Affinage

TOX

Thymocyte selection-associated high mobility group box protein TOX · UniProt O94900

Length
526 aa
Mass
57.5 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 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

TOX is a sequence-independent HMG-box DNA-binding protein that acts as a transcriptional and epigenetic programmer of T cell fate, operating downstream of TCR-coupled calcineurin/NFAT signaling in both thymic development and chronic antigen settings (PMID:11850626, PMID:15078895, PMID:31207603). During thymic positive selection, calcineurin-dependent TOX induction is sufficient to drive CD8 lineage entry through CD8 demethylation and Runx3 upregulation, and is genetically required for CD4 lineage commitment, including regulatory T, NKT, NK, and lymphoid tissue-inducer cell development, where it establishes a broad CD4 gene program beyond ThPOK (PMID:15078895, PMID:18195075, PMID:20818394, PMID:22021617). In chronic infection and tumors, persistent TCR stimulation and NFAT (with TOX2 and reciprocal NR4A regulation, and independent of AP-1) induce TOX, which becomes calcineurin-independent in a feed-forward loop and is both necessary and sufficient to install the exhausted CD8+ T cell program—establishing chromatin accessibility at inhibitory receptor loci (PD-1, TIM-3, TIGIT, CD244), suppressing effector transcription factors (Id2, TCF-1, Notch), and promoting persistence of progenitor-like exhausted cells (PMID:29768177, PMID:31207603, PMID:31207604, PMID:31152140, PMID:31209400). TOX functions as a durable epigenetic barrier: its continuous expression in committed exhausted cells maintains chromatin and transcriptional state, and inducible ablation restores fate flexibility toward effector-like differentiation while triggering apoptotic loss (PMID:31207605, PMID:40053604). This exhaustion program is tuned by an antagonistic Stat5–TOX circuit and is sustained by LAG-3 signaling and the CXCR4–JAK2/STAT3 axis (PMID:38091951, PMID:39121847, PMID:39317187). Beyond immune programming, TOX has cell-type-specific roles: it binds KU70/80 to suppress NHEJ and drive genomic instability in T-ALL, and is required for neural stem cell proliferation via calcineurin/NFAT-regulated targets including Sox2 and Tbr2 (PMID:25527292, PMID:28974511).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2002 Medium

    Established that TOX is an HMG-box factor whose expression is coupled to (pre-)TCR signaling in immature thymocytes and influences lineage commitment, placing it at the developmental decision point.

    Evidence Gene-chip expression profiling and transgenic overexpression with thymocyte flow phenotyping in mouse

    PMID:11850626

    Open questions at the time
    • DNA-binding mode and direct targets not defined
    • Mechanism of altered TCR sensitivity unresolved
  2. 2003 Medium

    Classified TOX as defining a subfamily of sequence-independent HMG-box proteins, framing its likely architectural/chromatin mode of action.

    Evidence Sequence alignment and phylogenetic analysis across species

    PMID:12697058

    Open questions at the time
    • No biochemical validation of DNA-binding mode in this work
    • Functional distinction from paralogs not tested
  3. 2004 High

    Showed TOX is sufficient to drive CD8 lineage selection via CD8 demethylation and Runx3 induction and is induced by calcineurin, linking a signaling pathway to nuclear/epigenetic changes during selection.

    Evidence Transgenic overexpression, calcineurin inhibitor treatment, DNA methylation and Runx3 analysis in mouse thymocytes

    PMID:15078895

    Open questions at the time
    • Direct chromatin targets not mapped
    • How TOX HMG-box specifies the demethylation event unknown
  4. 2008 High

    Defined TOX as genetically required for CD4 lineage development, distinguishing an obligatory developmental requirement from the gain-of-function phenotype.

    Evidence TOX-knockout mouse with flow cytometry and T cell functional assays

    PMID:18195075

    Open questions at the time
    • Molecular targets driving the transitional-stage block not identified
    • CD8 lineage independence mechanism unexplained
  5. 2010 High

    Extended the TOX requirement to NK and LTi cell development and lymphoid organogenesis, broadening its role across innate and adaptive lymphoid lineages.

    Evidence TOX-knockout mouse bone marrow analysis, flow cytometry, organogenesis assays; human HSC NK differentiation with knockdown/overexpression

    PMID:20818394 PMID:21126536

    Open questions at the time
    • Transcriptional targets in NK/LTi cells not defined
    • Relationship to T-bet regulation mechanistically incomplete
  6. 2011 High

    Demonstrated TOX controls a CD4 gene program (Id2, Foxo1, Thpok) beyond ThPOK induction, establishing it as a broad lineage programmer rather than a single-target activator.

