{"gene":"ETV7","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2000,"finding":"ETV7 (Tel-2) binds to Ets-binding sites in promoters of multiple genes and acts as a transcriptional repressor; only the isoform containing both the Pointed domain and the DNA-binding domain confers strong transcriptional repression. ETV7 specifically represses the retinoic acid receptor alpha and BMP-6 genes.","method":"Reporter assays, DNA-binding assays, analysis of alternatively spliced isoforms with domain deletions","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA-binding and reporter assays with domain-deletion isoforms in a single lab; two orthogonal methods","pmids":["11108721"],"is_preprint":false},{"year":2013,"finding":"Zebrafish ETV7 (etv7) transcriptionally regulates the lanosterol synthase (lss) gene in the cholesterol synthesis pathway; morpholino knockdown of etv7 causes loss of hemoglobin-containing red blood cells, a phenotype rescued by exogenous cholesterol, establishing ETV7's role in erythropoiesis through the cholesterol synthesis pathway.","method":"Morpholino knockdown in zebrafish, cholesterol rescue experiment, gene expression analysis","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype and biochemical rescue in zebrafish ortholog, single lab","pmids":["24357328"],"is_preprint":false},{"year":2018,"finding":"ETV7 interacts with mTOR in the cytoplasm and assembles a third mTOR complex, mTORC3, which is independent of ETV7's transcriptional activity, lacks canonical mTORC1/2 components (Raptor, Rictor, mLST8), and exhibits bimodal mTORC1/2 kinase activity. Tumor cell lines that lose mTORC3 expression become rapamycin-sensitive. Transgenic ETV7 expression in a rhabdomyosarcoma mouse model accelerates tumor onset.","method":"Co-immunoprecipitation, mass spectrometry complex characterization, rapamycin sensitivity assays, transgenic mouse model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function in multiple cell lines, in vivo mouse model, multiple orthogonal methods in a single rigorous study","pmids":["30258985"],"is_preprint":false},{"year":2018,"finding":"ETV7 directly binds to the DNAJC15 promoter and transcriptionally represses DNAJC15 expression, leading to increased doxorubicin efflux via nuclear pumps and doxorubicin resistance in breast cancer cells. DNA methylation is implicated as a co-factor in ETV7-mediated DNAJC15 repression.","method":"ChIP/promoter binding assays, gene knockdown/overexpression, doxorubicin sensitivity assays, efflux measurement","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter-binding identified, functional rescue experiments, single lab with multiple methods","pmids":["30025229"],"is_preprint":false},{"year":2018,"finding":"ETV7 transgenic mice crossed with tumor-prone Pten-conditional-knockout mice show greatly accelerated leukemogenesis, and ETV7 expression enhances colony-forming and self-renewal activities of primary myeloid Pten−/− cells, establishing ETV7 as a cooperating oncogene with Pten loss.","method":"Transgenic mouse generation, genetic cross with PtenΔ/Δ mice, colony-forming assays","journal":"Transgenic research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo mouse model plus ex vivo colony assay, single lab","pmids":["30478527"],"is_preprint":false},{"year":2021,"finding":"ETV7 overexpression in breast cancer cells represses a signature of interferon-responsive genes, promoting cancer stem-like cell plasticity (increased CD44+/CD24low population and mammosphere formation). Treatment with IFN-β partially reverses the stem-cell phenotype caused by ETV7, placing IFN-responsive gene repression downstream of ETV7 in this pathway.","method":"Stable overexpression, transcriptome profiling, mammosphere/CD44/CD24 flow cytometry, IFN-β rescue experiment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome profiling combined with functional phenotypic rescue, single lab","pmids":["34315857"],"is_preprint":false},{"year":2023,"finding":"ETV7 directly binds to intron I of the TNFRSF1A gene (encoding TNFR1) and down-regulates its expression by recruiting repressive chromatin remodelers and competing with STAT3 for binding to the TNFRSF1A locus, thereby reducing NF-κB signaling activation in breast cancer cells.","method":"ChIP assays, gene overexpression/knockdown, NF-κB signaling assays, competitive binding analysis with STAT3","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromatin binding shown by ChIP, functional downstream signaling measured, competitive binding mechanistic model, single lab","pmids":["37041130"],"is_preprint":false},{"year":2024,"finding":"ETV7 binds to two separate sequences within the mTOR kinase domain: the FRB sequence interacts with the ETV7 Pointed (PNT) domain, and the LBE sequence interacts with the ETV7 ETS domain. Forced expression of the mTOR FRB domain in mTORC3-expressing, rapamycin-resistant cells out-competes mTOR for ETV7 binding and