time
    • How cytoplasmic retention is sustained versus reversed not defined
    • Whether endogenous stoichiometry supports sequestration genome-wide untested
  4. 2005 High

    Showing that WOX1 stabilizes Ser46-phosphorylated p53 post-translationally tied WWOX directly to the p53 apoptotic checkpoint and MDM2 axis.

    Evidence Co-IP, Y2H domain mapping, siRNA, dominant-negative, protein-stability time course, and nutlin-3 pharmacology

    PMID:16219768

    Open questions at the time
    • Biochemical basis for p53 stabilization (e.g. blocking MDM2 access) not directly demonstrated
  5. 2005 Medium

    Identifying 17beta-estradiol and complement C1q as upstream activators of WWOX Tyr33 phosphorylation connected hormonal and immune cues to WWOX-driven apoptosis.

    Evidence Phospho-Tyr33 Western blotting, Co-IP, fractionation, and dominant-negative/Y33R apoptosis assays in cell lines

    PMID:15580310 PMID:19484134

    Open questions at the time
    • Receptor/signaling steps linking ligand to Tyr33 phosphorylation undefined
    • ER/AR independence shown only pharmacologically
  6. 2006 Medium

    Linking PKA-phosphorylated ezrin to apical WWOX localization showed that scaffolding partners position WWOX at specific membrane domains.

    Evidence Direct binding assays, ezrin polyproline/Tyr477 mutagenesis, Co-IP, and microscopy of apical localization and H,K-ATPase recruitment

    PMID:16438931

    Open questions at the time
    • Functional consequence of apical WWOX beyond H,K-ATPase recruitment unclear
    • Single study, not independently confirmed
  7. 2009 High

    Establishing membrane-receptor inputs (TGF-beta1/Hyal-2) and Wnt/Dvl control extended WWOX from cytosolic sequestration to receptor-proximal signal relay.

    Evidence Immunoelectron microscopy, live-cell FRET, Y2H domain mapping, Co-IP, and Smad/TCF-LEF reporter assays

    PMID:19366691 PMID:19465938

    Open questions at the time
    • How WWOX both quenches SMAD3 transcription (#10) and enhances Smad-driven promoters via Hyal-2 (#8) is context-dependent and not reconciled
  8. 2014 High

    Showing WWOX binds and limits HIF1alpha defined a tumor-suppressive metabolic role restraining the Warburg shift.

    Evidence Co-IP, WW domain mutagenesis, glucose-uptake and metabolic-flux assays, and Wwox knockout cells/mice

    PMID:25012504

    Open questions at the time
    • Whether WWOX controls HIF1alpha stability or only transactivation not fully separated
  9. 2016 High

    Placing WWOX in DSB repair-pathway choice (with BRCA1) and the ATR SSB checkpoint connected its tumor-suppressor activity to genome maintenance.

    Evidence Co-IP, HDR/NHEJ reporters, repair foci, RAD51 epistasis, xenograft radiation model; nuclear SSB accumulation, ITCH-mediated K274 ubiquitination, and ATM Co-IP

    PMID:26675548 PMID:27869163

    Open questions at the time
    • Molecular mechanism by which WWOX suppresses end-resection unresolved
    • Functional role of K274 ubiquitination at the checkpoint not fully defined
  10. 2016 High

    Genetic epistasis showed WWOX loss drives p53-dependent osteogenic failure and that p53 deletion both rescues bone formation and accelerates osteosarcoma, defining a WWOX-p53 network in bone.

    Evidence Stage-specific conditional Wwox/p53 knockouts with genetic rescue, histology, and expression analysis

    PMID:27550453

    Open questions at the time
    • Whether bone p53 regulation uses the same Tyr33/WW mechanism as in apoptosis untested
  11. 2019 Medium

    Identifying WWOX-AMPK interaction in muscle established a causal role in glucose oxidation, mitochondrial maintenance, and systemic insulin sensitivity.

    Evidence Co-IP and conditional skeletal-muscle Wwox knockout with metabolic phenotyping and mitochondrial assays

    PMID:30755385

    Open questions at the time
    • Whether WWOX directly modulates AMPK catalytic activity or acts as scaffold unclear
  12. 2020 High

    Neuron-specific WWOX loss producing epilepsy, impaired myelination, and GSK3beta hyperactivation defined the basis of WWOX-related neurodevelopmental encephalopathy.

