{"gene":"TLE1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1996,"finding":"TLE1 physically interacts with HES-1 (a mammalian Hairy-like/bHLH protein) through the C-terminal WRPW motif of HES-1, demonstrated by both yeast two-hybrid assay and GST pull-down assay, establishing conserved Groucho/TLE–Hairy/HES interactions in mammals.","method":"Yeast two-hybrid assay; GST fusion protein pull-down assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — two orthogonal in vitro binding assays (yeast two-hybrid + GST pull-down) in same study; interaction replicated in multiple subsequent studies","pmids":["8687460"],"is_preprint":false},{"year":1996,"finding":"TLE1 proteins are phosphorylated in vivo; higher-molecular-mass phosphorylated forms (~118 kDa) exhibit stronger nuclear association than faster-migrating forms (~90–93 kDa), implicating phosphorylation in nuclear targeting and function. The more slowly migrating nuclear forms are induced during neural determination of P19 cells.","method":"Cell fractionation; SDS-PAGE mobility shift analysis; neural differentiation of P19 cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation with functional context (neural differentiation), single lab, two orthogonal observations","pmids":["8713081"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of the C-terminal WD40 repeat domain of human TLE1 resolved to 1.6 Å reveals a seven-bladed β-propeller; structural comparison with C. elegans UNC-37 missense mutations identifies interaction surfaces for eh1-domain (Engrailed-type) transcription factors, suggesting an induced-fit binding site.","method":"X-ray crystallography (1.6 Å); comparative missense mutation analysis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional annotation of binding surfaces","pmids":["12057191"],"is_preprint":false},{"year":2002,"finding":"TLE1 interacts with the intracellular region of gp130 (the IL-6 family signal transducer) through its N-terminal Q domain; the membrane-proximal Box1/Box2 region of gp130 is essential for this interaction.","method":"Yeast two-hybrid assay; GST pull-down assay; co-immunoprecipitation","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal binding methods (yeast 2-hybrid, GST pull-down, co-IP), single lab","pmids":["12030375"],"is_preprint":false},{"year":2003,"finding":"TLE1 binds the oncoprotein Qin (winged-helix transcription factor) through a WRPW-containing region C-terminal to Qin's DNA-binding domain; co-expression causes phosphorylation of TLE1, and adding the WRPW motif to a transformation-defective Qin mutant restores TLE1 binding and significantly enhances transformation of chicken embryo fibroblasts.","method":"Yeast two-hybrid screen; mammalian two-hybrid assay; transformation assay in chicken embryo fibroblasts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays plus functional transformation rescue, single lab","pmids":["12660810"],"is_preprint":false},{"year":2003,"finding":"TLE1 functions as a coactivator (not corepressor) of the orphan nuclear receptor ERRγ by binding its AF-1 domain; demonstrated by phage display biopanning, GST pull-down, and reporter gene assay.","method":"Phage display biopanning; GST pull-down; reporter gene assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal methods (phage display, pull-down, reporter assay), single lab, unexpected coactivator activity","pmids":["14651967"],"is_preprint":false},{"year":2004,"finding":"PARP-1 is a component of the Groucho/TLE1 corepressor complex at HES1-regulated promoters; CaMKIIδ activation triggers PARP-1-mediated dismissal of the TLE corepressor complex from promoters and simultaneously phosphorylates HES1, switching HES1 from a TLE-dependent repressor to a transcriptional activator required for neurogenic gene activation.","method":"Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); promoter reporter assays; dominant-negative/kinase assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, ChIP, reporter assays) in a single rigorous study establishing a mechanistic pathway switch","pmids":["15607978"],"is_preprint":false},{"year":2004,"finding":"Protein kinase CK2 phosphorylates TLE1 in vivo at serine 239 within the conserved CcN domain; mutation of Ser-239 to alanine decreases Hes1-induced hyperphosphorylation, reduces nuclear association, reduces transcription repression activity, and impairs the ability of TLE1 to inhibit cortical neural progenitor differentiation into neurons.","method":"Site-directed mutagenesis; in vivo phosphorylation assay; nuclear fractionation; transcription repression assay; primary cortical neural progenitor differentiation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific phospho-site validated with multiple functional readouts (nuclear association, repression, neurogenesis) in same study","pmids":["15367661"],"is_preprint":false},{"year":2005,"finding":"TLE1 localizes not only to the nucleus but also to apical dendritic shafts of neocortical pyramidal neurons (layers III and V) and Purkinje cell dendrites in the adult rat brain, suggesting extranuclear functions in postmitotic neurons.","method":"Immunofluorescence/immunohistochemistry localization in adult rat brain sections","journal":"Brain research. Molecular brain research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment replicated across multiple neuronal cell types; functional consequence not directly tested in same paper","pmids":["16081186"],"is_preprint":false},{"year":2006,"finding":"Overexpression of Grg1/TLE1 (long isoform) in transgenic mice induces lung adenocarcinoma with elevated ErbB1 and ErbB2 receptor tyrosine kinases and reduced p53; the short isoform Grg5 (lacking SP and WD40 domains) does not induce tumors and co-expression of Grg5 with Grg1 reduces tumor burden.","method":"Transgenic mouse overexpression; tumor histology; Western blot for ErbB1/ErbB2/p53","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic gain-of-function with defined molecular mechanism (ErbB1/2 upregulation), domain-function analysis using short isoform, replicated across two transgenic lines","pmids":["16452182"],"is_preprint":false},{"year":2008,"finding":"TLE1 and TLE4 lie within the del(9q) commonly deleted region in AML; shRNA knockdown of TLE1 or TLE4 rescues AML1-ETO-expressing cells from cell-cycle arrest and apoptosis, and forced expression causes apoptosis and cell death, identifying TLE1 as a tumor suppressor that opposes AML1-ETO oncogenic activity.","method":"shRNA knockdown; forced expression; cell-cycle and apoptosis assays; zebrafish Gro3 knockdown cooperating with AML1-ETO","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments with defined cell-cycle/apoptosis phenotypes, validated in zebrafish model","pmids":["18258796"],"is_preprint":false},{"year":2008,"finding":"TLE1 promoter undergoes CpG island hypermethylation-associated silencing in diffuse large B-cell lymphoma and AML; reintroduction of TLE1 in hypermethylated cells causes growth inhibition and suppresses target genes including Cyclin D1, CSF1R, and Hes1; shRNA depletion in unmethylated cells enhances tumor growth.","method":"Bisulfite sequencing/methylation-specific PCR; colony and nude-mouse assays after reintroduction; shRNA knockdown","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments in vitro and in vivo, with identification of specific transcriptional targets","pmids":["18519670"],"is_preprint":false},{"year":2008,"finding":"TLE1 inhibition of cortical neuron differentiation requires its WD40 domain interaction with WRPW-motif proteins (Hes1); point mutation L743F in the WD40 domain selectively blocks Hes1 binding and anti-neurogenic activity but does not disrupt binding to Eh1-motif proteins (Engrailed1, FoxG1) or to Tcf3.","method":"Site-directed mutagenesis; co-immunoprecipitation; primary cortical neural progenitor differentiation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with domain-specific binding dissection and neuronal differentiation phenotype in primary cells, single lab","pmids":["18611861"],"is_preprint":false},{"year":2009,"finding":"Cofactor-activated (Hes1-induced) phosphorylation of TLE1 at Ser-286, Ser-289, and Ser-298 in the SP domain is required for its chromatin association and anti-neurogenic activity; mutation of these sites does not prevent TLE1 recruitment to DNA-bound partners but weakens chromatin interaction.","method":"Site-directed mutagenesis; mass spectrometry identification of phospho-sites; chromatin immunoprecipitation; primary cortical neuron differentiation assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis + MS phospho-site identification + ChIP + functional neuronal assay, single lab but multiple orthogonal methods","pmids":["19956621"],"is_preprint":false},{"year":2010,"finding":"TLE1 associates with ribosomal RNA genes during both mitosis and interphase through interaction with the osteogenic transcription factor Runx2; TLE1 depletion relieves Runx2-mediated rRNA gene repression, increases active-transcription histone modifications, enhances global protein synthesis, and accelerates cell proliferation.","method":"Co-immunoprecipitation; ChIP on rDNA; siRNA knockdown; histone modification analysis; protein synthesis assay; cell proliferation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, ChIP, knockdown, functional readouts) establishing TLE1 as Runx2 co-repressor at rRNA genes","pmids":["20160071"],"is_preprint":false},{"year":2010,"finding":"TLE1 and TLE3 both repress PROP1 transcriptional activity in conjunction with HESX1, and also repress PROP1 independently of HESX1 through direct protein-protein interaction; TLE1 interacts with HESX1 through an Eh1 (engrailed