    Evidence ThPOK overexpression rescue in TOX-KO mice with gene expression profiling

    PMID:22021617

    Open questions at the time
    • Direct vs indirect target relationships not resolved
    • Chromatin-level mechanism not assessed
  7. 2014 High

    Identified a non-immune role: TOX is a calcineurin/NFAT-regulated chromatin-binding factor controlling neural stem cell proliferation via direct targets, and provided the first direct genome-wide binding data.

    Evidence DamID-seq, calcineurin/NFAT manipulation, in utero electroporation in mouse cortex

    PMID:25527292

    Open questions at the time
    • Binding-motif specificity for a sequence-independent HMG protein unresolved
    • Generalizability of neural targets to lymphocytes unknown
  8. 2014 High

    Established TOX as a pro-survival factor in CTCL acting through suppression of CDK inhibitors, defining a cancer-relevant downstream axis.

    Evidence Stable shRNA knockdown in CTCL lines, xenografts, and CDKN1B/CDKN1C rescue

    PMID:25548321

    Open questions at the time
    • Whether TOX directly regulates CDKN1B/CDKN1C loci not shown
    • Connection to HMG-box DNA binding not tested
  9. 2017 High

    Revealed a chromatin-protective oncogenic mechanism: TOX binds KU70/80 to block NHEJ recruitment, driving genomic instability in T-ALL — a protein-protein rather than transcriptional activity.

    Evidence Zebrafish transgenic screen, Co-IP/pulldown, DNA repair assays, xenografts, shRNA

    PMID:28974511

    Open questions at the time
    • Structural basis of TOX-KU70/80 interaction not defined
    • Whether this occurs in non-malignant T cells unknown
  10. 2018 High

    Showed TOX represses effector-promoting transcription factors (Id2, TCF-1, Notch) and inhibitory CD244 in CTLs, foreshadowing its role as a dysfunction programmer.

    Evidence Mouse CNS autoimmunity model, conditional KO/overexpression, TF reporter assays, IL-12 treatment

    PMID:29768177

    Open questions at the time
    • Direct binding to repressed TF loci not mapped
    • Cytokine (IL-12) regulatory mechanism on TOX not resolved
  11. 2019 High

    Defined TOX as the necessary and sufficient master programmer of CD8+ T cell exhaustion, induced by NFAT in a calcineurin-independent feed-forward loop and acting with TOX2/NR4A to set exhaustion chromatin.

    Evidence Knockout, domain-deletion and overexpression mice, double-KO CAR T cells, ATAC-seq/RNA-seq, chronic LCMV and tumor models

    PMID:31152140 PMID:31207603 PMID:31207604 PMID:31207605 PMID:31209400

    Open questions at the time
    • How a sequence-independent HMG protein selects exhaustion loci unresolved
    • Cofactors mediating chromatin opening not fully identified
  12. 2019 Medium

    Identified upstream inducers and a non-transcriptional PD-1 trafficking role, broadening how TOX sustains the exhausted phenotype.

    Evidence VEGF-A treatment and tumor models; Co-IP/confocal of cytoplasmic TOX-PD1 with HCC knockdown/overexpression; BCL6-dependent TFH induction with miRNA-cluster models

    PMID:31173813 PMID:31704735 PMID:31844658

    Open questions at the time
    • Cytoplasmic TOX-PD1 recycling mechanism needs independent replication
    • Relative contribution of transcriptional vs trafficking roles unclear
  13. 2021 Medium

    Showed TOX expression can be driven by inflammatory cytokines independent of TCR and does not strictly equate to exhaustion, refining its interpretation as an activation-state marker.

    Evidence Ex vivo cytokine treatment of human and mouse memory CD8+ T cells with KO controls

    PMID:34032638

    Open questions at the time
    • Whether cytokine-induced TOX is functionally equivalent to TCR-induced TOX unknown
    • Single-lab finding
  14. 2021 Medium

    Established a tumor-suppressive role in colorectal cancer via inhibition of mTOR signaling, contrasting with its oncogenic roles in T-cell malignancies.

    Evidence CRC cell line knockdown, rapamycin rescue, in vivo tumor/metastasis models, GSEA

    PMID:33897695

    Open questions at the time
    • Direct vs indirect link between TOX and mTOR not established
    • Mechanism distinguishing tumor-suppressor vs oncogene contexts unknown
  15. 2023 High

    Defined a reciprocal Stat5–TOX antagonism that can rewire exhausted cells toward effector/NK-like states, identifying a therapeutically tractable counter-circuit.