    Evidence Neuron-specific conditional knockout mice plus human brain organoids; transcriptomics, oligodendrocyte maturation, electrophysiology, and lithium/GSK3beta pharmacological epistasis

    PMID:32000863 PMID:33914858

    Open questions at the time
    • How WWOX loss elevates GSK3beta activity mechanistically unknown
    • Link between myelination defect and seizure phenotype not causally dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • The catalytic substrate and physiological reaction of the WWOX SDR oxidoreductase domain remain undefined, leaving its enzymatic contribution to metabolism, Golgi function, and Tau handling unresolved.
  • No endogenous SDR substrate identified
  • Enzymatic versus scaffolding contributions of the SDR domain not separated
  • No structural model linking SDR activity to disease phenotypes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 5 GO:0140110 transcription regulator activity 4 GO:0016491 oxidoreductase activity 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 4 GO:0005739 mitochondrion 2 GO:0005764 lysosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1430728 Metabolism 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1266738 Developmental Biology 2 R-HSA-73894 DNA Repair 2 R-HSA-9612973 Autophagy 1
Partners
AMPKBRCA1HIF1AJAK2JNK1SMAD3TP53TP73
Complex memberships
Hyal-2/WWOX/Smad4 complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 WWOX physically interacts via its first WW domain with the p53 homolog p73; Src kinase phosphorylates WWOX at tyrosine 33 in the first WW domain and enhances this binding. WWOX expression redistributes nuclear p73 to the cytoplasm, suppressing its transcriptional activity, and cytoplasmic p73 contributes to WWOX proapoptotic activity. Co-immunoprecipitation, WW domain mutagenesis, subcellular fractionation/localization assays, transfection-based transcriptional reporter assays Proceedings of the National Academy of Sciences of the United States of America High 15070730
2004 WWOX physically interacts with AP-2gamma transcription factor via its first WW domain binding the PPPY motif of AP-2gamma. Mutation of tyrosine 33 in the first WW domain of WWOX or the PPPY motif in AP-2gamma dramatically reduces interaction. WWOX expression triggers redistribution of nuclear AP-2gamma to the cytoplasm, suppressing its transactivating function. Co-immunoprecipitation, site-directed mutagenesis, subcellular localization assays, transcriptional reporter assays Cancer research High 15548692
2003 JNK1 physically interacts with WWOX (WOX1) when WWOX is phosphorylated at Tyr33. Activated JNK1 inhibits WWOX-mediated apoptosis. Mutation of Tyr33 to Arg33 abrogates WWOX binding to JNK1 and abolishes WWOX apoptotic activity, indicating Tyr33 phosphorylation is required both for JNK1 binding and for WWOX-mediated cell death. Co-immunoprecipitation, yeast two-hybrid analysis, site-directed mutagenesis, apoptosis assays (multiple cell lines) The Journal of biological chemistry High 12514174
2005 WWOX (WOX1) Tyr33-phosphorylated form physically interacts with Ser46-phosphorylated p53. This interaction stabilizes p53 protein and is essential for apoptosis induced by UV, anisomycin, etoposide, and TNF. siRNA knockdown of WOX1 abolishes p53 protein accumulation (but not p53 mRNA) after UV, and dominant-negative WOX1 (blocking Tyr33 phosphorylation) also blocks UV-induced p53 expression. MDM2 inhibition by nutlin-3 increases WOX1–p53 binding and p53 stability. Co-immunoprecipitation, yeast two-hybrid domain mapping, siRNA knockdown, dominant-negative overexpression, time-course protein stability assay, nutlin-3 pharmacological inhibition The Journal of biological chemistry High 16219768
2003 WWOX (WOX1) undergoes Tyr33 phosphorylation at its first WW domain in response to stress/apoptotic stimuli, enabling complex formation with activated p53 and JNK1. The p53/WOX1 complex translocates to the mitochondria and then to the nucleus to mediate apoptosis. WOX1 mutants inactivated for nuclear translocation or Tyr33 phosphorylation fail to induce apoptosis. Phosphorylation assays, co-immunoprecipitation, subcellular fractionation, dominant-negative mutagenesis, apoptosis assays Biochemical pharmacology Medium 14555208
2005 17beta-estradiol activates WWOX (WOX1) via Tyr33 phosphorylation and promotes nuclear translocation of p53/WOX1 complex independently of estrogen receptor and androgen receptor status. Western blotting for Tyr33 phosphorylation, co-immunoprecipitation, subcellular fractionation, immunohistochemistry in multiple cell lines and in vivo tissues Oncogene Medium 15580310
2006 PKA-mediated phosphorylation of ezrin at Ser66 regulates interaction between ezrin and WWOX. Ezrin directly binds the first WW domain of WWOX via its C-terminal polyproline sequence (470PPPPPPVY477), with Tyr477 essential for the interaction. PKA-mediated ezrin phosphorylation is necessary and sufficient for apical localization of WWOX protein; disruption of the ezrin-WWOX interaction eliminates apical WWOX localization and impairs H,K-ATPase recruitment. Biochemical binding assays, site-directed mutagenesis, co-immunoprecipitation, subcellular localization by microscopy Biochemical and biophysical research communications Medium 16438931