renders these cells rapamycin-sensitive in vivo.","method":"Domain mapping by co-immunoprecipitation with deletion/mutation constructs, competitive displacement assay in vivo","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-level binding mapping with multiple constructs and functional competition assay, single lab","pmids":["39337528"],"is_preprint":false},{"year":2024,"finding":"ETV7 activates transcription of IFIT3 in colorectal cancer cells (as shown by luciferase reporter, RT-qPCR, and western blot), and IFIT3 knockdown reverses ETV7-driven cell proliferation and migration, establishing an ETV7→IFIT3 transcriptional activation axis in colorectal cancer.","method":"Luciferase reporter assay, RT-qPCR, western blotting, siRNA knockdown, rescue experiments","journal":"Functional & integrative genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter activity assay plus epistatic rescue, single lab, multiple orthogonal methods","pmids":["38200280"],"is_preprint":false},{"year":2025,"finding":"ETV7 binds to specific memory and exhaustion gene loci in CD8+ T cells, transcriptionally skewing the transcriptional program from memory toward terminal exhaustion. ETV7 introduction drives T cell differentiation from memory to terminal exhaustion; ETV7 depletion enhances antitumor efficacy of CD8+ T cells and CAR-T cells in solid tumor models.","method":"scRNA-seq, scATAC-seq, ETV7 overexpression/knockout in mouse CD8+ T cells, in vivo tumor models, ChIP-like chromatin accessibility analysis","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genomic and functional methods, gain- and loss-of-function in vivo, mechanistic chromatin binding established","pmids":["39805956"],"is_preprint":false},{"year":2026,"finding":"ETV7 transcriptionally upregulates CXCL1, leading to increased neutrophil recruitment and enhanced neutrophil extracellular trap (NET) formation in the tumor microenvironment, which promotes colorectal cancer aggressiveness and 5-FU resistance. Pharmacological inhibition of CXCL1 or degradation of NETs attenuates ETV7-driven malignant phenotypes.","method":"ETV7 overexpression/knockdown, CXCL1 promoter/transcription assays, neutrophil recruitment assays, NET detection, pharmacological inhibition in vitro and in vivo","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional upregulation of CXCL1 by ETV7 shown with functional epistasis and pharmacological rescue, single lab","pmids":["41917269"],"is_preprint":false}],"current_model":"ETV7 is a dual-function ETS transcription factor that, in addition to its canonical role as a transcriptional repressor/activator (repressing DNAJC15, TNFRSF1A, and interferon-responsive genes; activating IFIT3 and CXCL1) via direct promoter/chromatin binding, assembles a rapamycin-resistant third mTOR complex (mTORC3) in the cytoplasm by binding the mTOR kinase domain through its PNT and ETS domains, conferring bimodal mTORC1/2 kinase activity and promoting cancer cell proliferation and drug resistance; additionally, ETV7 acts as a central transcriptional node in CD8+ T cells that drives terminal exhaustion by reshaping chromatin accessibility at memory and exhaustion gene loci."},"narrative":{"mechanistic_narrative":"ETV7 is an ETS-family transcription factor that functions predominantly as a sequence-specific transcriptional repressor, with full repressive activity requiring an isoform containing both its Pointed (PNT) and DNA-binding ETS domains [PMID:11108721]. Through direct promoter and chromatin binding it represses a defined set of targets — DNAJC15, where repression drives doxorubicin efflux and chemoresistance [PMID:30025229]; the TNFR1-encoding TNFRSF1A gene, where it recruits repressive chromatin remodelers and competes with STAT3 to dampen NF-κB signaling [PMID:37041130]; and a signature of interferon-responsive genes, the loss of which promotes cancer stem-like plasticity reversible by IFN-β [PMID:34315857]. In other contexts ETV7 acts as a transcriptional activator, driving IFIT3 in colorectal cancer to promote proliferation and migration [PMID:38200280] and upregulating CXCL1 to recruit neutrophils and enhance NET formation, fueling tumor aggressiveness and 5-FU resistance [PMID:41917269]. Beyond transcription, ETV7 has a separable cytoplasmic function: it binds the mTOR kinase domain to assemble a rapamycin-resistant complex, mTORC3, that lacks Raptor, Rictor, and mLST8 yet possesses bimodal mTORC1/2 kinase activity and accelerates tumorigenesis [PMID:30258985], with the PNT domain engaging the mTOR FRB sequence and the ETS domain engaging the LBE sequence [PMID:39337528]. In CD8+ T cells, ETV7 binds memory and exhaustion gene loci to reshape chromatin accessibility and drive terminal exhaustion, and its depletion improves antitumor T-cell and CAR-T efficacy [PMID:39805956]. Across these settings ETV7 behaves as a pro-tumorigenic factor, cooperating with Pten loss to accelerate leukemogenesis [PMID:30478527].","teleology":[{"year":2000,"claim":"Established the foundational molecular identity of ETV7 as a sequence-specific ETS transcriptional repressor and defined the domain requirement for that activity.","evidence":"Reporter and DNA-binding assays with domain-deletion isoforms, repressing RARA and BMP-6","pmids":["11108721"],"confidence":"Medium","gaps":["Did not identify endogenous physiological targets beyond reporter contexts","Repressive cofactors not defined","No in vivo or disease context"]},{"year":2013,"claim":"Connected ETV7 transcriptional output to a concrete developmental phenotype, showing it regulates cholesterol synthesis to enable erythropoiesis.","evidence":"Morpholino knockdown in zebrafish with cholesterol rescue and lss expression analysis","pmids":["24357328"],"confidence":"Medium","gaps":["Ortholog-based, mammalian relevance not tested","Direct binding to lss promoter not shown","Mechanism linking ETV7 to lss regulation unresolved"]},{"year":2018,"claim":"Revealed a transcription-independent function: ETV7 nucleates a novel cytoplasmic mTOR complex (mTORC3) that confers rapamycin resistance and drives tumorigenesis.","evidence":"Reciprocal Co-IP, mass spectrometry, rapamycin sensitivity assays, and transgenic rhabdomyosarcoma mouse model","pmids":["30258985"],"confidence":"High","gaps":["Structural basis of complex assembly not resolved","Substrate specificity of mTORC3 not fully mapped","How ETV7 confers bimodal kinase activity unclear"]},{"year":2018,"claim":"Linked ETV7 repression of DNAJC15 to a clinically relevant chemoresistance mechanism via drug efflux.","evidence":"ChIP/promoter binding, knockdown/overexpression, doxorubicin sensitivity and efflux assays in breast cancer cells","pmids":["30025229"],"confidence":"Medium","gaps":["Role of DNA methylation as cofactor not mechanistically dissected","Repressive chromatin machinery not identified","Single lab, single tumor type"]},{"year":2018,"claim":"Demonstrated ETV7 acts as a cooperating oncogene, accelerating leukemogenesis in the context of Pten loss.","evidence":"Transgenic mouse genetic cross with Pten-conditional knockout and colony-forming/self-renewal assays","pmids":["30478527"],"confidence":"Medium","gaps":["Whether the cooperation is transcriptional or mTORC3-dependent not separated","Direct target genes in this context unknown"]},{"year":2021,"claim":"Defined an ETV7-driven immune-evasion axis in which interferon-gene repression promotes cancer stem-like plasticity.","evidence":"Stable overexpression, transcriptome profiling, mammosphere/CD44/CD24 flow cytometry, and IFN-β rescue","pmids":["34315857"],"confidence":"Medium","gaps":["Direct ETV7 binding at the repressed IFN loci not all confirmed","Repressive cofactor identity unclear"]},{"year":2023,"claim":"Provided a mechanistic model for ETV7 repression: chromatin-remodeler recruitment and competition with STAT3 at TNFRSF1A to suppress NF-κB signaling.","evidence":"ChIP, overexpression/knockdown, NF-κB assays, and competitive binding analysis with STAT3 in breast cancer cells","pmids":["37041130"],"confidence":"Medium","gaps":["Specific chromatin remodelers not named","Generality of STAT3 competition across other loci untested"]},{"year":2024,"claim":"Mapped the molecular interface of ETV7-mTOR binding and showed it is therapeutically targetable by competitive displacement.","evidence":"Domain mapping by Co-IP with deletion/mutation constructs and in vivo FRB-domain competitive displacement assay","pmids":["39337528"],"confidence":"Medium","gaps":["No high-resolution structure of the ETV7-mTOR interface","Stoichiometry and other mTORC3 components remain incomplete"]},{"year":2024,"claim":"Extended ETV7 to a transcriptional-activator role, defining an ETV7→IFIT3 axis that promotes colorectal cancer proliferation and migration.","evidence":"Luciferase reporter, RT-qPCR, western blot, siRNA knockdown, and rescue in colorectal cancer cells","pmids":["38200280"],"confidence":"Medium","gaps":["What determines repressor vs activator behavior of ETV7 not resolved","Direct binding at the IFIT3 promoter requires further mapping"]},{"year":2025,"claim":"Identified ETV7 as a central chromatin node driving CD8+ T-cell terminal exhaustion, with therapeutic implications for T-cell and CAR-T therapy.","evidence":"scRNA-seq, scATAC-seq, gain/loss-of-function in mouse CD8+ T cells, and in vivo solid tumor models","pmids":["39805956"],"confidence":"High","gaps":["Direct vs indirect targets within exhaustion loci not fully separated","Cofactors reshaping chromatin accessibility unknown","Upstream signals inducing ETV7 in T cells unclear"]},{"year":2026,"claim":"Connected ETV7 transcriptional activation of CXCL1 to a tumor-microenvironment mechanism of neutrophil recruitment, NET formation, and chemoresistance.","evidence":"Overexpression/knockdown, CXCL1 transcription assays, neutrophil/NET assays, and pharmacological inhibition in vitro and in