homology) domain.","method":"Co-immunoprecipitation; transcriptional reporter assay; transgenic mouse pituitary expression","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus reporter assay in cell culture plus in vivo transgenic model, single lab","pmids":["20181723"],"is_preprint":false},{"year":2011,"finding":"TLE1 physically interacts with NOD2; both proteins co-localize around the nuclear membrane; TLE1 inhibits NF-κB activation by NOD2 in HEK293 cells.","method":"Yeast two-hybrid screen of intestinal epithelial library; co-immunoprecipitation in mammalian cells; co-localization imaging; NF-κB reporter assay","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast 2-hybrid confirmed by co-IP and co-localization, functional NF-κB reporter, single lab","pmids":["21699783"],"is_preprint":false},{"year":2012,"finding":"TLE1 promotes resistance to anoikis in mammary epithelial and breast cancer cells; mechanistically, TLE1 inhibits the Bit1 anoikis pathway by reducing formation of the proapoptotic Bit1-AES complex in part through sequestration of AES in the nucleus. Cytoplasmic Bit1 induces cytoplasmic translocation and degradation of nuclear TLE1.","method":"TLE1 overexpression and siRNA knockdown; anoikis/apoptosis assays; co-immunoprecipitation (Bit1-AES complex); subcellular fractionation","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function, defined molecular mechanism (AES sequestration, Bit1-TLE1 crosstalk), multiple orthogonal methods","pmids":["22952044"],"is_preprint":false},{"year":2012,"finding":"TLE1 promotes neuronal survival in postmitotic cerebellar granule neurons; this survival-promoting activity requires CK2-mediated phosphorylation at Ser-239 and Ser-253 and PI3K-Akt signaling, and critically depends on interaction with FoxG1 (the FoxG1 survival activity reciprocally depends on TLE1).","method":"Ectopic expression and knockdown in cerebellar granule neurons; pharmacological inhibitors; point mutants (Ser-239/253); cell viability/apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of specific phospho-sites + pathway inhibitors + reciprocal dependence (TLE1/FoxG1) in primary neurons","pmids":["22354967"],"is_preprint":false},{"year":2014,"finding":"TLE1 promotes epithelial-to-mesenchymal transition (EMT) in A549 lung cancer cells through transcriptional repression of E-cadherin; TLE1 recruits histone deacetylase (HDAC) activity to the E-cadherin promoter, and HDAC inhibitor TSA partially reverses TLE1-induced E-cadherin repression and cell migration.","method":"TLE1 overexpression and siRNA knockdown; cell morphology/migration assays; RT-PCR/Western blot for EMT markers; chromatin immunoprecipitation; TSA pharmacological rescue","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain/loss-of-function, ChIP showing HDAC recruitment to E-cadherin promoter, pharmacological rescue, multiple orthogonal methods","pmids":["25446087"],"is_preprint":false},{"year":2014,"finding":"Grg1/TLE1 is the predominant Groucho expressed in human pancreatic β-cells and acts functionally similarly to Grg3 in establishing monohormonal β-cell identity by repressing α-cell genes (glucagon, Arx); ectopic Grg1 expression in α-cells represses glucagon.","method":"Immunostaining in human islets; ectopic expression in α-cells; qRT-PCR for α/β-cell markers","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization in human tissue plus functional ectopic expression experiment, single lab","pmids":["24487024"],"is_preprint":false},{"year":2016,"finding":"Tle1 deficiency in mice causes chronic inflammation with increased NF-κB phosphorylation/activation and decreased Hes1 expression in macrophages; Tle1-deficient macrophages produce increased inflammatory cytokines in response to TLR agonists/LPS, demonstrating TLE1 as a major negative regulator of the NF-κB inflammatory pathway in vivo.","method":"Tle1 knockout mice; cytokine/chemokine quantification; Western blot for NF-κB phosphorylation; macrophage LPS stimulation assays; skin TPA inflammation model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model with multiple tissue readouts plus ex vivo macrophage functional assays, multiple orthogonal methods","pmids":["26831087"],"is_preprint":false},{"year":2017,"finding":"TLE1 is phosphorylated in response to Ras-ERK pathway activation; this phosphorylation attenuates TLE1 repressor activity and causes rapid nuclear exclusion of TLE1 following EGFR activation. Unphosphorylatable TLE1 dominantly suppresses Ras-ERK target gene induction and blocks oncogenic H-Ras phenotypes in human mammary cells in vitro and in vivo.","method":"Phosphorylation assays; nuclear/cytoplasmic fractionation; transcriptional reporter assays; Drosophila transgenic phenotype analysis; tumor implantation in mice","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods across human cells and Drosophila model; gain-of-function, phospho-mimetic, and unphosphorylatable mutants; in vivo validation","pmids":["28192406"],"is_preprint":false},{"year":2017,"finding":"Structure-enabled design of a stapled peptide inhibitor (cycFWRPW) targeting the TLE1 WD40 β-propeller domain; co-crystal structure with TLE1 confirms the binding mode; the constrained peptide binds potently but with ~5-fold reduced affinity compared to linear peptide due to a side-chain shift.","method":"Isothermal titration calorimetry; thermal shift assay; X-ray co-crystallography","journal":"Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of inhibitor complex + biophysical binding measurements in single rigorous study","pmids":["28326635"],"is_preprint":false},{"year":2017,"finding":"TLE1 promotes anoikis resistance and tumorigenicity in lung cancer cells via ZEB1-mediated E-cadherin repression; ZEB1 recruits TLE1 to the E-cadherin promoter to impose histone deacetylation and gene silencing; Bit1 tumor suppressor negatively regulates TLE1-mediated E-cadherin repression.","method":"TLE1 overexpression and siRNA knockdown; chromatin immunoprecipitation; in vivo tumorigenicity assay; ZEB1 siRNA epistasis","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP showing ZEB1-TLE1 co-occupancy at E-cadherin promoter, epistasis experiments, in vivo xenograft, multiple orthogonal methods","pmids":["29069783"],"is_preprint":false},{"year":2018,"finding":"FOXG1 and TLE1 form a transcriptional repressor complex in glioblastoma-initiating cells that targets ~150 FOXG1 genomic loci; ChIP-Seq and RNA-Seq identify shared targets including negative regulators of NOTCH signaling (e.g., CHAC1), suggesting FOXG1:TLE1 crosstalk with NOTCH pathway in GBM.","method":"ChIP-Seq; RNA-Seq in patient-derived brain tumor-initiating cells","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide binding + transcriptome profiling in patient-derived cells, single lab","pmids":["29316219"],"is_preprint":false},{"year":2020,"finding":"Tle1 suppresses NOD2-dependent NF-κB activation in the liver; in hepatic ischemia/reperfusion injury, Tle1 expression decreases while NOD2 increases; Tle1-siRNA knockdown aggravates liver dysfunction and enhances NOD2/NF-κB signaling, whereas NOD2 alteration does not affect Tle1 expression, placing Tle1 upstream of NOD2 in this pathway.","method":"Mouse I/R model; Tle1 siRNA knockdown; hypoxia/reoxygenation cell model; Western blot for NOD2/NF-κB; liver function assays","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro loss-of-function with epistasis (NOD2 alteration does not affect TLE1), single lab","pmids":["32114961"],"is_preprint":false},{"year":2021,"finding":"A specific N-terminal phosphorylation site present in TLE1 but absent from TLE3 determines their differential functional activities; mutating or reconstituting this site converts TLE1 activity to TLE3-like behavior and vice versa, demonstrated in lung cancer cells (paclitaxel sensitivity) and an adipocyte differentiation system.","method":"Site-directed mutagenesis of phosphorylation site; retroviral transduction; paclitaxel sensitivity assay; adipocyte differentiation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional validation in two cellular systems (cancer drug sensitivity + differentiation), single lab","pmids":["33571907"],"is_preprint":false},{"year":2023,"finding":"FTO m6A demethylase regulates TLE1 mRNA stability and expression through m6A modification; PEITC treatment inhibits FTO, increases m6A methylation of TLE1 mRNA, reduces TLE1 protein levels, and suppresses NSCLC cell migration via the Akt/NF-κB pathway downstream of TLE1.","method":"FTO knockdown/overexpression; m6A methylation assay; mRNA stability assay; migration/invasion assays; Akt/NF-κB pathway Western blot","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic writer (FTO) identified for TLE1 mRNA m6A modification with functional pathway validation, single lab","pmids":["37848553"],"is_preprint":false},{"year":2024,"finding":"TLE1 protects the blood-brain barrier and reduces PANoptosis after cerebral ischemia/reperfusion via the TLE1/PI3K/AKT signaling pathway; TLE1 overexpression is protective, and its knockdown abolishes the protective effects of esculentoside H treatment; PI3K inhibitor LY294002 blocks TLE1-dependent protection.","method":"AAV-mediated TLE1 overexpression/knockdown in rat MCAO model; PI3K inhibitor LY294002; infarct volume, BBB permeability, neuronal death assays","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain- and loss-of-function with pharmacological pathway inhibition, single lab","pmids":["38857750"],"is_preprint":false},{"year":2024,"finding":"Foxq1 promotes alveolar epithelial cell death through TLE1-mediated inhibition of NF-κB signaling; TLE1 acts downstream of Foxq1 to suppress NF-κB/Bcl2/Bax pathway in ALI; Foxq1 knockdown promotes cell survival whereas