2009 WWOX physically associates with Dishevelled (Dvl) family proteins (identified by yeast two-hybrid and co-immunoprecipitation). WWOX expression inhibits Wnt/beta-catenin transcriptional activity, while WWOX knockdown stimulates it and enhances Wnt-3a-induced beta-catenin stability. WWOX sequesters Dvl-2 (including a nuclear-localized Dvl-2 mutant) in the cytoplasm, preventing nuclear import of Dvl proteins. Yeast two-hybrid, co-immunoprecipitation, TCF/LEF reporter assays, beta-catenin stability assay, subcellular localization Oncogene High 19465938
2009 TGF-beta1 binds cell-surface hyaluronidase Hyal-2 on microvilli (in TGF-beta receptor II-deficient cells), resulting in recruitment of WWOX (WOX1) and formation of Hyal-2/WWOX complexes that relocate to the nucleus. TGF-beta1 strengthens binding of the catalytic domain of Hyal-2 with the Tyr33-phosphorylated WW domain of WWOX. WOX1 and Hyal-2 together dramatically enhance Smad-driven promoter activation (8-9-fold), leading to cell death. Immunoelectron microscopy, FRET in live cells, co-immunoprecipitation, yeast two-hybrid domain mapping, Smad promoter reporter assays The Journal of biological chemistry High 19366691
2009 Complement C1q activates WWOX (WOX1) via Tyr33 phosphorylation in prostate cancer cells. Exogenous C1q significantly induces apoptosis of WWOX-overexpressing DU145 cells but not control cells; dominant-negative and Y33R mutant WWOX blocks this apoptotic effect. WWOX activation by C1q destabilizes cell adhesion, causing formation of clustered microvilli, cell shrinkage, membrane blebbing, and death. Exogenous protein treatment, dominant-negative and point-mutant constructs, TIRF microscopy, apoptosis assays, immunostaining PloS one Medium 19484134
2013 WWOX physically interacts with SMAD3 via WW domain 1, as shown by co-immunoprecipitation and GST pull-down. WWOX expression dramatically decreases SMAD3 occupancy at ANGPTL4 and SERPINE1 promoters, quenches TGFβ-responsive reporter activation, and leads to redistribution of SMAD3 from the nuclear to the cytoplasmic compartment. Co-immunoprecipitation, GST pull-down, ChIP, transcriptional reporter assays, confocal microscopy for subcellular localization BMC cancer High 24330518
2014 WWOX physically interacts with HIF1alpha via its first WW domain and modulates HIF1alpha protein levels and transactivation function. WWOX-deficient cells exhibit increased HIF1alpha levels and activity, increased glucose uptake, enhanced glycolysis, and diminished mitochondrial respiration (Warburg-like effect). WWOX-deficient cells show increased GLUT1 levels in vivo. Co-immunoprecipitation, WW domain mutagenesis, glucose uptake assays, metabolic flux assays, Wwox knockout cells and mouse models Cell death and differentiation High 25012504
2003 WWOX normally resides in the Golgi apparatus; Golgi localization requires an intact SDR (short-chain dehydrogenase/reductase) domain. Aberrantly spliced WWOX isoforms lacking the SDR domain show abnormal intracellular localization to the nucleus and may act as dominant-negative inhibitors of full-length WWOX. The WW domain ligand is identified as the PPXY motif. Subcellular localization by immunofluorescence/fractionation, domain deletion constructs, analysis of aberrant splice forms Cytogenetic and genome research Medium 14526170
2007 WWOX interacts with AP-2gamma and prevents AP-2gamma from entering the nucleus to bind the ERBB2 promoter and activate ERBB2 transcription. Ectopic WWOX reduced ErbB2 protein expression in vitro. WWOX suppresses AP-2gamma/ErbB2-induced prostate cancer cell growth and PSA secretion, requiring functional androgen receptor. Co-immunoprecipitation, ChIP (AP-2gamma on ERBB2 promoter), Western blotting, cell growth and PSA assays Molecular cancer research : MCR Medium 17704139
2009 Sciatic nerve transection in rats induces rapid JNK1 activation and WOX1 upregulation in DRG neurons; phospho-WOX1 physically interacts with phospho-CREB and phospho-c-Jun in nuclei (immunoelectron microscopy and FRET). WOX1 blocks prosurvival CREB-, CRE-, and AP-1-mediated promoter activation in vitro but enhances NF-kappaB promoter activation via its WW domains. WOX1 directly activates NF-kappaB-regulated promoter. FRET analysis in vivo, immunoelectron microscopy, co-immunoprecipitation, promoter reporter assays, in vivo nerve transection model PloS one Medium 19918364
2011 WWOX (WOX1) physically interacts with MEK1 in lysosomes in Jurkat T cells. PMA induces dissociation of the WOX1/MEK1 complex, leading to MEK1 relocation to lipid rafts and WOX1 relocation to mitochondria for apoptosis. The MEK inhibitor U0126 inhibits PMA-induced dissociation and supports cell survival. Co-immunoprecipitation, subcellular fractionation, pharmacological inhibitors (U0126, PD98059), apoptosis assays in multiple leukemia cell lines Genes & cancer Medium 21901168
2013 WWOX physically interacts with mTOR, and this interaction potentiates MTX-induced mTOR phosphorylation and its downstream substrate p70 S6 kinase, leading to downregulation of autophagy proteins (Beclin-1, Atg12-Atg5, LC3-II) and suppression of autophagosome formation. WWOX knockdown in SCC-15 cells blocks MTX-induced mTOR signaling and autophagy inhibition, causing chemotherapy resistance. Co-immunoprecipitation, Western blotting for autophagy markers, siRNA knockdown, apoptosis assays, autophagosome imaging Cell death & disease Medium 24008736