vivo","pmids":["41917269"],"confidence":"Medium","gaps":["Direct ETV7 occupancy at the CXCL1 promoter not fully established","Relationship to other ETV7 axes in colorectal cancer not integrated"]},{"year":null,"claim":"It remains unresolved what molecular switch dictates ETV7's choice between transcriptional repression, transcriptional activation, and cytoplasmic mTORC3 assembly within a given cell.","evidence":"No discovery in the corpus reconciles the determinants of ETV7's divergent functional modes","pmids":[],"confidence":"Medium","gaps":["No structural model of ETV7 in any complex","Cofactor partners distinguishing repressor from activator states unidentified","Crosstalk between mTORC3 activity and ETV7 transcriptional programs untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,5,6,8,9,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,6,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,7]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,6,8,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,6,9,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,4,8,10]}],"complexes":["mTORC3"],"partners":["MTOR","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y603","full_name":"Transcription factor ETV7","aliases":["ETS translocation variant 7","ETS-related protein Tel2","Tel-related Ets factor","Transcription factor Tel-2"],"length_aa":341,"mass_kda":39.0,"function":"Transcriptional repressor; binds to the DNA sequence 5'-CCGGAAGT-3'. Isoform A does not seem to have a repressor activity. Isoform C does not seem to have a repressor activity","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y603/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ETV7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ETV7","total_profiled":1310},"omim":[{"mim_id":"605255","title":"ETS VARIANT TRANSCRIPTION FACTOR 7; ETV7","url":"https://www.omim.org/entry/605255"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":15.0},{"tissue":"skin 1","ntpm":14.5}],"url":"https://www.proteinatlas.org/search/ETV7"},"hgnc":{"alias_symbol":["TEL2","TEL-2"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y603","domains":[{"cath_id":"1.10.150.50","chopping":"42-121","consensus_level":"high","plddt":82.4686,"start":42,"end":121},{"cath_id":"1.10.10.10","chopping":"227-309","consensus_level":"high","plddt":89.364,"start":227,"end":309}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y603","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y603-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y603-F1-predicted_aligned_error_v6.png","plddt_mean":64.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ETV7","jax_strain_url":"https://www.jax.org/strain/search?query=ETV7"},"sequence":{"accession":"Q9Y603","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y603.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y603/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y603"}},"corpus_meta":[{"pmid":"30258985","id":"PMC_30258985","title":"ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer.","date":"2018","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/30258985","citation_count":89,"is_preprint":false},{"pmid":"11108721","id":"PMC_11108721","title":"Tel-2 is a novel transcriptional repressor related to the Ets factor Tel/ETV-6.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11108721","citation_count":45,"is_preprint":false},{"pmid":"30025229","id":"PMC_30025229","title":"ETV7-Mediated DNAJC15 Repression Leads to Doxorubicin Resistance in Breast Cancer Cells.","date":"2018","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30025229","citation_count":32,"is_preprint":false},{"pmid":"33424867","id":"PMC_33424867","title":"Integrated Analysis of the ETS Family in Melanoma Reveals a Regulatory Role of ETV7 in the Immune Microenvironment.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33424867","citation_count":24,"is_preprint":false},{"pmid":"39805956","id":"PMC_39805956","title":"ETV7 limits the antiviral and antitumor efficacy of CD8+ T cells by diverting their fate toward exhaustion.","date":"2025","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39805956","citation_count":22,"is_preprint":false},{"pmid":"34315857","id":"PMC_34315857","title":"ETV7 regulates breast cancer stem-like cell features by repressing IFN-response genes.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34315857","citation_count":20,"is_preprint":false},{"pmid":"37041130","id":"PMC_37041130","title":"ETV7 reduces inflammatory responses in breast cancer cells by repressing the TNFR1/NF-κB axis.