overexpression induces death, effects mediated through TLE1.","method":"Foxq1 knockdown and overexpression in MLE-12 cells; LPS ALI mouse model; Western blot for NF-κB/Bcl2/Bax; cell viability assays","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis placing TLE1 downstream of Foxq1 in NF-κB pathway, in vitro and in vivo, single lab","pmids":["38574238"],"is_preprint":false},{"year":2025,"finding":"TLE1 drives EGFR-TKI resistance in EGFR-mutant lung adenocarcinoma through EMT; TLE1 interacts with ZEB1 to suppress E-cadherin expression; exogenous TLE1 reduces sensitivity to gefitinib/osimertinib and knockdown of endogenous TLE1 in resistant cells partially restores drug sensitivity; Bit1 release by TKI treatment causes nuclear exclusion of TLE1 via cytosolic Bit1-AES complex formation.","method":"TLE1 overexpression and knockdown in PC9/HCC827 and derived resistant lines; co-immunoprecipitation (TLE1-ZEB1); subcellular fractionation; apoptosis and viability assays; RNA-seq","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function, co-IP for ZEB1 interaction, RNA-seq, multiple cell models; single lab","pmids":["40482589"],"is_preprint":false},{"year":2026,"finding":"Tle1 overexpression in CD8+ T cells enhances effector proliferation during acute and chronic viral infections and improves CTL responses to PD-1/PD-L1 blockade; Tle1 enhances TCR signaling and immunoinhibitory receptor expression (PD-1, LAG-3) through repression of TCF-1; genome-wide Tle1 binding profiles show cooperation with Ets, AP-1, and Runx transcription factors.","method":"Retroviral Tle1 overexpression in CD8+ T cells; viral infection models; transcriptome analysis; ChIP-Seq/genome-wide binding profiles; PD-1 blockade experiments","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with genome-wide binding data and TCF-1 epistasis, multiple viral models, single lab","pmids":["41810855"],"is_preprint":false}],"current_model":"TLE1 is a transcriptional corepressor that lacks intrinsic DNA-binding but is recruited to target promoters by diverse DNA-binding partners (HES1/WRPW motif, Engrailed/Eh1 motif, Runx2, FoxG1, ZEB1, NOD2, HESX1, PROP1, gp130) via its seven-bladed WD40 β-propeller domain; its repressive activity—which involves histone deacetylase recruitment and chromatin association—is regulated by multiple phosphorylation events (CK2 at Ser-239/253, Ras-ERK pathway causing nuclear exclusion, cofactor-activated SP-domain phosphorylation at Ser-286/289/298) and can be switched off by PARP-1-mediated complex dismissal or Bit1-induced cytoplasmic sequestration, allowing context-dependent corepressor-to-coactivator transitions; physiologically TLE1 suppresses neuronal differentiation, maintains β-cell identity by repressing glucagon, inhibits NF-κB-driven inflammation, and acts as a tumor suppressor in hematopoietic malignancies, while in certain contexts (lung adenocarcinoma) it promotes oncogenesis through ZEB1-dependent E-cadherin repression and EMT-associated anoikis resistance and drug resistance."},"narrative":{"mechanistic_narrative":"TLE1 is a transcriptional corepressor that lacks intrinsic DNA-binding activity and is recruited to target genes by sequence-specific transcription factors, imposing repression through chromatin association and histone deacetylase recruitment [PMID:8687460, PMID:25446087]. Its C-terminal WD40 domain forms a seven-bladed β-propeller that provides distinct binding surfaces: a WRPW/WRPW-motif site engaged by Hairy/HES-family proteins such as HES-1, and an eh1/Engrailed-type surface used by Eh1-motif partners [PMID:8687460, PMID:12057191, PMID:18611861]. Through these interfaces TLE1 partners with HES1, Runx2, FoxG1/HESX1, ZEB1, NOD2, and gp130, and selective WD40 point mutations (e.g., L743F) uncouple Hes1 binding from Eh1-motif factor binding [PMID:12030375, PMID:18611861, PMID:20160071, PMID:20181723, PMID:21699783]. TLE1 repressor activity is gated by phosphorylation: CK2 modifies Ser-239/Ser-253 within the CcN domain and cofactor (Hes1)-activated phosphorylation at Ser-286/289/298 in the SP domain promotes nuclear/chromatin association and repression, whereas Ras-ERK-driven phosphorylation triggers nuclear exclusion and loss of repression [PMID:15367661, PMID:19956621, PMID:22354967, PMID:28192406]. The complex is also switched off by PARP-1-mediated dismissal from HES1 promoters and by Bit1-induced cytoplasmic sequestration of nuclear TLE1, enabling repressor-to-activator transitions [PMID:15607978, PMID:22952044]. Functionally TLE1 suppresses neuronal differentiation while promoting survival of postmitotic neurons, maintains pancreatic β-cell identity by repressing glucagon, and is a negative regulator of NOD2/NF-κB-driven inflammation [PMID:15367661, PMID:22354967, PMID:24487024, PMID:21699783, PMID:26831087]. In cancer TLE1 has dual roles: it acts as a tumor suppressor in hematopoietic malignancies, where del(9q) loss and CpG-island hypermethylation silence it and forced re-expression drives apoptosis and represses Cyclin D1, CSF1R, and Hes1, yet promotes oncogenesis in lung adenocarcinoma by partnering with ZEB1 to repress E-cadherin, driving EMT, anoikis resistance, and EGFR-TKI resistance [PMID:18258796, PMID:18519670, PMID:29069783, PMID:25446087, PMID:40482589].","teleology":[{"year":1996,"claim":"Established that mammalian TLE1 engages Hairy/HES-class transcription factors, defining the conserved Groucho/TLE recruitment principle in mammals.","evidence":"Yeast two-hybrid and GST pull-down mapping the HES-1 WRPW motif interaction","pmids":["8687460"],"confidence":"High","gaps":["Did not resolve which TLE domain mediates binding","No promoter or repression readout in this study"]},{"year":1996,"claim":"Linked TLE1 phosphorylation state to subcellular distribution and differentiation, raising phosphorylation as a regulatory layer.","evidence":"Cell fractionation and SDS-PAGE mobility shifts across P19 neural differentiation","pmids":["8713081"],"confidence":"Medium","gaps":["No specific phospho-sites or kinases identified","Causal link between phosphorylation and nuclear targeting not yet tested by mutagenesis"]},{"year":2002,"claim":"Provided the structural basis for partner recognition by solving the WD40 β-propeller and locating the eh1-domain interaction surface.","evidence":"1.6 Å X-ray crystallography with comparative UNC-37 missense analysis","pmids":["12057191"],"confidence":"High","gaps":["Full-length and N-terminal domains not structurally resolved","Mechanism of induced-fit binding inferred, not directly captured with bound partner"]},{"year":2002,"claim":"Mapped a distinct N-terminal Q-domain interaction to the IL-6 signal transducer gp130, extending TLE1 partners beyond classical transcription factors.","evidence":"Yeast two-hybrid, GST pull-down, and co-IP mapping the Box1/Box2 region","pmids":["12030375"],"confidence":"Medium","gaps":["Functional consequence for cytokine signaling not established","Single lab, no in vivo validation"]},{"year":2003,"claim":"Showed TLE1 can act as a coactivator depending on partner, indicating context-dependent rather than uniformly repressive output.","evidence":"Phage display biopanning, GST pull-down, and reporter assays with ERRγ AF-1 domain","pmids":["14651967"],"confidence":"Medium","gaps":["Mechanism of the coactivator switch unresolved","No endogenous target gene validation"]},{"year":2003,"claim":"Demonstrated that TLE1 binding contributes to oncogenic transformation, an early link between corepressor recruitment and cancer phenotypes.","evidence":"Two-hybrid and chicken embryo fibroblast transformation rescue with WRPW-engineered Qin","pmids":["12660810"],"confidence":"Medium","gaps":["Direct repression targets driving transformation not identified","Mammalian relevance untested"]},{"year":2004,"claim":"Defined a dynamic off-switch for the corepressor: PARP-1 dismissal of the TLE complex coupled to HES1 conversion to an activator during neurogenesis.","evidence":"Co-IP, ChIP, reporter and kinase assays linking CaMKIIδ/PARP-1 to complex dismissal","pmids":["15607978"],"confidence":"High","gaps":["Generality of PARP-1 dismissal beyond HES1 promoters unknown","Stoichiometry/timing of dismissal not quantified"]},{"year":2004,"claim":"Identified CK2 phosphorylation of Ser-239 as a determinant of nuclear association, repression, and anti-neurogenic activity, validating phosphorylation as functional control.","evidence":"Site-directed mutagenesis with in vivo phosphorylation, fractionation, repression, and cortical progenitor differentiation assays","pmids":["15367661"],"confidence":"High","gaps":["Other CK2 or cofactor-dependent sites not yet mapped here","Direct chromatin binding consequence not measured"]},{"year":2005,"claim":"Revealed extranuclear TLE1 in postmitotic neuronal dendrites, implying functions beyond promoter repression.","evidence":"Immunolocalization in adult rat neocortical and Purkinje neurons","pmids":["16081186"],"confidence":"Medium","gaps":["No functional role for dendritic TLE1 demonstrated","Interacting partners at this site unknown"]},{"year":2006,"claim":"Provided in vivo evidence that long-isoform TLE1 overexpression drives lung adenocarcinoma, with isoform domain requirements defining oncogenic potential.","evidence":"Transgenic mouse gain-of-function with ErbB1/2 and p53 profiling and Grg5 short-isoform comparison","pmids":["16452182"],"confidence":"High","gaps":["Direct transcriptional targets linking TLE1 to ErbB upregulation not defined","Partner factor driving tumorigenesis unidentified in this model"]},{"year":2008,"claim":"Established TLE1 as a tumor suppressor in hematopoietic malignancy opposing AML1-ETO, defining loss-of-function as oncogenic in this