2016 WWOX interacts with BRCA1 and contributes to DNA double-strand break (DSB) repair pathway choice. WWOX-deficient cells exhibit enhanced homology-directed repair (HDR) and decreased non-homologous end-joining (NHEJ). WWOX expression suppresses DSB repair at the end-resection step of HDR. Silencing RAD51 (critical for HDR) resensitizes WWOX-deficient cells to radiation. Co-immunoprecipitation (Wwox-Brca1), immunofluorescence of DNA damage repair foci, HDR/NHEJ reporter assays, RAD51 siRNA epistasis, xenograft radiation resistance model Oncogene High 27869163
2016 WWOX modulates the ATR-mediated DNA single-strand break (SSB) checkpoint. WWOX accumulates in the nucleus after SSBs. WWOX is ubiquitinated at lysine 274 by the E3 ubiquitin ligase ITCH following SSBs. WWOX interacts with ATM, and ATM inhibition reduces ATR checkpoint activation, indicating WWOX modulates ATR signaling in an ATM-dependent manner. WWOX deficiency is associated with reduced ATR checkpoint activation and increased chromosomal breaks. Nuclear fractionation after SSB induction, ubiquitination assay with ITCH, co-immunoprecipitation (WWOX-ATM), pharmacological ATM inhibition, chromosomal break analysis Oncotarget Medium 26675548
2007 Zfra (a 31-amino-acid zinc finger-like protein) binds WWOX (WOX1) and sequesters it in the cytoplasm, counteracting the apoptotic functions of Tyr33-phosphorylated WOX1 and Ser46-phosphorylated p53. Alteration of Ser8 in Zfra abolishes its regulation of WOX1 and p53. Interactions confirmed by GST pull-down, Co-IP, and yeast two-hybrid. GST pull-down, co-immunoprecipitation, yeast two-hybrid, subcellular localization assays, apoptosis assays BMC molecular biology Medium 17567906
2017 Hyaluronan (HA) activates the Hyal-2/WWOX/Smad4 signaling complex: WWOX acts as a bridge binding both Hyal-2 and Smad4 (by yeast two-hybrid). High molecular weight HA stimulates rapid formation of endogenous Hyal-2/WWOX/Smad4 complex and nuclear relocation. Real-time tri-molecular FRET analysis confirms HA-induced signaling: Smad4→WWOX→p53 and Smad4→Hyal-2→WWOX. Overexpression of the complex causes bubbling cell death in WWOX-expressing cells; WWOX-deficient cells fail to translocate Smad2/3/4 to the nucleus. Yeast two-hybrid domain analysis, co-immunoprecipitation, tri-molecular FRET in live cells, nuclear fractionation, WWOX-deficient cell comparison, apoptosis assays Oncotarget High 27845895
2018 WWOX interacts with JAK2 to inhibit JAK2 and STAT3 phosphorylation in breast cancer cells. WWOX overexpression suppresses STAT3 activation, inhibits STAT3 binding to the IL-6 promoter, and represses IL-6 cytokine expression, thereby suppressing proliferation and metastasis of triple-negative breast cancer cells. Co-immunoprecipitation (WWOX-JAK2), STAT3 phosphorylation assays, ChIP (STAT3 at IL-6 promoter), cell proliferation and invasion assays, WWOX overexpression/knockdown Nature communications Medium 30154439
2017 WWOX directly interacts with c-Jun in human alveolar epithelial cells; its absence results in increased nuclear translocation of c-Jun and increased c-Jun- and IL-8-dependent neutrophil chemotaxis. WWOX loss in mouse lungs causes neutrophil influx, vascular leak, and inflammatory cytokine production. JNK inhibition abrogates the neutrophil influx caused by WWOX knockdown. Co-immunoprecipitation (WWOX-c-Jun), siRNA knockdown in vitro, in vivo WWOX knockdown in mice, JNK pharmacological inhibition, neutrophil chemotaxis assays American journal of physiology. Lung cellular and molecular physiology Medium 28283473
2019 WWOX is a negative regulator of c-MYC; WWOX loss leads to c-MYC activation, which regulates miR-146a expression, which in turn regulates fibronectin levels, contributing to EMT in TNBC. Anti-miR-146a rescues the WWOX antimetastatic phenotype; overexpression of MYC in WWOX-expressing cells overrides WWOX effects on miR-146a and fibronectin. WWOX overexpression/depletion, miRNA expression analysis, miR-146a inhibitor rescue, MYC overexpression epistasis, fibronectin Western blotting, invasion/metastasis assays Cancer research Medium 30622118
2019 WWOX physically interacts with AMPK (AMP-activated protein kinase) in skeletal muscle cells. WWOX somatic loss in skeletal muscle (WwoxΔSKM mice) results in impaired AMPK activation and significant HIF1alpha accumulation, associated with reduced mitochondrial quantity and activity, lower glucose oxidation, glucose intolerance, and insulin resistance. Co-immunoprecipitation (WWOX-AMPK), conditional knockout mouse model, metabolic phenotyping (glucose tolerance test, insulin tolerance test), mitochondrial assays Molecular metabolism Medium 30755385