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37041130","citation_count":20,"is_preprint":false},{"pmid":"24357328","id":"PMC_24357328","title":"Zebrafish ETV7 regulates red blood cell development through the cholesterol synthesis pathway.","date":"2013","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/24357328","citation_count":16,"is_preprint":false},{"pmid":"30341925","id":"PMC_30341925","title":"The regulation of interferon type I pathway-related genes RSAD2 and ETV7 specifically indicates antibody-mediated rejection after kidney transplantation.","date":"2018","source":"Clinical transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/30341925","citation_count":12,"is_preprint":false},{"pmid":"38282047","id":"PMC_38282047","title":"Exosomal miR-361-3p promotes the viability of breast cancer cells by targeting ETV7 and BATF2 to upregulate the PAI-1/ERK pathway.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38282047","citation_count":9,"is_preprint":false},{"pmid":"38200280","id":"PMC_38200280","title":"ETV7 promotes colorectal cancer progression through upregulation of IFIT3.","date":"2024","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38200280","citation_count":5,"is_preprint":false},{"pmid":"30478527","id":"PMC_30478527","title":"Establishment of a transgenic mouse to model ETV7 expressing human tumors.","date":"2018","source":"Transgenic research","url":"https://pubmed.ncbi.nlm.nih.gov/30478527","citation_count":5,"is_preprint":false},{"pmid":"39337528","id":"PMC_39337528","title":"Assembly of mTORC3 Involves Binding of ETV7 to Two Separate Sequences in the mTOR Kinase Domain.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39337528","citation_count":5,"is_preprint":false},{"pmid":"1928758","id":"PMC_1928758","title":"Morphological analysis of the cellular interaction between thymocytes and a thymic stromal cell line (TEL-2).","date":"1991","source":"The Anatomical record","url":"https://pubmed.ncbi.nlm.nih.gov/1928758","citation_count":5,"is_preprint":false},{"pmid":"38791386","id":"PMC_38791386","title":"Mitigation of Breast Cancer Cells' Invasiveness via Down Regulation of ETV7, Hippo, and PI3K/mTOR Pathways by Vitamin D3 Gold-Nanoparticles.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38791386","citation_count":3,"is_preprint":false},{"pmid":"8742694","id":"PMC_8742694","title":"Morphological study of thymus stromal cells (TEL-2 cell) which play a role in the elimination of double positive immature thymocytes by phagocytosis.","date":"1996","source":"The Anatomical record","url":"https://pubmed.ncbi.nlm.nih.gov/8742694","citation_count":3,"is_preprint":false},{"pmid":"38865588","id":"PMC_38865588","title":"Curbing Breast Cancer by Altering V-ATPase Action on F-Actin, Heterochromatin, ETV7 and mTORC2 Signaling.","date":"2024","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38865588","citation_count":1,"is_preprint":false},{"pmid":"41917269","id":"PMC_41917269","title":"ETV7 promotes 5-FU resistance and malignant progression through CXCL1-induced NETs formation in colorectal cancer.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41917269","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11201,"output_tokens":2770,"usd":0.037576,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10156,"output_tokens":3782,"usd":0.072665,"stage2_stop_reason":"end_turn"},"total_usd":0.110241,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"ETV7 (Tel-2) binds to Ets-binding sites in promoters of multiple genes and acts as a transcriptional repressor; only the isoform containing both the Pointed domain and the DNA-binding domain confers strong transcriptional repression. ETV7 specifically represses the retinoic acid receptor alpha and BMP-6 genes.\",\n      \"method\": \"Reporter assays, DNA-binding assays, analysis of alternatively spliced isoforms with domain deletions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA-binding and reporter assays with domain-deletion isoforms in a single lab; two orthogonal methods\",\n      \"pmids\": [\"11108721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Zebrafish ETV7 (etv7) transcriptionally regulates the lanosterol synthase (lss) gene in the cholesterol synthesis pathway; morpholino knockdown of etv7 causes loss of hemoglobin-containing red blood cells, a phenotype rescued by exogenous cholesterol, establishing ETV7's role in erythropoiesis through the cholesterol synthesis pathway.\",\n      \"method\": \"Morpholino knockdown in zebrafish, cholesterol rescue experiment, gene expression analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype and biochemical rescue in zebrafish ortholog, single lab\",\n      \"pmids\": [\"24357328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ETV7 interacts with mTOR in the cytoplasm and assembles a third mTOR complex, mTORC3, which is independent of ETV7's transcriptional activity, lacks canonical mTORC1/2 components (Raptor, Rictor, mLST8), and exhibits bimodal mTORC1/2 kinase activity. Tumor cell lines that lose mTORC3 expression become rapamycin-sensitive. Transgenic ETV7 expression in a rhabdomyosarcoma mouse model accelerates tumor onset.