context.","evidence":"shRNA knockdown and forced expression with cell-cycle/apoptosis assays and zebrafish modeling","pmids":["18258796"],"confidence":"High","gaps":["Direct TLE1 target genes mediating apoptosis not fully resolved","Recruiting DNA-binding partner at relevant loci unspecified"]},{"year":2008,"claim":"Showed TLE1 is epigenetically silenced in lymphoma/AML and identified repression targets, reinforcing its tumor-suppressive role.","evidence":"Bisulfite/MSP methylation analysis with reintroduction, colony, nude-mouse, and knockdown assays identifying Cyclin D1, CSF1R, Hes1","pmids":["18519670"],"confidence":"High","gaps":["DNA-binding factors recruiting TLE1 to these promoters not mapped","Mechanism of growth inhibition downstream of targets incomplete"]},{"year":2008,"claim":"Genetically dissected the WD40 domain to show partner-selective repression, separating Hes1-dependent anti-neurogenic activity from Eh1-motif binding.","evidence":"L743F mutagenesis with co-IP and cortical progenitor differentiation assays","pmids":["18611861"],"confidence":"High","gaps":["Structural basis of partner discrimination at this residue not crystallographically resolved","Other WD40 surface residues governing partner choice untested"]},{"year":2009,"claim":"Defined cofactor-activated SP-domain phosphorylation (Ser-286/289/298) as required for chromatin association distinct from partner recruitment.","evidence":"Mutagenesis plus mass-spectrometry phospho-mapping, ChIP, and neuron differentiation assays","pmids":["19956621"],"confidence":"High","gaps":["Kinase executing SP-domain phosphorylation not identified","Chromatin contact mechanism (histone vs nucleosome) unresolved"]},{"year":2010,"claim":"Extended TLE1 repression to rRNA genes via Runx2, linking the corepressor to ribosome biogenesis and proliferation control.","evidence":"Co-IP, rDNA ChIP, siRNA, histone modification, protein synthesis and proliferation assays","pmids":["20160071"],"confidence":"High","gaps":["Mitotic vs interphase rDNA association mechanism not fully separated","Whether HDAC mediates the rDNA silencing not directly shown here"]},{"year":2010,"claim":"Established TLE1 cooperation with HESX1/PROP1 in pituitary transcriptional repression, including HESX1-independent repression via direct contact.","evidence":"Co-IP, reporter assays, and transgenic pituitary expression with Eh1-domain mapping","pmids":["20181723"],"confidence":"Medium","gaps":["Physiological pituitary phenotype of TLE1 loss not tested","Endogenous target promoters not identified"]},{"year":2011,"claim":"Identified TLE1 as a NOD2-interacting suppressor of NF-κB, opening a role in innate immune/inflammatory regulation.","evidence":"Yeast two-hybrid screen, co-IP, co-localization, and NF-κB reporter in HEK293","pmids":["21699783"],"confidence":"Medium","gaps":["In vivo relevance not tested in this study","Whether repression is transcriptional or signaling-level unresolved"]},{"year":2012,"claim":"Showed TLE1 promotes anoikis resistance in breast cells by sequestering AES and antagonizing the Bit1 pathway, revealing a cytoplasmic regulatory crosstalk.","evidence":"Overexpression/knockdown, anoikis assays, Bit1-AES co-IP, and fractionation","pmids":["22952044"],"confidence":"High","gaps":["Trigger for Bit1-driven TLE1 cytoplasmic translocation in physiological settings unclear","Degradation machinery for cytoplasmic TLE1 not defined"]},{"year":2012,"claim":"Demonstrated a pro-survival role for TLE1 in postmitotic neurons requiring CK2 phospho-sites, PI3K-Akt, and FoxG1, contrasting its anti-neurogenic role in progenitors.","evidence":"Ectopic expression/knockdown, inhibitors, Ser-239/253 mutants, and viability assays in cerebellar granule neurons","pmids":["22354967"],"confidence":"High","gaps":["Target genes mediating neuronal survival not identified","Mechanistic link from PI3K-Akt to TLE1 not detailed"]},{"year":2014,"claim":"Linked TLE1 to EMT in lung cancer by HDAC-dependent E-cadherin repression, establishing an oncogenic transcriptional output.","evidence":"Overexpression/knockdown, migration assays, EMT marker analysis, ChIP, and TSA rescue in A549 cells","pmids":["25446087"],"confidence":"High","gaps":["DNA-binding factor recruiting TLE1 to E-cadherin not yet identified in this study","Specific HDAC isoform unconfirmed"]},{"year":2014,"claim":"Showed TLE1 maintains pancreatic β-cell identity by repressing α-cell genes, defining a developmental/endocrine role.","evidence":"Human islet immunostaining and ectopic expression in α-cells with marker qRT-PCR","pmids":["24487024"],"confidence":"Medium","gaps":["DNA-binding partner repressing glucagon/Arx not identified","Loss-of-function in vivo β-cell phenotype not tested"]},{"year":2016,"claim":"Provided in vivo proof that TLE1 is a major negative regulator of NF-κB inflammation via knockout phenotypes in macrophages and skin.","evidence":"Tle1 knockout mice with cytokine quantification, NF-κB Western blots, LPS macrophage stimulation, and TPA model","pmids":["26831087"],"confidence":"High","gaps":["Direct molecular step at which TLE1 blocks NF-κB not fully defined","Relationship between reduced Hes1 and NF-κB activation not mechanistically dissected"]},{"year":2017,"claim":"Defined Ras-ERK phosphorylation as the switch that excludes TLE1 from the nucleus and disables repression, integrating it into oncogenic signaling.","evidence":"Phosphorylation assays, fractionation, reporters, Drosophila phenotypes, and mouse tumor implantation with mutant TLE1","pmids":["28192406"],"confidence":"High","gaps":["Exact ERK-targeted residues not pinpointed here","Target gene set derepressed upon nuclear exclusion not enumerated"]},{"year":2017,"claim":"Delivered a structure-guided peptide inhibitor of the WD40 partner-binding site, validating the propeller as a druggable interface.","evidence":"ITC, thermal shift, and X-ray co-crystallography of the cycFWRPW stapled peptide","pmids":["28326635"],"confidence":"High","gaps":["Cellular efficacy of the inhibitor not demonstrated","Affinity reduced relative to linear peptide"]},{"year":2017,"claim":"Identified ZEB1 as the DNA-binding partner recruiting TLE1 to the E-cadherin promoter, mechanistically grounding TLE1-driven anoikis resistance and tumorigenicity in lung cancer.","evidence":"Overexpression/knockdown, ChIP co-occupancy, ZEB1 epistasis, and in vivo tumorigenicity assays","pmids":["29069783"],"confidence":"High","gaps":["HDAC isoform recruited unspecified","Quantitative contribution of Bit1 regulation in vivo not resolved"]},{"year":2018,"claim":"Mapped genome-wide FOXG1:TLE1 repressor occupancy in glioblastoma-initiating cells, connecting the complex to NOTCH-regulatory targets.","evidence":"ChIP-Seq and RNA-Seq in patient-derived brain tumor-initiating cells","pmids":["29316219"],"confidence":"Medium","gaps":["Functional/therapeutic consequence of FOXG1:TLE1 targets not tested","Direct vs indirect NOTCH crosstalk unresolved"]},{"year":2020,"claim":"Positioned Tle1 upstream of NOD2 in liver ischemia/reperfusion, extending its NF-κB-suppressive role to organ injury.","evidence":"Mouse I/R model, Tle1 siRNA, hypoxia/reoxygenation cells, and epistasis Western blots","pmids":["32114961"],"confidence":"Medium","gaps":["Mechanism of Tle1 downregulation during I/R unknown","Single lab, no rescue with TLE1 re-expression in vivo"]},{"year":2021,"claim":"Identified a TLE1-specific N-terminal phospho-site distinguishing it functionally from TLE3, demonstrating site-swapping converts paralog behavior.","evidence":"Mutagenesis and reconstitution with paclitaxel sensitivity and adipocyte differentiation readouts","pmids":["33571907"],"confidence":"Medium","gaps":["Kinase responsible for the differential site not identified","Mechanistic link from this site to repression output incomplete"]},{"year":2023,"claim":"Showed TLE1 mRNA is controlled by FTO-mediated m6A demethylation, adding a post-transcriptional regulatory layer relevant to NSCLC migration.","evidence":"FTO knockdown/overexpression, m6A and mRNA stability assays, migration assays, and Akt/NF-κB Western blots","pmids":["37848553"],"confidence":"Medium","gaps":["m6A reader interpreting TLE1 mRNA marks not identified","Direct vs indirect Akt/NF-κB effects not separated"]},{"year":2024,"claim":"Implicated TLE1 in PI3K/AKT-dependent blood-brain barrier protection and PANoptosis reduction after cerebral ischemia/reperfusion.","evidence":"AAV TLE1 overexpression/knockdown in rat MCAO with LY294002 and BBB/neuronal death readouts","pmids":["38857750"],"confidence":"Medium","gaps":["Transcriptional targets mediating protection not identified","Whether TLE1 acts directly in PI3K/AKT pathway unresolved"]},{"year":2024,"claim":"Placed TLE1 downstream of Foxq1 in NF-κB suppression governing alveolar epithelial cell death in acute lung injury.","evidence":"Foxq1 knockdown/overexpression in MLE-12 cells, LPS ALI model, and NF-κB/Bcl2/Bax analyses","pmids":["38574238"],"confidence":"Medium","gaps":["Direct Foxq1-TLE1 physical interaction not demonstrated","Promoter targets driving the death phenotype unidentified"]},{"year":2025,"claim":"Demonstrated TLE1-ZEB1-driven EMT as a mechanism of EGFR-TKI resistance, with Bit1-AES-mediated nuclear exclusion modulating drug response.","evidence":"Overexpression/knockdown in PC9/HCC827 and resistant lines, TLE1-ZEB1 co-IP, fractionation, and RNA-seq","pmids":["40482589"],"confidence":"Medium","gaps":["Clinical correlation of TLE1 with TKI resistance not established","Single lab, mechanism overlaps prior ZEB1 model"]},{"year":2026,"claim":"Revealed a CD8+ T-cell role where Tle1 enhances effector responses and checkpoint-blockade efficacy via TCF-1 repression and cooperation