    Evidence Constitutive Stat5a mice, orthogonal IL-2:IL2Rβ system, ATAC-seq/RNA-seq in LCMV and tumor models

    PMID:38091951

    Open questions at the time
    • Molecular basis of mutual antagonism not defined
    • Whether Stat5 directly represses TOX locus unknown
  16. 2024 High

    Identified upstream signals sustaining TOX — LAG-3 and the CXCR4-JAK2/STAT3 axis — connecting surface receptor inputs to TOX-programmed exhaustion.

    Evidence LAG-3 and CXCR4 genetic/pharmacological loss-of-function, single-cell multi-omics, cytotoxicity assays, human validation

    PMID:39121847 PMID:39317187

    Open questions at the time
    • Direct molecular link from these pathways to TOX transcription not mapped
    • Hierarchy among upstream inputs unresolved
  17. 2025 High

    Distinguished maintenance from initiation: continuous TOX is required to hold the exhausted chromatin/transcriptional state, and its removal restores fate flexibility, establishing TOX as a durable epigenetic barrier.

    Evidence Inducible Cre deletion in committed Tex cells with ATAC-seq/RNA-seq in LCMV and tumor models

    PMID:40053604

    Open questions at the time
    • Chromatin-maintaining cofactors not identified
    • Why TOX loss triggers apoptosis in committed cells mechanistically unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a sequence-independent HMG-box protein achieves locus-selective chromatin programming, and what cofactor machinery it recruits to open and maintain exhaustion loci, remains the central unresolved question.
  • No defined chromatin-remodeling/cofactor complex for TOX
  • No structural model of TOX bound to target chromatin
  • Mechanistic basis of context-dependent oncogene vs tumor-suppressor behavior unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-168256 Immune System 5 R-HSA-4839726 Chromatin organization 4 R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 1
Partners
KU70KU80PDCD1