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry complex characterization, rapamycin sensitivity assays, transgenic mouse model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function in multiple cell lines, in vivo mouse model, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"30258985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ETV7 directly binds to the DNAJC15 promoter and transcriptionally represses DNAJC15 expression, leading to increased doxorubicin efflux via nuclear pumps and doxorubicin resistance in breast cancer cells. DNA methylation is implicated as a co-factor in ETV7-mediated DNAJC15 repression.\",\n      \"method\": \"ChIP/promoter binding assays, gene knockdown/overexpression, doxorubicin sensitivity assays, efflux measurement\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter-binding identified, functional rescue experiments, single lab with multiple methods\",\n      \"pmids\": [\"30025229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ETV7 transgenic mice crossed with tumor-prone Pten-conditional-knockout mice show greatly accelerated leukemogenesis, and ETV7 expression enhances colony-forming and self-renewal activities of primary myeloid Pten−/− cells, establishing ETV7 as a cooperating oncogene with Pten loss.\",\n      \"method\": \"Transgenic mouse generation, genetic cross with PtenΔ/Δ mice, colony-forming assays\",\n      \"journal\": \"Transgenic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo mouse model plus ex vivo colony assay, single lab\",\n      \"pmids\": [\"30478527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ETV7 overexpression in breast cancer cells represses a signature of interferon-responsive genes, promoting cancer stem-like cell plasticity (increased CD44+/CD24low population and mammosphere formation). Treatment with IFN-β partially reverses the stem-cell phenotype caused by ETV7, placing IFN-responsive gene repression downstream of ETV7 in this pathway.\",\n      \"method\": \"Stable overexpression, transcriptome profiling, mammosphere/CD44/CD24 flow cytometry, IFN-β rescue experiment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome profiling combined with functional phenotypic rescue, single lab\",\n      \"pmids\": [\"34315857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ETV7 directly binds to intron I of the TNFRSF1A gene (encoding TNFR1) and down-regulates its expression by recruiting repressive chromatin remodelers and competing with STAT3 for binding to the TNFRSF1A locus, thereby reducing NF-κB signaling activation in breast cancer cells.\",\n      \"method\": \"ChIP assays, gene overexpression/knockdown, NF-κB signaling assays, competitive binding analysis with STAT3\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromatin binding shown by ChIP, functional downstream signaling measured, competitive binding mechanistic model, single lab\",\n      \"pmids\": [\"37041130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ETV7 binds to two separate sequences within the mTOR kinase domain: the FRB sequence interacts with the ETV7 Pointed (PNT) domain, and the LBE sequence interacts with the ETV7 ETS domain. Forced expression of the mTOR FRB domain in mTORC3-expressing, rapamycin-resistant cells out-competes mTOR for ETV7 binding and renders these cells rapamycin-sensitive in vivo.\",\n      \"method\": \"Domain mapping by co-immunoprecipitation with deletion/mutation constructs, competitive displacement assay in vivo\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-level binding mapping with multiple constructs and functional competition assay, single lab\",\n      \"pmids\": [\"39337528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ETV7 activates transcription of IFIT3 in colorectal cancer cells (as shown by luciferase reporter, RT-qPCR, and western blot), and IFIT3 knockdown reverses ETV7-driven cell proliferation and migration, establishing an ETV7→IFIT3 transcriptional activation axis in colorectal cancer.\",\n      \"method\": \"Luciferase reporter assay, RT-qPCR, western blotting, siRNA knockdown, rescue experiments\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter activity assay plus epistatic rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38200280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ETV7 binds to specific memory and exhaustion gene loci in CD8+ T cells, transcriptionally skewing the transcriptional program from memory toward terminal exhaustion. ETV7 introduction drives T cell differentiation from memory to terminal exhaustion; ETV7 depletion enhances antitumor efficacy of CD8+ T cells and CAR-T cells in solid tumor models.\",\n      \"method\": \"scRNA-seq, scATAC-seq, ETV7 overexpression/knockout in mouse CD8+ T cells, in vivo tumor models, ChIP-like chromatin accessibility analysis\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genomic and functional methods, gain- and loss-of-function in vivo, mechanistic chromatin binding established\",\n      \"pmids\": [\"39805956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ETV7 transcriptionally upregulates CXCL1, leading to increased neutrophil recruitment and enhanced neutrophil extracellular trap (NET) formation in the tumor microenvironment, which promotes colorectal cancer aggressiveness and 5-FU resistance. Pharmacological inhibition of CXCL1 or degradation of NETs attenuates ETV7-driven malignant phenotypes.