with Ets/AP-1/Runx factors.","evidence":"Retroviral Tle1 overexpression, viral infection models, transcriptomics, ChIP-Seq, and PD-1 blockade experiments","pmids":["41810855"],"confidence":"Medium","gaps":["Direct physical interaction with Ets/AP-1/Runx not biochemically validated","Endogenous Tle1 loss-of-function phenotype in T cells not tested"]},{"year":null,"claim":"How a single corepressor toggles between tumor-suppressive and oncogenic outputs, and how phosphorylation/partner choice deterministically dictates this in a given tissue, remains unresolved.","evidence":"No single study integrates the phosphorylation code, partner selection, and context-specific functional outcome","pmids":[],"confidence":"Low","gaps":["No unified model linking specific phospho-states to specific partner-recruited repression outputs","Kinases for several functional phospho-sites unidentified","Determinants of corepressor-to-coactivator switching incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator 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Inhibits NF-kappa-B-regulated gene expression. Inhibits the transcriptional activation mediated by FOXA2, and by CTNNB1 and TCF family members in Wnt signaling. Enhances FOXG1/BF-1- and HES1-mediated transcriptional repression (By similarity). The effects of full-length TLE family members may be modulated by association with dominant-negative AES. Unusual function as coactivator for ESRRG","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q04724/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TLE1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TLE1","total_profiled":1310},"omim":[{"mim_id":"618645","title":"PHD FINGER PROTEIN 12; PHF12","url":"https://www.omim.org/entry/618645"},{"mim_id":"611882","title":"PROLINE-RICH NUCLEAR RECEPTOR COACTIVATOR 2; PNRC2","url":"https://www.omim.org/entry/611882"},{"mim_id":"611273","title":"SKI FAMILY TRANSCRIPTIONAL COREPRESSOR 1; SKOR1","url":"https://www.omim.org/entry/611273"},{"mim_id":"610331","title":"HES FAMILY bHLH TRANSCRIPTION FACTOR 6; HES6","url":"https://www.omim.org/entry/610331"},{"mim_id":"605132","title":"TLE FAMILY MEMBER 4, TRANSCRIPTIONAL COREPRESSOR; TLE4","url":"https://www.omim.org/entry/605132"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TLE1"},"hgnc":{"alias_symbol":["ESG1","GRG1","ESG","TLE-1"],"prev_symbol":[]},"alphafold":{"accession":"Q04724","domains":[{"cath_id":"2.130.10.10","chopping":"473-768","consensus_level":"medium","plddt":96.6252,"start":473,"end":768}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04724","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q04724-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q04724-F1-predicted_aligned_error_v6.png","plddt_mean":68.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TLE1","jax_strain_url":"https://www.jax.org/strain/search?query=TLE1"},"sequence":{"accession":"Q04724","fasta_url":"https://rest.uniprot.org/uniprotkb/Q04724.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q04724/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04724"}},"corpus_meta":[{"pmid":"15607978","id":"PMC_15607978","title":"Activating the PARP-1 sensor component of the groucho/ TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway.","date":"2004","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15607978","citation_count":255,"is_preprint":false},{"pmid":"19363472","id":"PMC_19363472","title":"TLE1 expression is not specific for synovial sarcoma: a whole section study of 163 soft tissue and bone neoplasms.","date":"2009","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/19363472","citation_count":165,"is_preprint":false},{"pmid":"21571956","id":"PMC_21571956","title":"Immunohistochemical staining for TLE1 distinguishes synovial sarcoma from histologic mimics.","date":"2011","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21571956","citation_count":160,"is_preprint":false},{"pmid":"8687460","id":"PMC_8687460","title":"Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif.","date":"1996","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8687460","citation_count":131,"is_preprint":false},{"pmid":"19809272","id":"PMC_19809272","title":"Prospective evaluation of TLE1 as a diagnostic immunohistochemical marker in synovial sarcoma.","date":"2009","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19809272","citation_count":106,"is_preprint":false},{"pmid":"20189377","id":"PMC_20189377","title":"TLE1 is a robust diagnostic biomarker for synovial sarcomas and correlates with t(X;18): analysis of 319 cases.","date":"2010","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/20189377","citation_count":83,"is_preprint":false},{"pmid":"18258796","id":"PMC_18258796","title":"Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18258796","citation_count":78,"is_preprint":false},{"pmid":"26831087","id":"PMC_26831087","title":"Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26831087","citation_count":64,"is_preprint":false},{"pmid":"12057191","id":"PMC_12057191","title":"Crystal structure of the C-terminal WD40 repeat domain of the human Groucho/TLE1 transcriptional corepressor.","date":"2002","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/12057191","citation_count":59,"is_preprint":false},{"pmid":"16608701","id":"PMC_16608701","title":"Modelling transcriptional feedback loops: the role of Gro/TLE1 in Hes1 oscillations.","date":"2006","source":"Philosophical transactions. 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Alveolar Epithelial Cell Death through Tle1-mediated Inhibition of the NF-κB Signaling Pathway.","date":"2024","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38574238","citation_count":9,"is_preprint":false},{"pmid":"32065829","id":"PMC_32065829","title":"Reduced Expression of the Co-regulator TLE1 in Type 2 Diabetes Is Associated with Increased Islet α-Cell Number.","date":"2020","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32065829","citation_count":9,"is_preprint":false},{"pmid":"30608261","id":"PMC_30608261","title":"Frequent TLE1 Expression in Cutaneous Neoplasms.","date":"2019","source":"The American Journal of dermatopathology","url":"https://pubmed.ncbi.nlm.nih.gov/30608261","citation_count":8,"is_preprint":false},{"pmid":"31893185","id":"PMC_31893185","title":"Is TLE1 Expression Limited to Synovial Sarcoma? 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microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34673590","citation_count":2,"is_preprint":false},{"pmid":"30410809","id":"PMC_30410809","title":"TLE1 Positive Clear Cell Sarcoma of the Kidney: A Case Report and Review of the Literature.","date":"2018","source":"Case reports in pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30410809","citation_count":2,"is_preprint":false},{"pmid":"27879218","id":"PMC_27879218","title":"Generation of a TLE1 homozygous knockout human embryonic stem cell line using CRISPR-Cas9.","date":"2016","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27879218","citation_count":2,"is_preprint":false},{"pmid":"31020273","id":"PMC_31020273","title":"A rare case of TLE1-positive sclerosing epithelioid fibrosarcoma expanding the differential diagnosis of TLE1-positive tumors: a case report.","date":"2019","source":"AME case 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zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21081038","citation_count":0,"is_preprint":false},{"pmid":"38233028","id":"PMC_38233028","title":"TLE1 Expression in NUT Carcinoma: A Case Report Highlighting a Potential Diagnostic Pitfall for the Pathologist.","date":"2024","source":"International journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38233028","citation_count":0,"is_preprint":false},{"pmid":"21183761","id":"PMC_21183761","title":"Expression, purification, crystallization, and preliminary X-ray diffraction analysis of the human TLE1 Q domain.","date":"2010","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/21183761","citation_count":0,"is_preprint":false},{"pmid":"41933729","id":"PMC_41933729","title":"\"Molecular insights into the bactericidal toxin Tle1 of Pseudomonas aeruginosa: Interaction with VgrG, its adaptor, and its immunity protein\".","date":"2026","source":"The Journal of 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pull-down assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two orthogonal in vitro binding assays (yeast two-hybrid + GST pull-down) in same study; interaction replicated in multiple subsequent studies\",\n      \"pmids\": [\"8687460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TLE1 proteins are phosphorylated in vivo; higher-molecular-mass phosphorylated forms (~118 kDa) exhibit stronger nuclear association than faster-migrating forms (~90–93 kDa), implicating phosphorylation in nuclear targeting and function. The more slowly migrating nuclear forms are induced during neural determination of P19 cells.\",\n      \"method\": \"Cell fractionation; SDS-PAGE mobility shift analysis; neural differentiation of P19 cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation with functional context (neural differentiation), single lab, two orthogonal observations\",\n      \"pmids\": [\"8713081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of the C-terminal WD40 repeat domain of human TLE1 resolved to 1.6 Å reveals a seven-bladed β-propeller; structural comparison with C. elegans UNC-37 missense mutations identifies interaction surfaces for eh1-domain (Engrailed-type) transcription factors, suggesting an induced-fit binding site.