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 TOX encodes an HMG-box DNA-binding protein whose expression is upregulated by both pre-TCR and TCR activation of immature thymocytes but not by TCR activation of mature naïve T cells. Transgenic overexpression of TOX expands CD8+ and reduces CD4+ single positive thymocyte subpopulations by perturbing lineage commitment through reduced sensitivity to TCR-mediated signaling. Gene chip expression profiling, transgenic mouse overexpression, thymocyte phenotyping by flow cytometry Nature immunology Medium 11850626
2003 TOX defines a novel subfamily of HMG-box proteins based on sequence alignment; the TOX HMG-box domain is most similar to sequence-independent DNA-binding HMG proteins. Three additional human/murine paralogs share the TOX HMG-box domain. The TOX subtype of HMG-box domain first appeared in invertebrates and was duplicated in early vertebrates. Sequence alignment, phylogenetic analysis, tissue expression profiling BMC genomics Medium 12697058
2004 TOX expression is sufficient to induce CD8 gene demethylation and changes in coreceptor gene expression associated with β-selection, and sufficient to initiate positive selection to the CD8 lineage in the absence of MHC-TCR interactions. TOX-mediated positive selection is associated with upregulation of Runx3, implicating CD4 silencing. TOX upregulation in double-positive thymocytes is calcineurin-dependent, linking this signaling pathway to nuclear changes during positive selection. Transgenic mouse overexpression, calcineurin inhibitor treatment, DNA methylation analysis, flow cytometry, Runx3 expression analysis The Journal of experimental medicine High 15078895
2008 Loss of TOX causes a severe block at the CD4(lo)CD8(lo) transitional stage of positive selection in the thymus, resulting in failure of CD4 lineage T cells (including regulatory T cells and NKT cells) to develop, while functional CD8+ T cells still develop in TOX-deficient mice. TOX-knockout mouse, flow cytometry, T cell functional assays The Journal of experimental medicine High 18195075
2010 TOX is required for the development of both NK cells and lymphoid tissue-inducer (LTi) cells. TOX is upregulated in immature NK cells in bone marrow, and its absence leads to loss of mature NK cells and failure of lymphoid tissue organogenesis. TOX-knockout mouse, bone marrow analysis, flow cytometry, lymphoid tissue organogenesis assay Nature immunology High 20818394
2011 TOX is required to establish the full CD4+ T cell lineage gene program independently of its influence on ThPOK expression. Enforced ThPOK can restore some CD4 development in TOX-deficient mice, but rescued CD4 cells are defective in expression of Id2, Foxo1, and endogenous Thpok, indicating TOX controls a broader CD4 gene program beyond ThPOK induction. TOX-knockout mouse, retroviral ThPOK overexpression rescue, gene expression profiling, flow cytometry Journal of immunology High 22021617
2014 TOX in neural stem cells is regulated by calcineurin/NFAT signaling. DamID-seq chromatin binding analysis identified TOX binding motif and downstream transcriptional targets including Sox2, Tbr2, and Prox1. TOX promotes neural stem cell proliferation and neurite outgrowth of newborn neurons during corticogenesis. DamID combined with deep sequencing, calcineurin/NFAT pathway manipulation, in utero electroporation, gene expression analysis The EMBO journal High 25527292
2014 TOX knockdown in cutaneous T-cell lymphoma (CTCL) cells promotes apoptosis and reduces cell cycle progression, reduces viability and colony-forming ability in vitro, and reduces tumor growth in vivo. TOX knockdown increases CDK inhibitors CDKN1B and CDKN1C, and blocking CDKN1B/CDKN1C reverses the growth inhibition caused by TOX knockdown. Stable shRNA knockdown in CTCL cell lines, xenograft mouse model, cell cycle analysis, CDKN1B/CDKN1C rescue experiments Blood High 25548321
2017 TOX acts as a collaborating oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL) by binding directly to KU70/80 and suppressing recruitment of this complex to DNA breaks, thereby inhibiting non-homologous end joining (NHEJ) repair and elevating genomic instability. Zebrafish transgenic screen, co-immunoprecipitation/pulldown of TOX-KU70/80 complex, DNA repair assays, xenograft mouse model, shRNA knockdown Cancer discovery High 28974511