2020 WWOX neuronal deletion produces brain hyperexcitability, intractable epilepsy, reduced maturation of oligodendrocytes, reduced myelinated axons, and impaired axonal conductivity in mice. A significant decrease in transcript levels of myelination genes is observed. These phenotypes are recapitulated in human brain organoids with WWOX deletion, establishing a neuronal-specific role for WWOX in myelination and brain excitability. Neuron-specific conditional Wwox knockout mice, transcriptomic analysis, oligodendrocyte maturation assays, electrophysiology (transcranial motor evoked potentials), human brain organoids with WWOX deletion Brain : a journal of neurology High 33914858
2020 Wwox gene ablation in mice causes a significantly increased activation of GSK3beta in cerebral cortex, hippocampus, and cerebellum, leading to spontaneous epilepsy. Inhibition of GSK3beta by lithium ion significantly abolishes PTZ-induced seizures in Wwox-/- mice, placing GSK3beta activation downstream of Wwox loss as a mechanism for epilepsy. Wwox knockout mice, GSK3beta phosphorylation assays, lithium treatment (pharmacological epistasis), seizure susceptibility assays Acta neuropathologica communications Medium 32000863
2016 Wwox deletion in osteoblast progenitors (but not mature osteoblasts) causes severe inhibition of osteogenesis accompanied by p53 upregulation. Deletion of p53 in Wwox-null preosteoblasts (Wwox;p53Δosx1 double KO) rescues the osteogenic defect and results in accelerated development of osteosarcomas, establishing a WWOX-p53 epistatic network in bone formation. Conditional knockout mice (Wwox and p53 in osteoblast progenitors vs mature osteoblasts), genetic rescue (p53 deletion), histology, gene expression analysis Cancer research High 27550453
2011 Bmi1 (polycomb group protein) suppresses WWOX expression in small-cell lung cancer cells, as demonstrated by chromatin immunoprecipitation showing Bmi1 occupancy at the WWOX locus. Bmi1 reduction by shRNA increases WWOX expression and induces apoptosis in SCLC cells. Chromatin immunoprecipitation (Bmi1 at WWOX locus), quantitative RT-PCR, shRNA knockdown of Bmi1, apoptosis assays Cancer science Medium 21276135
2014 In liver-specific Wwox knockout (WwoxΔHep) mice, ApoA-I and Abca1 levels are decreased. Total Wwox-/- mice show marked reductions in serum HDL cholesterol. Female WwoxΔHep mice display increased plasma triglycerides and altered lipid metabolic pathways, with significant reduction of ApoA-I and Lpl, and upregulation of Fas, Angptl4, and Lipg, suggesting WWOX modulates HDL cholesterol and lipid metabolism via multiple pathways including the ApoA-I/ABCA1 pathway and fatty acid biosynthesis. Liver-specific and total Wwox knockout mouse models, lipoprotein profiling, microarray gene expression analysis, Western blotting Circulation. Cardiovascular genetics Medium 24871327
2022 WWOX physically interacts with SMAD3 and BMP2 (components of TGF-beta signaling pathway) in pancreatic cells. In the absence of WWOX, TGFbeta/BMP signaling is enhanced, leading to increased macrophage infiltration and enhanced cancer stemness. Combined conditional deletion of Wwox with KRasG12D activation in mice accelerates formation of pancreatic precursor lesions and carcinoma. Co-immunoprecipitation (WWOX-SMAD3 and WWOX-BMP2), conditional knockout/KRas activation mouse model, macrophage infiltration assays, stemness assays, WWOX overexpression in PDX models Cell death & disease Medium 36572673
2015 WWOX (in Drosophila melanogaster ortholog) modulates cellular outgrowths caused by genetic deficiencies in mitochondrial respiratory complex components. This modulation requires the enzyme active site (SDR domain) of WWOX. Defective respiratory complex-induced outgrowths are mediated by reactive oxygen species, dependent on the Akt pathway, and sensitive to autophagy and HIF levels. WWOX reduction diminishes ability to respond to metabolic perturbation, implying its role in regulating balance between oxidative phosphorylation and glycolysis. In vivo Drosophila genetic interaction screen, enzyme active-site mutant analysis, ROS assays, epistasis with Akt pathway components Genes, chromosomes & cancer Medium 26390919
2018 WWOX physically interacts with Tau via its C-terminal SDR domain and interacts with Tau-phosphorylating enzymes ERK, JNK, and GSK-3beta, thereby limiting their activity and supporting neuronal survival. Loss of WWOX in neuroblastoma cells results in aggregation of TRAPPC6ADelta, TIAF1, amyloid beta, and Tau in sequential manner. 17beta-estradiol binds WWOX at an NSYK motif in the C-terminal SDR domain. Co-immunoprecipitation, siRNA knockdown with aggregation assays, protein binding domain analysis Frontiers in neuroscience Low 30158849
2008 WWOX (WOX1) is rapidly upregulated and phosphorylated at Tyr33 in neurons injured by MPP+ (dopaminergic neurotoxin) in rat brains. WWOX is present in condensed nuclei and damaged mitochondria of degenerative neurons. WWOX physically interacts with JNK1 in brain extracts; MPP+ rapidly increases WOX1/JNK1 binding followed by dissociation (required for WOX1 apoptotic function). A Tyr33-phosphorylated WWOX peptide (11 aa) blocks MPP+-induced neuronal death in rat brains, while non-phospho-WOX1 peptide has no effect. In vivo rat MPP+ model, immunohistochemistry, immunoelectron microscopy, co-immunoprecipitation from brain extracts, dominant-negative transfection, synthetic phospho-peptide injection The European journal of neuroscience Medium 18371080