\",\n      \"method\": \"X-ray crystallography (1.6 Å); comparative missense mutation analysis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional annotation of binding surfaces\",\n      \"pmids\": [\"12057191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TLE1 interacts with the intracellular region of gp130 (the IL-6 family signal transducer) through its N-terminal Q domain; the membrane-proximal Box1/Box2 region of gp130 is essential for this interaction.\",\n      \"method\": \"Yeast two-hybrid assay; GST pull-down assay; co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal binding methods (yeast 2-hybrid, GST pull-down, co-IP), single lab\",\n      \"pmids\": [\"12030375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TLE1 binds the oncoprotein Qin (winged-helix transcription factor) through a WRPW-containing region C-terminal to Qin's DNA-binding domain; co-expression causes phosphorylation of TLE1, and adding the WRPW motif to a transformation-defective Qin mutant restores TLE1 binding and significantly enhances transformation of chicken embryo fibroblasts.\",\n      \"method\": \"Yeast two-hybrid screen; mammalian two-hybrid assay; transformation assay in chicken embryo fibroblasts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays plus functional transformation rescue, single lab\",\n      \"pmids\": [\"12660810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TLE1 functions as a coactivator (not corepressor) of the orphan nuclear receptor ERRγ by binding its AF-1 domain; demonstrated by phage display biopanning, GST pull-down, and reporter gene assay.\",\n      \"method\": \"Phage display biopanning; GST pull-down; reporter gene assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal methods (phage display, pull-down, reporter assay), single lab, unexpected coactivator activity\",\n      \"pmids\": [\"14651967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PARP-1 is a component of the Groucho/TLE1 corepressor complex at HES1-regulated promoters; CaMKIIδ activation triggers PARP-1-mediated dismissal of the TLE corepressor complex from promoters and simultaneously phosphorylates HES1, switching HES1 from a TLE-dependent repressor to a transcriptional activator required for neurogenic gene activation.\",\n      \"method\": \"Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); promoter reporter assays; dominant-negative/kinase assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, ChIP, reporter assays) in a single rigorous study establishing a mechanistic pathway switch\",\n      \"pmids\": [\"15607978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Protein kinase CK2 phosphorylates TLE1 in vivo at serine 239 within the conserved CcN domain; mutation of Ser-239 to alanine decreases Hes1-induced hyperphosphorylation, reduces nuclear association, reduces transcription repression activity, and impairs the ability of TLE1 to inhibit cortical neural progenitor differentiation into neurons.\",\n      \"method\": \"Site-directed mutagenesis; in vivo phosphorylation assay; nuclear fractionation; transcription repression assay; primary cortical neural progenitor differentiation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific phospho-site validated with multiple functional readouts (nuclear association, repression, neurogenesis) in same study\",\n      \"pmids\": [\"15367661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TLE1 localizes not only to the nucleus but also to apical dendritic shafts of neocortical pyramidal neurons (layers III and V) and Purkinje cell dendrites in the adult rat brain, suggesting extranuclear functions in postmitotic neurons.\",\n      \"method\": \"Immunofluorescence/immunohistochemistry localization in adult rat brain sections\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment replicated across multiple neuronal cell types; functional consequence not directly tested in same paper\",\n      \"pmids\": [\"16081186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpression of Grg1/TLE1 (long isoform) in transgenic mice induces lung adenocarcinoma with elevated ErbB1 and ErbB2 receptor tyrosine kinases and reduced p53; the short isoform Grg5 (lacking SP and WD40 domains) does not induce tumors and co-expression of Grg5 with Grg1 reduces tumor burden.\",\n      \"method\": \"Transgenic mouse overexpression; tumor histology; Western blot for ErbB1/ErbB2/p53\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic gain-of-function with defined molecular mechanism (ErbB1/2 upregulation), domain-function analysis using short isoform, replicated across two transgenic lines\",\n      \"pmids\": [\"16452182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TLE1 and TLE4 lie within the del(9q) commonly deleted region in AML; shRNA knockdown of TLE1 or TLE4 rescues AML1-ETO-expressing cells from cell-cycle arrest and apoptosis, and forced expression causes apoptosis and cell death, identifying TLE1 as a tumor suppressor that opposes AML1-ETO oncogenic activity.\",\n      \"method\": \"shRNA knockdown; forced expression; cell-cycle and apoptosis assays; zebrafish Gro3 knockdown cooperating with AML1-ETO\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments with defined cell-cycle/apoptosis phenotypes, validated in zebrafish model\",\n      \"pmids\": [\"18258796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TLE1 promoter undergoes CpG island hypermethylation-associated silencing in diffuse large B-cell lymphoma and AML; reintroduction of TLE1 in hypermethylated cells causes growth inhibition and suppresses target genes including Cyclin D1, CSF1R, and Hes1; shRNA depletion in unmethylated cells enhances tumor growth.\",\n      \"method\": \"Bisulfite sequencing/methylation-specific PCR; colony and nude-mouse assays after reintroduction; shRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments in vitro and in vivo, with identification of specific transcriptional targets\",\n      \"pmids\": [\"18519670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TLE1 inhibition of cortical neuron differentiation requires its WD40 domain interaction with WRPW-motif proteins (Hes1); point mutation L743F in the WD40 domain selectively blocks Hes1 binding and anti-neurogenic activity but does not disrupt binding to Eh1-motif proteins (Engrailed1, FoxG1) or to Tcf3.\",\n      \"method\": \"Site-directed mutagenesis; co-immunoprecipitation; primary cortical neural progenitor differentiation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with domain-specific binding dissection and neuronal differentiation phenotype in primary cells, single lab\",\n      \"pmids\": [\"18611861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cofactor-activated (Hes1-induced) phosphorylation of TLE1 at Ser-286, Ser-289, and Ser-298 in the SP domain is required for its chromatin association and anti-neurogenic activity; mutation of these sites does not prevent TLE1 recruitment to DNA-bound partners but weakens chromatin interaction.\",\n      \"method\": \"Site-directed mutagenesis; mass spectrometry identification of phospho-sites; chromatin immunoprecipitation; primary cortical neuron differentiation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis + MS phospho-site identification + ChIP + functional neuronal assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19956621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TLE1 associates with ribosomal RNA genes during both mitosis and interphase through interaction with the osteogenic transcription factor Runx2; TLE1 depletion relieves Runx2-mediated rRNA gene repression, increases active-transcription histone modifications, enhances global protein synthesis, and accelerates cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation; ChIP on rDNA; siRNA knockdown; histone modification analysis; protein synthesis assay; cell proliferation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, ChIP, knockdown, functional readouts) establishing TLE1 as Runx2 co-repressor at rRNA genes\",\n      \"pmids\": [\"20160071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TLE1 and TLE3 both repress PROP1 transcriptional activity in conjunction with HESX1, and also repress PROP1 independently of HESX1 through direct protein-protein interaction; TLE1 interacts with HESX1 through an Eh1 (engrailed homology) domain.\",\n      \"method\": \"Co-immunoprecipitation; transcriptional reporter assay; transgenic mouse pituitary expression\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus reporter assay in cell culture plus in vivo transgenic model, single lab\",\n      \"pmids\": [\"20181723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TLE1 physically interacts with NOD2; both proteins co-localize around the nuclear membrane; TLE1 inhibits NF-κB activation by NOD2 in HEK293 cells.\",\n      \"method\": \"Yeast two-hybrid screen of intestinal epithelial library; co-immunoprecipitation in mammalian cells; co-localization imaging; NF-κB reporter assay\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast 2-hybrid confirmed by co-IP and co-localization, functional NF-κB reporter, single lab\",\n      \"pmids\": [\"21699783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TLE1 promotes resistance to anoikis in mammary epithelial and breast cancer cells; mechanistically, TLE1 inhibits the Bit1 anoikis pathway by reducing formation of the proapoptotic Bit1-AES complex in part through sequestration of AES in the nucleus. Cytoplasmic Bit1 induces cytoplasmic translocation and degradation of nuclear TLE1.