2018 TOX expression in CD8+ CTLs during LCMV infection is essential for their encephalitogenic properties in a CNS autoimmunity model. TOX represses activity of transcription factors Id2, TCF-1, and Notch that drive CTL differentiation, and reduces expression of inhibitory checkpoint receptor CD244 on CTL surfaces, leading to increased CTL-mediated CNS damage. TOX expression is inhibited by IL-12 during Listeria infection. Mouse CNS inflammation model, TOX conditional knockout/overexpression, transcription factor activity reporter assays, flow cytometry, IL-12 treatment Immunity High 29768177
2019 TOX is induced by calcineurin and NFAT2 signaling downstream of persistent TCR stimulation, and operates in a feed-forward loop in which it becomes calcineurin-independent and is sustained in exhausted T cells. TOX is required for the transcriptional and epigenetic programming of exhausted CD8+ T cells; in the absence of TOX, exhausted T cells do not form. TOX-knockout mouse, calcineurin inhibitor treatment, ATAC-seq chromatin accessibility, RNA-seq, chronic LCMV infection model Nature High 31207603
2019 TOX expression is driven by chronic TCR stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induces a transcriptional program associated with T cell exhaustion. Deletion of Tox in tumor-specific T cells abrogates the exhaustion program including upregulation of inhibitory receptors (PD-1, TIM-3, CD244, TIGIT), while chromatin at these loci remains largely inaccessible. Tox-deleted tumor-specific T cells fail to persist in tumors despite retaining non-exhausted immunophenotype. Tox conditional knockout in tumor models, lentiviral overexpression in effector T cells, ATAC-seq, RNA-seq, tumor infiltrating lymphocyte analysis Nature High 31207604
2019 TOX is required for normal progression of T cell dysfunction and maintenance of exhausted T cells during chronic LCMV infection. Removal of TOX's DNA-binding domain reduces PD-1 mRNA and protein expression, augments cytokine production, and results in more polyfunctional T cells. However, TOX-deleted T cells ultimately undergo massive decline, notably among TCF-1+ self-renewing T cells, linking TOX-mediated suppression of effector function to protection against immunopathology. TOX DNA-binding domain deletion mutant mice, chronic LCMV infection model, flow cytometry, intracellular cytokine staining, PD-1 mRNA/protein analysis Nature High 31207605
2019 TOX and TOX2 are induced by NFAT downstream of calcium/calcineurin signaling even in the absence of AP-1 (FOS-JUN). TOX and TOX2 double knockout CAR T cells show increased cytokine expression, decreased inhibitory receptor expression, and increased chromatin accessibility at NFκB and bZIP motif-containing regions. TOX and NR4A transcription factors positively regulate each other, forming a cooperative network driving CD8+ T cell exhaustion. NFAT activation assays, TOX/TOX2 double-knockout CAR T cells, ATAC-seq, RNA-seq, tumor growth assays, NR4A genetic interaction analysis Proceedings of the National Academy of Sciences of the United States of America High 31152140
2019 TOX promotes CD8+ T cell exhaustion in hepatocellular carcinoma by binding to PD-1 in the cytoplasm, facilitating endocytic recycling of PD-1 and thereby maintaining abundant PD-1 expression at the cell surface. TOX downregulation reduces surface PD-1, inhibits tumor growth, and improves anti-PD-1 response. Co-immunoprecipitation of TOX-PD1 complex, laser confocal detection, flow cytometry, TOX overexpression/knockdown in mouse HCC model and patient-derived xenograft, transcriptome sequencing Journal of hepatology Medium 31173813
2019 TOX is highly expressed in progenitor-like CD8+ T cells in chronic infection and is required for programming of progenitor-like CD8+ T cells. TOX-containing gene coexpression module has higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. TOX promotes persistence of antiviral CD8+ T cells. Single-cell RNA-seq, ATAC-seq/histone mark profiling, TOX-knockout mouse, chronic LCMV infection model Nature immunology High 31209400
2019 VEGF-A induces TOX expression in T cells to drive exhaustion-specific transcriptional programs. Combined blockade of PD-1 and VEGF-A restores antitumor T cell function in microsatellite stable colorectal cancer. In vitro T cell treatment with VEGF-A, ex vivo and in vivo mouse tumor models, TOX expression analysis by flow cytometry Science immunology Medium 31704735
2019 TOX is a central transcription regulator in follicular helper T (TFH) cell development. TOX is upregulated in TFH cells in a BCL6-dependent manner, and in turn TOX promotes expression of multiple molecules critical for TFH cell differentiation and function. MiR-23~27~24 clusters regulate TFH cells partly by targeting TOX. miRNA cluster knockout and overexpression mouse models, flow cytometry, gene expression analysis, BCL6 knockdown Science advances Medium 31844658