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proceedings of the National Academy of Sciences of the United States of America 209 15070730
2004 Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor. Cancer research 142 15548692
2009 WWOX: its genomics, partners, and functions. Journal of cellular biochemistry 118 19708029
2003 JNK1 physically interacts with WW domain-containing oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis. The Journal of biological chemistry 116 12514174
2005 WWOX gene restoration prevents lung cancer growth in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America 115 16223882
2004 Loss of WWOX expression in gastric carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 112 15131042
2005 WOX1 is essential for tumor necrosis factor-, UV light-, staurosporine-, and p53-mediated cell death, and its tyrosine 33-phosphorylated form binds and stabilizes serine 46-phosphorylated p53. The Journal of biological chemistry 109 16219768
2007 WWOX in biological control and tumorigenesis. Journal of cellular physiology 108 17458891
2018 Loss of Wwox drives metastasis in triple-negative breast cancer by JAK2/STAT3 axis. Nature communications 94 30154439
2009 Complement C1q activates tumor suppressor WWOX to induce apoptosis in prostate cancer cells. PloS one 94 19484134
2006 A role for the WWOX gene in prostate cancer. Cancer research 93 16818616
2010 WWOX gene and gene product: tumor suppression through specific protein interactions. Future oncology (London, England) 90 20146584
2009 Inhibition of the Wnt/beta-catenin pathway by the WWOX tumor suppressor protein. Oncogene 89 19465938
2014 WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies. Biochimica et biophysica acta 84 24932569
2005 17beta-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo. Oncogene 83 15580310
2014 Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation. Cell death and differentiation 78 25012504
2009 Transforming growth factor beta1 signaling via interaction with cell surface Hyal-2 and recruitment of WWOX/WOX1. The Journal of biological chemistry 74 19366691
2003 WWOX, the common chromosomal fragile site, FRA16D, cancer gene. Cytogenetic and genome research 73 14526170
2005 Roles of FHIT and WWOX fragile genes in cancer. Cancer letters 69 16225988
2009 WWOX, the tumour suppressor gene affected in multiple cancers. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 65 19609013
2003 Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses. Biochemical pharmacology 65 14555208
2003 Expression of FRA16D/WWOX and FRA3B/FHIT genes in hematopoietic malignancies. Molecular cancer research : MCR 62 14638866
2005 WOX1 is essential for UVB irradiation-induced apoptosis and down-regulated via translational blockade in UVB-induced cutaneous squamous cell carcinoma in vivo. Clinical cancer research : an official journal of the American Association for Cancer Research 60 16115915
2007 WWOX expression in different histologic types and subtypes of non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 57 17289881
2015 Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells. The Journal of biological chemistry 52 26499798
2006 PKA-mediated protein phosphorylation regulates ezrin-WWOX interaction. Biochemical and biophysical research communications 51 16438931
2004 Expression of WW domain-containing oxidoreductase WOX1 in the developing murine nervous system. Neuroscience 51 15026124
2002 A potential role of p53 and WOX1 in mitochondrial apoptosis (review). International journal of molecular medicine 51 11744990
2009 Dramatic co-activation of WWOX/WOX1 with CREB and NF-kappaB in delayed loss of small dorsal root ganglion neurons upon sciatic nerve transection in rats. PloS one 48 19918364
2022 Exosomal miR-625-3p secreted by cancer-associated fibroblasts in colorectal cancer promotes EMT and chemotherapeutic resistance by blocking the CELF2/WWOX pathway. Pharmacological research 44 36336217
2020 WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders. International journal of molecular sciences 44 33255508
2014 WWOX: a fragile tumor suppressor. Experimental biology and medicine (Maywood, N.J.) 44 25538133
2016 Wwox-Brca1 interaction: role in DNA repair pathway choice. Oncogene 43 27869163
2011 Role of the WWOX tumor suppressor gene in bone homeostasis and the pathogenesis of osteosarcoma. American journal of cancer research 43 21731849