\",\n      \"method\": \"TLE1 overexpression and siRNA knockdown; anoikis/apoptosis assays; co-immunoprecipitation (Bit1-AES complex); subcellular fractionation\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function, defined molecular mechanism (AES sequestration, Bit1-TLE1 crosstalk), multiple orthogonal methods\",\n      \"pmids\": [\"22952044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TLE1 promotes neuronal survival in postmitotic cerebellar granule neurons; this survival-promoting activity requires CK2-mediated phosphorylation at Ser-239 and Ser-253 and PI3K-Akt signaling, and critically depends on interaction with FoxG1 (the FoxG1 survival activity reciprocally depends on TLE1).\",\n      \"method\": \"Ectopic expression and knockdown in cerebellar granule neurons; pharmacological inhibitors; point mutants (Ser-239/253); cell viability/apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of specific phospho-sites + pathway inhibitors + reciprocal dependence (TLE1/FoxG1) in primary neurons\",\n      \"pmids\": [\"22354967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TLE1 promotes epithelial-to-mesenchymal transition (EMT) in A549 lung cancer cells through transcriptional repression of E-cadherin; TLE1 recruits histone deacetylase (HDAC) activity to the E-cadherin promoter, and HDAC inhibitor TSA partially reverses TLE1-induced E-cadherin repression and cell migration.\",\n      \"method\": \"TLE1 overexpression and siRNA knockdown; cell morphology/migration assays; RT-PCR/Western blot for EMT markers; chromatin immunoprecipitation; TSA pharmacological rescue\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain/loss-of-function, ChIP showing HDAC recruitment to E-cadherin promoter, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"25446087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Grg1/TLE1 is the predominant Groucho expressed in human pancreatic β-cells and acts functionally similarly to Grg3 in establishing monohormonal β-cell identity by repressing α-cell genes (glucagon, Arx); ectopic Grg1 expression in α-cells represses glucagon.\",\n      \"method\": \"Immunostaining in human islets; ectopic expression in α-cells; qRT-PCR for α/β-cell markers\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization in human tissue plus functional ectopic expression experiment, single lab\",\n      \"pmids\": [\"24487024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tle1 deficiency in mice causes chronic inflammation with increased NF-κB phosphorylation/activation and decreased Hes1 expression in macrophages; Tle1-deficient macrophages produce increased inflammatory cytokines in response to TLR agonists/LPS, demonstrating TLE1 as a major negative regulator of the NF-κB inflammatory pathway in vivo.\",\n      \"method\": \"Tle1 knockout mice; cytokine/chemokine quantification; Western blot for NF-κB phosphorylation; macrophage LPS stimulation assays; skin TPA inflammation model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model with multiple tissue readouts plus ex vivo macrophage functional assays, multiple orthogonal methods\",\n      \"pmids\": [\"26831087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TLE1 is phosphorylated in response to Ras-ERK pathway activation; this phosphorylation attenuates TLE1 repressor activity and causes rapid nuclear exclusion of TLE1 following EGFR activation. Unphosphorylatable TLE1 dominantly suppresses Ras-ERK target gene induction and blocks oncogenic H-Ras phenotypes in human mammary cells in vitro and in vivo.\",\n      \"method\": \"Phosphorylation assays; nuclear/cytoplasmic fractionation; transcriptional reporter assays; Drosophila transgenic phenotype analysis; tumor implantation in mice\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods across human cells and Drosophila model; gain-of-function, phospho-mimetic, and unphosphorylatable mutants; in vivo validation\",\n      \"pmids\": [\"28192406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Structure-enabled design of a stapled peptide inhibitor (cycFWRPW) targeting the TLE1 WD40 β-propeller domain; co-crystal structure with TLE1 confirms the binding mode; the constrained peptide binds potently but with ~5-fold reduced affinity compared to linear peptide due to a side-chain shift.\",\n      \"method\": \"Isothermal titration calorimetry; thermal shift assay; X-ray co-crystallography\",\n      \"journal\": \"Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of inhibitor complex + biophysical binding measurements in single rigorous study\",\n      \"pmids\": [\"28326635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TLE1 promotes anoikis resistance and tumorigenicity in lung cancer cells via ZEB1-mediated E-cadherin repression; ZEB1 recruits TLE1 to the E-cadherin promoter to impose histone deacetylation and gene silencing; Bit1 tumor suppressor negatively regulates TLE1-mediated E-cadherin repression.\",\n      \"method\": \"TLE1 overexpression and siRNA knockdown; chromatin immunoprecipitation; in vivo tumorigenicity assay; ZEB1 siRNA epistasis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP showing ZEB1-TLE1 co-occupancy at E-cadherin promoter, epistasis experiments, in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"29069783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXG1 and TLE1 form a transcriptional repressor complex in glioblastoma-initiating cells that targets ~150 FOXG1 genomic loci; ChIP-Seq and RNA-Seq identify shared targets including negative regulators of NOTCH signaling (e.g., CHAC1), suggesting FOXG1:TLE1 crosstalk with NOTCH pathway in GBM.\",\n      \"method\": \"ChIP-Seq; RNA-Seq in patient-derived brain tumor-initiating cells\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide binding + transcriptome profiling in patient-derived cells, single lab\",\n      \"pmids\": [\"29316219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tle1 suppresses NOD2-dependent NF-κB activation in the liver; in hepatic ischemia/reperfusion injury, Tle1 expression decreases while NOD2 increases; Tle1-siRNA knockdown aggravates liver dysfunction and enhances NOD2/NF-κB signaling, whereas NOD2 alteration does not affect Tle1 expression, placing Tle1 upstream of NOD2 in this pathway.\",\n      \"method\": \"Mouse I/R model; Tle1 siRNA knockdown; hypoxia/reoxygenation cell model; Western blot for NOD2/NF-κB; liver function assays\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro loss-of-function with epistasis (NOD2 alteration does not affect TLE1), single lab\",\n      \"pmids\": [\"32114961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A specific N-terminal phosphorylation site present in TLE1 but absent from TLE3 determines their differential functional activities; mutating or reconstituting this site converts TLE1 activity to TLE3-like behavior and vice versa, demonstrated in lung cancer cells (paclitaxel sensitivity) and an adipocyte differentiation system.\",\n      \"method\": \"Site-directed mutagenesis of phosphorylation site; retroviral transduction; paclitaxel sensitivity assay; adipocyte differentiation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional validation in two cellular systems (cancer drug sensitivity + differentiation), single lab\",\n      \"pmids\": [\"33571907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FTO m6A demethylase regulates TLE1 mRNA stability and expression through m6A modification; PEITC treatment inhibits FTO, increases m6A methylation of TLE1 mRNA, reduces TLE1 protein levels, and suppresses NSCLC cell migration via the Akt/NF-κB pathway downstream of TLE1.\",\n      \"method\": \"FTO knockdown/overexpression; m6A methylation assay; mRNA stability assay; migration/invasion assays; Akt/NF-κB pathway Western blot\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic writer (FTO) identified for TLE1 mRNA m6A modification with functional pathway validation, single lab\",\n      \"pmids\": [\"37848553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TLE1 protects the blood-brain barrier and reduces PANoptosis after cerebral ischemia/reperfusion via the TLE1/PI3K/AKT signaling pathway; TLE1 overexpression is protective, and its knockdown abolishes the protective effects of esculentoside H treatment; PI3K inhibitor LY294002 blocks TLE1-dependent protection.\",\n      \"method\": \"AAV-mediated TLE1 overexpression/knockdown in rat MCAO model; PI3K inhibitor LY294002; infarct volume, BBB permeability, neuronal death assays\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain- and loss-of-function with pharmacological pathway inhibition, single lab\",\n      \"pmids\": [\"38857750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Foxq1 promotes alveolar epithelial cell death through TLE1-mediated inhibition of NF-κB signaling; TLE1 acts downstream of Foxq1 to suppress NF-κB/Bcl2/Bax pathway in ALI; Foxq1 knockdown promotes cell survival whereas overexpression induces death, effects mediated through TLE1.\",\n      \"method\": \"Foxq1 knockdown and overexpression in MLE-12 cells; LPS ALI mouse model; Western blot for NF-κB/Bcl2/Bax; cell viability assays\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis placing TLE1 downstream of Foxq1 in NF-κB pathway, in vitro and in vivo, single lab\",\n      \"pmids\": [\"38574238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TLE1 drives EGFR-TKI resistance in EGFR-mutant lung adenocarcinoma through EMT; TLE1 interacts with ZEB1 to suppress E-cadherin expression; exogenous TLE1 reduces sensitivity to gefitinib/osimertinib and knockdown of endogenous TLE1 in resistant cells partially restores drug sensitivity; Bit1 release by TKI treatment causes nuclear exclusion of TLE1 via cytosolic Bit1-AES complex formation.