2021 Inflammatory cytokines (independent of TCR signaling) are sufficient to increase TOX expression in both human and mouse memory CD8+ T cells. TOX expression reflects T cell activation state and is not exclusively linked to exhaustion. TOX is not necessary for cytokine-driven expression of PD-1. Ex vivo cytokine treatment of sorted human and mouse memory CD8+ T cells, TOX-knockout analysis, flow cytometry, intracellular cytokine staining JCI insight Medium 34032638
2023 Stat5a and Tox form a reciprocally antagonistic circuit in exhausted CD8+ T cells. Constitutive Stat5a activity antagonizes Tox expression and rewires CD8+ T cells from exhaustion toward durable effector/NK-like states with superior anti-tumor potential. Temporal induction of Stat5 via an orthogonal IL-2:IL2Rβ pair fosters intermediate exhausted T cell accumulation and partially reprograms the epigenetic landscape of exhaustion. Constitutive Stat5a transgenic mice, orthogonal IL-2:IL2Rβ pair system, ATAC-seq, RNA-seq, chronic LCMV infection and tumor models, flow cytometry Immunity High 38091951
2024 LAG-3 sustains TOX expression in exhausted CD8+ T cells during chronic infection. Loss of LAG-3 reduces TOX levels and exhausted T cell durability. LAG-3 drives a circuit generating a CD94/NKG2+ subset of exhausted T cells with enhanced cytotoxicity mediated by recognition of stress ligand Qa-1b (in mice) and HLA-E (in humans). LAG-3 knockout mouse, chronic LCMV infection, flow cytometry, TOX protein expression analysis, cytotoxicity assays, human sample validation Cell High 39121847
2025 Continuous TOX expression in committed exhausted CD8+ T cells is required to maintain chromatin accessibility and transcriptional patterns defining the exhausted state. Induced TOX ablation in committed exhausted T cells causes apoptotic loss, reduced inhibitory receptor expression, and decreased terminal differentiation. Removal of TOX from established exhausted T cells endows greater fate flexibility to differentiate toward effector-like T cells, indicating TOX acts as a durable epigenetic barrier reinforcing the exhausted developmental fate. Inducible Cre-mediated TOX deletion in committed Tex cells, ATAC-seq, RNA-seq, chronic LCMV infection and tumor models, flow cytometry, apoptosis assays Science immunology High 40053604
2010 TOX regulates NK cell differentiation from human hematopoietic stem cells in vitro. TOX knockdown decreases NK cell populations (identified by NK surface markers and receptors), while TOX overexpression enhances NK cell differentiation with effector function. TOX influences expression of T-bet during NK cell development. Lentiviral shRNA knockdown and overexpression of TOX in human HSC-derived NK cell differentiation cultures, flow cytometry, functional NK assays Immunology letters Medium 21126536
2016 GATA3 knockdown in CTCL cells decreases TOX mRNA and protein expression, indicating that GATA3 regulates TOX expression in CTCL. siRNA knockdown of GATA3 in CTCL cell lines, RT-PCR and Western blot for TOX expression Journal of the European Academy of Dermatology and Venereology Low 27345620
2019 In Sézary syndrome, TOX knockdown using siRNA rescues RUNX3 expression and reduces cell viability, demonstrating that TOX suppresses RUNX3 (a tumor suppressor) as part of the TOX-RUNX3 pathway. TOX upregulation correlates inversely with RUNX3, and GATA3 upregulation is part of the same pathway. siRNA knockdown of TOX in SS cells, qRT-PCR for RUNX3/GATA3, cell viability assay Oncotarget Low 31139323
2021 TOX suppresses mTOR signaling in colorectal cancer cells to inhibit cell proliferation, migration, invasion, and epithelial-mesenchymal transition, and promotes apoptosis. Rapamycin (mTOR inhibitor) partially rescues these phenotypes in TOX-knockdown cells, confirming mTOR as a downstream target. TOX knockdown in CRC cell lines, mTOR pathway analysis, rapamycin rescue experiment, in vivo tumor and metastasis models, GSEA Frontiers in immunology Medium 33897695
2024 CXCR4 orchestrates the TOX-programmed exhausted phenotype of CD8+ T cells via the JAK2/STAT3 pathway. CXCR4 blockade mitigates the exhausted phenotype by regulating JAK2-STAT3 signaling, and Cxcr4-deficient CD8+ T cells epigenetically mitigate the transition from functional to exhausted T cell phenotypes. CXCR4 pharmacological blockade and genetic deletion, single-cell RNA/TCR/ATAC-seq, JAK2/STAT3 pathway analysis, in vivo tumor models Cell genomics Medium 39317187