\",\n      \"method\": \"ETV7 overexpression/knockdown, CXCL1 promoter/transcription assays, neutrophil recruitment assays, NET detection, pharmacological inhibition in vitro and in vivo\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional upregulation of CXCL1 by ETV7 shown with functional epistasis and pharmacological rescue, single lab\",\n      \"pmids\": [\"41917269\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ETV7 is a dual-function ETS transcription factor that, in addition to its canonical role as a transcriptional repressor/activator (repressing DNAJC15, TNFRSF1A, and interferon-responsive genes; activating IFIT3 and CXCL1) via direct promoter/chromatin binding, assembles a rapamycin-resistant third mTOR complex (mTORC3) in the cytoplasm by binding the mTOR kinase domain through its PNT and ETS domains, conferring bimodal mTORC1/2 kinase activity and promoting cancer cell proliferation and drug resistance; additionally, ETV7 acts as a central transcriptional node in CD8+ T cells that drives terminal exhaustion by reshaping chromatin accessibility at memory and exhaustion gene loci.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ETV7 is an ETS-family transcription factor that functions predominantly as a sequence-specific transcriptional repressor, with full repressive activity requiring an isoform containing both its Pointed (PNT) and DNA-binding ETS domains [#0]. Through direct promoter and chromatin binding it represses a defined set of targets — DNAJC15, where repression drives doxorubicin efflux and chemoresistance [#3]; the TNFR1-encoding TNFRSF1A gene, where it recruits repressive chromatin remodelers and competes with STAT3 to dampen NF-\\u03baB signaling [#6]; and a signature of interferon-responsive genes, the loss of which promotes cancer stem-like plasticity reversible by IFN-\\u03b2 [#5]. In other contexts ETV7 acts as a transcriptional activator, driving IFIT3 in colorectal cancer to promote proliferation and migration [#8] and upregulating CXCL1 to recruit neutrophils and enhance NET formation, fueling tumor aggressiveness and 5-FU resistance [#10]. Beyond transcription, ETV7 has a separable cytoplasmic function: it binds the mTOR kinase domain to assemble a rapamycin-resistant complex, mTORC3, that lacks Raptor, Rictor, and mLST8 yet possesses bimodal mTORC1/2 kinase activity and accelerates tumorigenesis [#2], with the PNT domain engaging the mTOR FRB sequence and the ETS domain engaging the LBE sequence [#7]. In CD8+ T cells, ETV7 binds memory and exhaustion gene loci to reshape chromatin accessibility and drive terminal exhaustion, and its depletion improves antitumor T-cell and CAR-T efficacy [#9]. Across these settings ETV7 behaves as a pro-tumorigenic factor, cooperating with Pten loss to accelerate leukemogenesis [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the foundational molecular identity of ETV7 as a sequence-specific ETS transcriptional repressor and defined the domain requirement for that activity.\",\n      \"evidence\": \"Reporter and DNA-binding assays with domain-deletion isoforms, repressing RARA and BMP-6\",\n      \"pmids\": [\"11108721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify endogenous physiological targets beyond reporter contexts\", \"Repressive cofactors not defined\", \"No in vivo or disease context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected ETV7 transcriptional output to a concrete developmental phenotype, showing it regulates cholesterol synthesis to enable erythropoiesis.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with cholesterol rescue and lss expression analysis\",\n      \"pmids\": [\"24357328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog-based, mammalian relevance not tested\", \"Direct binding to lss promoter not shown\", \"Mechanism linking ETV7 to lss regulation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a transcription-independent function: ETV7 nucleates a novel cytoplasmic mTOR complex (mTORC3) that confers rapamycin resistance and drives tumorigenesis.\",\n      \"evidence\": \"Reciprocal Co-IP, mass spectrometry, rapamycin sensitivity assays, and transgenic rhabdomyosarcoma mouse model\",\n      \"pmids\": [\"30258985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of complex assembly not resolved\", \"Substrate specificity of mTORC3 not fully mapped\", \"How ETV7 confers bimodal kinase activity unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked ETV7 repression of DNAJC15 to a clinically relevant chemoresistance mechanism via drug efflux.