2013 WWOX suppresses autophagy for inducing apoptosis in methotrexate-treated human squamous cell carcinoma. Cell death & disease 42 24008736
2020 Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice. Acta neuropathologica communications 41 32000863
2016 WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma. Cancer research 40 27550453
2014 The WWOX gene modulates high-density lipoprotein and lipid metabolism. Circulation. Cardiovascular genetics 40 24871327
2013 The cancer gene WWOX behaves as an inhibitor of SMAD3 transcriptional activity via direct binding. BMC cancer 39 24330518
2007 Zfra affects TNF-mediated cell death by interacting with death domain protein TRADD and negatively regulates the activation of NF-kappaB, JNK1, p53 and WOX1 during stress response. BMC molecular biology 39 17567906
2018 WWOX Phosphorylation, Signaling, and Role in Neurodegeneration. Frontiers in neuroscience 38 30158849
2014 The common fragile site FRA16D gene product WWOX: roles in tumor suppression and genomic stability. Cellular and molecular life sciences : CMLS 37 25245215
2016 WWOX modulates the ATR-mediated DNA damage checkpoint response. Oncotarget 36 26675548
2010 Molecular analysis of WWOX expression correlation with proliferation and apoptosis in glioblastoma multiforme. Journal of neuro-oncology 35 20535528
2008 MPP+-induced neuronal death in rats involves tyrosine 33 phosphorylation of WW domain-containing oxidoreductase WOX1. The European journal of neuroscience 33 18371080
2020 Pleiotropic tumor suppressor functions of WWOX antagonize metastasis. Signal transduction and targeted therapy 32 32300104
2019 Circular RNA CircMTO1 Inhibits Proliferation of Glioblastoma Cells via miR-92/WWOX Signaling Pathway. Medical science monitor : international medical journal of experimental and clinical research 32 31456594
2011 Identification of an In Vivo MEK/WOX1 Complex as a Master Switch for Apoptosis in T Cell Leukemia. Genes & cancer 32 21901168
2021 Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects. Brain : a journal of neurology 31 33914858
2019 WWOX Inhibits Metastasis of Triple-Negative Breast Cancer Cells via Modulation of miRNAs. Cancer research 31 30622118
2013 Characterization of WWOX inactivation in murine mammary gland development. Journal of cellular physiology 31 23254778
2020 WUSCHEL-related homeobox1 (WOX1) regulates vein patterning and leaf size in Cucumis sativus. Horticulture research 30 33328463
2018 WWOX Tumor Suppressor Gene in Breast Cancer, a Historical Perspective and Future Directions. Frontiers in oncology 30 30211123
2017 Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed. Oncotarget 30 27845895
2018 WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia. Cell death & disease 29 29724996
2018 WWOX, the FRA16D gene: A target of and a contributor to genomic instability. Genes, chromosomes & cancer 29 30350478
2011 Bmi1 regulates cell fate via tumor suppressor WWOX repression in small-cell lung cancer cells. Cancer science 29 21276135
2009 Association between CpG island methylation of the WWOX gene and its expression in breast cancers. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 29 19188760
2015 WWOX, the chromosomal fragile site FRA16D spanning gene: its role in metabolism and contribution to cancer. Experimental biology and medicine (Maywood, N.J.) 28 25595186
2020 Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development. Frontiers in neuroscience 27 32581702
2016 HYAL-2-WWOX-SMAD4 Signaling in Cell Death and Anticancer Response. Frontiers in cell and developmental biology 27 27999774
2015 Alteration of WWOX in human cancer: a clinical view. Experimental biology and medicine (Maywood, N.J.) 27 25681467
2018 Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer. Cell death & disease 26 30082886
2018 Modeling WWOX Loss of Function in vivo: What Have We Learned? Frontiers in oncology 26 30370248
2013 WWOX induces apoptosis and inhibits proliferation in cervical cancer and cell lines. International journal of molecular medicine 26 23525362
2010 WWOX gene may contribute to progression of non-small-cell lung cancer (NSCLC). Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 26 20480411
2008 WWOX tumor suppressor gene. Histology and histopathology 26 18437686
2007 Wwox suppresses prostate cancer cell growth through modulation of ErbB2-mediated androgen receptor signaling. Molecular cancer research : MCR 26 17704139