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 1282 31207603
2019 TOX is a critical regulator of tumour-specific T cell differentiation. Nature 894 31207604
2019 TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 729 31207605
2019 TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proceedings of the National Academy of Sciences of the United States of America 634 31152140
2019 Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nature immunology 440 31209400
1990 The in vivo micronucleus assay in mammalian bone marrow and peripheral blood. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 384 2195332
1981 Sister-chromatid exchanges: a report of the GENE-TOX program. Mutation research 381 6173747
1981 Mutagenesis by chemical agents in V79 chinese hamster cells: a review and analysis of the literature. A report of the Gene-Tox Program. Mutation research 286 7035931
1983 An evaluation of the mouse sperm morphology test and other sperm tests in nonhuman mammals. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 285 6835246
2019 TOX promotes the exhaustion of antitumor CD8+ T cells by preventing PD1 degradation in hepatocellular carcinoma. Journal of hepatology 245 31173813
1981 Mammalian in vivo and in vitro cytogenetic assays: a report of the U.S. EPA's gene-tox program. Mutation research 243 7035930
1990 Molecular cloning and DNA sequence analysis of a diphtheria tox iron-dependent regulatory element (dtxR) from Corynebacterium diphtheriae. Proceedings of the National Academy of Sciences of the United States of America 208 2116013
1983 Cell transformation by chemical agents--a review and analysis of the literature. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 204 6339891
2010 Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue-inducer cell and NK cell lineages. Nature immunology 199 20818394
2019 VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers. Science immunology 193 31704735
2020 TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Science immunology 188 32620560
2008 Development of all CD4 T lineages requires nuclear factor TOX. The Journal of experimental medicine 185 18195075
1994 Tagged mutations at the Tox1 locus of Cochliobolus heterostrophus by restriction enzyme-mediated integration. Proceedings of the National Academy of Sciences of the United States of America 160 7809094
2002 TOX: an HMG box protein implicated in the regulation of thymocyte selection. Nature immunology 151 11850626
2000 Biology and molecular epidemiology of diphtheria toxin and the tox gene. The Journal of infectious diseases 143 10657208
1983 The sex-linked recessive lethal test for mutagenesis in Drosophila melanogaster. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 135 6413857
2020 Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer. Genome medicine 132 32111241
2003 TOX defines a conserved subfamily of HMG-box proteins. BMC genomics 109 12697058
1983 Unscheduled DNA synthesis tests. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 109 6358881
2018 A glass-based, continuously zonated and vascularized human liver acinus microphysiological system (vLAMPS) designed for experimental modeling of diseases and ADME/TOX. Lab on a chip 108 30063238
1987 Chemical carcinogens. A review and analysis of the literature of selected chemicals and the establishment of the Gene-Tox Carcinogen Data Base. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 104 3540654
1984 Testing of chemicals for genetic activity with Saccharomyces cerevisiae: a report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 104 6374444
2023 Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure. Immunity 100 38091951
2011 The many roles of TOX in the immune system. Current opinion in immunology 92 22209117
2024 LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity. Cell 86 39121847
2004 Tox-Prot, the toxin protein annotation program of the Swiss-Prot protein knowledgebase. Toxicon : official journal of the International Society on Toxinology 82 15683867
2020 TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection. Gut 69 33097558
1992 Binding of the metalloregulatory protein DtxR to the diphtheria tox operator requires a divalent heavy metal ion and protects the palindromic sequence from DNase I digestion. The Journal of biological chemistry 69 1400485
1974 Synthesis of diphtheria tox-gene products in Escherichia coli extracts. Proceedings of the National Academy of Sciences of the United States of America 65 4204202
2018 Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells. Immunity 64 29768177
1981 An evaluation of tests using DNA repair-deficient bacteria for predicting genotoxicity and carcinogenicity. A report of the U.S. EPA's Gene-TOX Program. Mutation research 64 6799817
2014 Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma. Blood 63 25548321
2004 TOX provides a link between calcineurin activation and CD8 lineage commitment. The Journal of experimental medicine 62 15078895
2011 TOX is required for development of the CD4 T cell lineage gene program. Journal of immunology (Baltimore, Md. : 1950) 59 22021617
1981 The GENE-TOX program: genetic activity evaluation. Journal of chemical information and computer sciences 58 7240352
2018 Organs-on-a-chip: Current applications and consideration points for in vitro ADME-Tox studies. Drug metabolism and pharmacokinetics 57 29398302
2017 TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia. Cancer discovery 57 28974511
2021 TOX as a potential target for immunotherapy in lymphocytic malignancies. Biomarker research 56 33743809
2016 Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Archives of toxicology 48 27188386
2010 TOX regulates the differentiation of human natural killer cells from hematopoietic stem cells in vitro. Immunology letters 48 21126536
2018 TOX expression decreases with progression of colorectal cancers and is associated with CD4 T-cell density and Fusobacterium nucleatum infection. Human pathology 47 29792893
2022 Tox-GAN: An Artificial Intelligence Approach Alternative to Animal Studies-A Case Study With Toxicogenomics. Toxicological sciences : an official journal of the Society of Toxicology 45 34971401
2021 GGL-Tox: Geometric Graph Learning for Toxicity Prediction. Journal of chemical information and modeling 45 33719422
2014 ABC transporters in multi-drug resistance and ADME-Tox of small molecule tyrosine kinase inhibitors. Pharmaceutical research 45 24842659
1983 Detection and expression of DNA homologous to the tox gene in nontoxinogenic isolates of Corynebacterium diphtheriae. Infection and immunity 45 6311753
1982 An evaluation of the host-mediated assay and body fluid analysis. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 45 7050697
1976 Characterization and genetic mapping of nontoxinogenic (tox) mutants of corynebacteriophage beta. Journal of virology 45 820871