\",\n      \"evidence\": \"ChIP/promoter binding, knockdown/overexpression, doxorubicin sensitivity and efflux assays in breast cancer cells\",\n      \"pmids\": [\"30025229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of DNA methylation as cofactor not mechanistically dissected\", \"Repressive chromatin machinery not identified\", \"Single lab, single tumor type\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated ETV7 acts as a cooperating oncogene, accelerating leukemogenesis in the context of Pten loss.\",\n      \"evidence\": \"Transgenic mouse genetic cross with Pten-conditional knockout and colony-forming/self-renewal assays\",\n      \"pmids\": [\"30478527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the cooperation is transcriptional or mTORC3-dependent not separated\", \"Direct target genes in this context unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined an ETV7-driven immune-evasion axis in which interferon-gene repression promotes cancer stem-like plasticity.\",\n      \"evidence\": \"Stable overexpression, transcriptome profiling, mammosphere/CD44/CD24 flow cytometry, and IFN-\\u03b2 rescue\",\n      \"pmids\": [\"34315857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ETV7 binding at the repressed IFN loci not all confirmed\", \"Repressive cofactor identity unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided a mechanistic model for ETV7 repression: chromatin-remodeler recruitment and competition with STAT3 at TNFRSF1A to suppress NF-\\u03baB signaling.\",\n      \"evidence\": \"ChIP, overexpression/knockdown, NF-\\u03baB assays, and competitive binding analysis with STAT3 in breast cancer cells\",\n      \"pmids\": [\"37041130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific chromatin remodelers not named\", \"Generality of STAT3 competition across other loci untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped the molecular interface of ETV7-mTOR binding and showed it is therapeutically targetable by competitive displacement.\",\n      \"evidence\": \"Domain mapping by Co-IP with deletion/mutation constructs and in vivo FRB-domain competitive displacement assay\",\n      \"pmids\": [\"39337528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the ETV7-mTOR interface\", \"Stoichiometry and other mTORC3 components remain incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended ETV7 to a transcriptional-activator role, defining an ETV7\\u2192IFIT3 axis that promotes colorectal cancer proliferation and migration.\",\n      \"evidence\": \"Luciferase reporter, RT-qPCR, western blot, siRNA knockdown, and rescue in colorectal cancer cells\",\n      \"pmids\": [\"38200280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What determines repressor vs activator behavior of ETV7 not resolved\", \"Direct binding at the IFIT3 promoter requires further mapping\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified ETV7 as a central chromatin node driving CD8+ T-cell terminal exhaustion, with therapeutic implications for T-cell and CAR-T therapy.\",\n      \"evidence\": \"scRNA-seq, scATAC-seq, gain/loss-of-function in mouse CD8+ T cells, and in vivo solid tumor models\",\n      \"pmids\": [\"39805956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect targets within exhaustion loci not fully separated\", \"Cofactors reshaping chromatin accessibility unknown\", \"Upstream signals inducing ETV7 in T cells unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected ETV7 transcriptional activation of CXCL1 to a tumor-microenvironment mechanism of neutrophil recruitment, NET formation, and chemoresistance.\",\n      \"evidence\": \"Overexpression/knockdown, CXCL1 transcription assays, neutrophil/NET assays, and pharmacological inhibition in vitro and in vivo\",\n      \"pmids\": [\"41917269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ETV7 occupancy at the CXCL1 promoter not fully established\", \"Relationship to other ETV7 axes in colorectal cancer not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what molecular switch dictates ETV7's choice between transcriptional repression, transcriptional activation, and cytoplasmic mTORC3 assembly within a given cell.\",\n      \"evidence\": \"No discovery in the corpus reconciles the determinants of ETV7's divergent functional modes\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ETV7 in any complex\", \"Cofactor partners distinguishing repressor from activator states unidentified\", \"Crosstalk between mTORC3 activity and ETV7 transcriptional programs untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 5, 6, 8, 9, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 6, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 6, 8, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 6, 9, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4, 8, 10]}\n    ],\n    \"complexes\": [\"mTORC3\"],\n    \"partners\": [\"MTOR\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}