2019 WWOX somatic ablation in skeletal muscles alters glucose metabolism. Molecular metabolism 25 30755385
2015 Regulation of cell signaling and apoptosis by tumor suppressor WWOX. Experimental biology and medicine (Maywood, N.J.) 25 25595191
2013 The role of the WWOX gene in leukemia and its mechanisms of action. Oncology reports 25 23525648
2021 Molecular Functions of WWOX Potentially Involved in Cancer Development. Cells 23 33946771
2018 Phosphorylation/de-phosphorylation in specific sites of tumor suppressor WWOX and control of distinct biological events. Experimental biology and medicine (Maywood, N.J.) 23 29310447
2010 WWOX gene is associated with HDL cholesterol and triglyceride levels. BMC medical genetics 23 20942981
2023 WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk. Epilepsia 22 36779245
2014 Diverse effect of WWOX overexpression in HT29 and SW480 colon cancer cell lines. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 22 24938873
2021 Neurological Disorders Associated with WWOX Germline Mutations-A Comprehensive Overview. Cells 21 33916893
2015 Tumor suppressor WWOX moderates the mitochondrial respiratory complex. Genes, chromosomes & cancer 21 26390919
2011 Decreased expression of WWOX in the development of esophageal squamous cell carcinoma. Molecular carcinogenesis 21 22213016
2020 The WWOX gene in brain development and pathology. Experimental biology and medicine (Maywood, N.J.) 20 32389029
2019 Decoding the link between WWOX and p53 in aggressive breast cancer. Cell cycle (Georgetown, Tex.) 20 31075076
2014 The fragile site WWOX gene and the developing brain. Experimental biology and medicine (Maywood, N.J.) 20 25416187
2013 Role of WWOX and NF-κB in lung cancer progression. Translational respiratory medicine 20 27234396
2012 Overexpression of WW domain-containing oxidoreductase WOX1 preferentially induces apoptosis in human glioblastoma cells harboring mutant p53. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20 22898080
2020 MiR-214 Mediates Cell Proliferation and Apoptosis of Nasopharyngeal Carcinoma Through Targeting Both WWOX and PTEN. Cancer biotherapy & radiopharmaceuticals 19 32101017
2015 Ectopic WWOX Expression Inhibits Growth of 5637 Bladder Cancer Cell In Vitro and In Vivo. Cell biochemistry and biophysics 19 27352332
2014 Common Chromosomal Fragile Site Gene WWOX in Metabolic Disorders and Tumors. International journal of biological sciences 19 24520212
2006 WWOX, a chromosomal fragile site gene and its role in cancer. Advances in experimental medicine and biology 19 17163164
2021 WWOX and Its Binding Proteins in Neurodegeneration. Cells 18 34359949
2017 Functions and Epigenetic Regulation of Wwox in Bone Metastasis from Breast Carcinoma: Comparison with Primary Tumors. International journal of molecular sciences 18 28045433
2017 Loss of lung WWOX expression causes neutrophilic inflammation. American journal of physiology. Lung cellular and molecular physiology 18 28283473
2015 Modulation of Sonic hedgehog signaling and WW domain containing oxidoreductase WOX1 expression enhances radiosensitivity of human glioblastoma cells. Experimental biology and medicine (Maywood, N.J.) 18 25595187
2012 Aberrant expression of WWOX protein in epithelial ovarian cancer: a clinicopathologic and immunohistochemical study. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 18 22317867
2022 Loss of tumor suppressor WWOX accelerates pancreatic cancer development through promotion of TGFβ/BMP2 signaling. Cell death & disease 17 36572673
2017 Decreased WWOX expression promotes angiogenesis in osteosarcoma. Oncotarget 17 28977834
2015 Epigenetic and genetic alterations affect the WWOX gene in head and neck squamous cell carcinoma. PloS one 17 25612104
2022 The WWOX/HIF1A Axis Downregulation Alters Glucose Metabolism and Predispose to Metabolic Disorders. International journal of molecular sciences 16 35328751
2020 WWOX promotes apoptosis and inhibits autophagy in paclitaxel‑treated ovarian carcinoma cells. Molecular medicine reports 16 33300063
2015 WWOX, large common fragile site genes, and cancer. Experimental biology and medicine (Maywood, N.J.) 16 25595185
2021 Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes. EMBO molecular medicine 15 34747138

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