2014 Tox: a multifunctional transcription factor and novel regulator of mammalian corticogenesis. The EMBO journal 44 25527292
1984 Chromosome mutation tests for mutagenesis in Drosophila melanogaster. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 44 6431279
2014 TOX expression in different subtypes of cutaneous lymphoma. Archives of dermatological research 41 25216799
2021 Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8+ T cells. JCI insight 39 34032638
2021 Increased lactate in AML blasts upregulates TOX expression, leading to exhaustion of CD8+ cytolytic T cells. American journal of cancer research 38 34873490
1983 Integration of corynebacteriophages beta tox+, omega tox+, and gamma tox- into two attachment sites on the Corynebacterium diphtheriae chromosome. Journal of bacteriology 38 6402488
1976 Orientation of the tox gene in the prophage of corynebacteriophage beta. Journal of virology 37 820874
1988 The genetic toxicology of Gene-Tox non-carcinogens. Mutation research 35 3285185
2018 TRPs in Tox: Involvement of Transient Receptor Potential-Channels in Chemical-Induced Organ Toxicity-A Structured Review. Cells 34 30087301
2018 Tox_(R)CNN: Deep learning-based nuclei profiling tool for drug toxicity screening. PLoS computational biology 34 30500821
2007 Biological fingerprinting analysis of traditional Chinese medicines with targeting ADME/Tox property for screening of bioactive compounds by chromatographic and MS methods. Mini reviews in medicinal chemistry 33 17266641
1984 Mutation tests in Neurospora crassa. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation research 33 6231482
2022 CD4+ T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2: Characterizing CD4+ T cells in Hodgkin lymphoma. Oncoimmunology 31 35111387
2015 TOX acts an oncological role in mycosis fungoides. PloS one 31 25811617
2005 Systems-ADME/Tox: resources and network approaches. Journal of pharmacological and toxicological methods 31 16054403
2021 Antigen-driven PD-1+ TOX+ BHLHE40+ and PD-1+ TOX+ EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ. European journal of immunology 30 33296081
2019 MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation. Science advances 30 31844658
2016 TOX expression and role in CTCL. Journal of the European Academy of Dermatology and Venereology : JEADV 29 27345620
2024 CXCR4 orchestrates the TOX-programmed exhausted phenotype of CD8+ T cells via JAK2/STAT3 pathway. Cell genomics 28 39317187
1982 DNA repair assays as tests for environmental mutagens. A report of the U.S. EPA Gene-Tox Program. Mutation research 28 7050696
2025 Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate. Science immunology 27 40053604
2019 LncRNA MALAT1 Suppression Protects Endothelium against oxLDL-Induced Inflammation via Inhibiting Expression of MiR-181b Target Gene TOX. Oxidative medicine and cellular longevity 27 31949884
2015 TOX gene: a novel target for human cancer gene therapy. American journal of cancer research 27 26885442
2019 Dysregulation of the TOX-RUNX3 pathway in cutaneous T-cell lymphoma. Oncotarget 26 31139323
2016 TOX expression in cutaneous T-cell lymphomas: an adjunctive diagnostic marker that is not tumour specific and not restricted to the CD4(+)  CD8(-) phenotype. The British journal of dermatology 25 26931394
2023 TOX regulates T lymphocytes differentiation and its function in tumor. Frontiers in immunology 24 36969216
2022 Role of in vitro two-dimensional (2D) and three-dimensional (3D) cell culture systems for ADME-Tox screening in drug discovery and development: a comprehensive review. ADMET & DMPK 24 36778905
2023 QSAR, ADME-Tox, molecular docking and molecular dynamics simulations of novel selective glycine transporter type 1 inhibitors with memory enhancing properties. Heliyon 23 36865465
2021 Hibiscus sabdariffa anthocyanins are potential modulators of estrogen receptor alpha activity with favourable toxicology: a computational analysis using molecular docking, ADME/Tox prediction, 2D/3D QSAR and molecular dynamics simulation. Journal of biomolecular structure & dynamics 23 34854367
2020 Expression pattern, regulation, and clinical significance of TOX in breast cancer. Cancer immunology, immunotherapy : CII 23 32757053
2019 Corynebacterium diphtheriae: Diphtheria Toxin, the tox Operon, and Its Regulation by Fe2+ Activation of apo-DtxR. Microbiology spectrum 23 31267892
1997 Analysis of heterogeneity of Corynebacterium diphtheriae toxin gene, tox, and its regulatory element, dtxR, by direct sequencing. Research in microbiology 23 9404504
2006 Comparative analysis of argK-tox clusters and their flanking regions in phaseolotoxin-producing Pseudomonas syringae pathovars. Journal of molecular evolution 22 16927007
1985 DNA relationships among some tox-bearing corynebacteriophages. Infection and immunity 22 2993167
2021 NLRP3 Regulates IL-4 Expression in TOX+ CD4+ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression. Frontiers in immunology 21 34220814
2022 Increased TOX expression associates with exhausted T cells in patients with multiple myeloma. Experimental hematology & oncology 20 35246241
2017 TOX and ADIPOQ Gene Polymorphisms Are Associated with Antipsychotic-Induced Weight Gain in Han Chinese. Scientific reports 20 28327672
2021 Increased TOX expression concurrent with PD-1, Tim-3, and CD244 expression in T cells from patients with acute myeloid leukemia. Cytometry. Part B, Clinical cytometry 19 34913594
2021 TOX Acts as a Tumor Suppressor by Inhibiting mTOR Signaling in Colorectal Cancer. Frontiers in immunology 18 33897695
2003 A novel PEPP homeobox gene, TOX, is highly glutamic acid rich and specifically expressed in murine testis and ovary. Biology of reproduction 18 14627546
2021 Increased TOX expression concurrent with PD-1, Tim-3, and CD244 in T cells from patients with non-Hodgkin lymphoma. Asia-Pacific journal of clinical oncology 17 33608984
2015 Polymorphisms in TOX and NCOA2 genes and their associations with reproductive traits in cattle. Reproduction, fertility, and development 17 25482955
2009 Biochemical evidence for ToxR and ToxJ binding to the tox operons of Burkholderia glumae and mutational analysis of ToxR. Journal of bacteriology 17 19465657
2019 Chemical structure modifications and nano-technology applications for improving ADME-Tox properties, a review. Archiv der Pharmazie 16 30609117
2015 Differential expression of TOX by skin-infiltrating T cells in Sézary syndrome and erythrodermic dermatitis. Journal of cutaneous pathology 16 25777533
2009 Spodoptera frugiperda X-tox protein, an immune related defensin rosary, has lost the function of ancestral defensins. PloS one 16 19710910
2020 High-mobility group box (TOX) antibody a useful tool for the identification of B and T cell subpopulations. PloS one 15 32106280
2015 TOX and CDKN2A/B Gene Polymorphisms Are Associated with Type 2 Diabetes in Han Chinese. Scientific reports 14 26139146

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