\",\n      \"method\": \"TLE1 overexpression and knockdown in PC9/HCC827 and derived resistant lines; co-immunoprecipitation (TLE1-ZEB1); subcellular fractionation; apoptosis and viability assays; RNA-seq\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function, co-IP for ZEB1 interaction, RNA-seq, multiple cell models; single lab\",\n      \"pmids\": [\"40482589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Tle1 overexpression in CD8+ T cells enhances effector proliferation during acute and chronic viral infections and improves CTL responses to PD-1/PD-L1 blockade; Tle1 enhances TCR signaling and immunoinhibitory receptor expression (PD-1, LAG-3) through repression of TCF-1; genome-wide Tle1 binding profiles show cooperation with Ets, AP-1, and Runx transcription factors.\",\n      \"method\": \"Retroviral Tle1 overexpression in CD8+ T cells; viral infection models; transcriptome analysis; ChIP-Seq/genome-wide binding profiles; PD-1 blockade experiments\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with genome-wide binding data and TCF-1 epistasis, multiple viral models, single lab\",\n      \"pmids\": [\"41810855\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TLE1 is a transcriptional corepressor that lacks intrinsic DNA-binding but is recruited to target promoters by diverse DNA-binding partners (HES1/WRPW motif, Engrailed/Eh1 motif, Runx2, FoxG1, ZEB1, NOD2, HESX1, PROP1, gp130) via its seven-bladed WD40 β-propeller domain; its repressive activity—which involves histone deacetylase recruitment and chromatin association—is regulated by multiple phosphorylation events (CK2 at Ser-239/253, Ras-ERK pathway causing nuclear exclusion, cofactor-activated SP-domain phosphorylation at Ser-286/289/298) and can be switched off by PARP-1-mediated complex dismissal or Bit1-induced cytoplasmic sequestration, allowing context-dependent corepressor-to-coactivator transitions; physiologically TLE1 suppresses neuronal differentiation, maintains β-cell identity by repressing glucagon, inhibits NF-κB-driven inflammation, and acts as a tumor suppressor in hematopoietic malignancies, while in certain contexts (lung adenocarcinoma) it promotes oncogenesis through ZEB1-dependent E-cadherin repression and EMT-associated anoikis resistance and drug resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TLE1 is a transcriptional corepressor that lacks intrinsic DNA-binding activity and is recruited to target genes by sequence-specific transcription factors, imposing repression through chromatin association and histone deacetylase recruitment [#0, #19]. Its C-terminal WD40 domain forms a seven-bladed β-propeller that provides distinct binding surfaces: a WRPW/WRPW-motif site engaged by Hairy/HES-family proteins such as HES-1, and an eh1/Engrailed-type surface used by Eh1-motif partners [#0, #2, #12]. Through these interfaces TLE1 partners with HES1, Runx2, FoxG1/HESX1, ZEB1, NOD2, and gp130, and selective WD40 point mutations (e.g., L743F) uncouple Hes1 binding from Eh1-motif factor binding [#3, #12, #14, #15, #16]. TLE1 repressor activity is gated by phosphorylation: CK2 modifies Ser-239/Ser-253 within the CcN domain and cofactor (Hes1)-activated phosphorylation at Ser-286/289/298 in the SP domain promotes nuclear/chromatin association and repression, whereas Ras-ERK-driven phosphorylation triggers nuclear exclusion and loss of repression [#7, #13, #18, #22]. The complex is also switched off by PARP-1-mediated dismissal from HES1 promoters and by Bit1-induced cytoplasmic sequestration of nuclear TLE1, enabling repressor-to-activator transitions [#6, #17]. Functionally TLE1 suppresses neuronal differentiation while promoting survival of postmitotic neurons, maintains pancreatic β-cell identity by repressing glucagon, and is a negative regulator of NOD2/NF-κB-driven inflammation [#7, #18, #20, #16, #21]. In cancer TLE1 has dual roles: it acts as a tumor suppressor in hematopoietic malignancies, where del(9q) loss and CpG-island hypermethylation silence it and forced re-expression drives apoptosis and represses Cyclin D1, CSF1R, and Hes1, yet promotes oncogenesis in lung adenocarcinoma by partnering with ZEB1 to repress E-cadherin, driving EMT, anoikis resistance, and EGFR-TKI resistance [#10, #11, #24, #19, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that mammalian TLE1 engages Hairy/HES-class transcription factors, defining the conserved Groucho/TLE recruitment principle in mammals.\",\n      \"evidence\": \"Yeast two-hybrid and GST pull-down mapping the HES-1 WRPW motif interaction\",\n      \"pmids\": [\"8687460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which TLE domain mediates binding\", \"No promoter or repression readout in this study\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Linked TLE1 phosphorylation state to subcellular distribution and differentiation, raising phosphorylation as a regulatory layer.\",\n      \"evidence\": \"Cell fractionation and SDS-PAGE mobility shifts across P19 neural differentiation\",\n      \"pmids\": [\"8713081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No specific phospho-sites or kinases identified\", \"Causal link between phosphorylation and nuclear targeting not yet tested by mutagenesis\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Provided the structural basis for partner recognition by solving the WD40 β-propeller and locating the eh1-domain interaction surface.\",\n      \"evidence\": \"1.6 Å X-ray crystallography with comparative UNC-37 missense analysis\",\n      \"pmids\": [\"12057191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length and N-terminal domains not structurally resolved\", \"Mechanism of induced-fit binding inferred, not directly captured with bound partner\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped a distinct N-terminal Q-domain interaction to the IL-6 signal transducer gp130, extending TLE1 partners beyond classical transcription factors.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, and co-IP mapping the Box1/Box2 region\",\n      \"pmids\": [\"12030375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for cytokine signaling not established\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed TLE1 can act as a coactivator depending on partner, indicating context-dependent rather than uniformly repressive output.\",\n      \"evidence\": \"Phage display biopanning, GST pull-down, and reporter assays with ERRγ AF-1 domain\",\n      \"pmids\": [\"14651967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of the coactivator switch unresolved\", \"No endogenous target gene validation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that TLE1 binding contributes to oncogenic transformation, an early link between corepressor recruitment and cancer phenotypes.\",\n      \"evidence\": \"Two-hybrid and chicken embryo fibroblast transformation rescue with WRPW-engineered Qin\",\n      \"pmids\": [\"12660810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct repression targets driving transformation not identified\", \"Mammalian relevance untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined a dynamic off-switch for the corepressor: PARP-1 dismissal of the TLE complex coupled to HES1 conversion to an activator during neurogenesis.\",\n      \"evidence\": \"Co-IP, ChIP, reporter and kinase assays linking CaMKIIδ/PARP-1 to complex dismissal\",\n      \"pmids\": [\"15607978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of PARP-1 dismissal beyond HES1 promoters unknown\", \"Stoichiometry/timing of dismissal not quantified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified CK2 phosphorylation of Ser-239 as a determinant of nuclear association, repression, and anti-neurogenic activity, validating phosphorylation as functional control.\",\n      \"evidence\": \"Site-directed mutagenesis with in vivo phosphorylation, fractionation, repression, and cortical progenitor differentiation assays\",\n      \"pmids\": [\"15367661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other CK2 or cofactor-dependent sites not yet mapped here\", \"Direct chromatin binding consequence not measured\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed extranuclear TLE1 in postmitotic neuronal dendrites, implying functions beyond promoter repression.\",\n      \"evidence\": \"Immunolocalization in adult rat neocortical and Purkinje neurons\",\n      \"pmids\": [\"16081186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional role for dendritic TLE1 demonstrated\", \"Interacting partners at this site unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided in vivo evidence that long-isoform TLE1 overexpression drives lung adenocarcinoma, with isoform domain requirements defining oncogenic potential.\",\n      \"evidence\": \"Transgenic mouse gain-of-function with ErbB1/2 and p53 profiling and Grg5 short-isoform comparison\",\n      \"pmids\": [\"16452182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets linking TLE1 to ErbB upregulation not defined\", \"Partner factor driving tumorigenesis unidentified in this model\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established TLE1 as a tumor suppressor in hematopoietic malignancy opposing AML1-ETO, defining loss-of-function as oncogenic in this context.\",\n      \"evidence\": \"shRNA knockdown and forced expression with cell-cycle/apoptosis assays and zebrafish modeling\",\n      \"pmids\": [\"18258796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TLE1 target genes mediating apoptosis not fully resolved\", \"Recruiting DNA-binding partner at relevant loci unspecified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed TLE1 is epigenetically silenced in lymphoma/AML and identified repression targets, reinforcing its tumor-suppressive role.\",\n      \"evidence\": \"Bisulfite/MSP methylation analysis with reintroduction, colony, nude-mouse, and knockdown assays identifying Cyclin D1, CSF1R, Hes1\",\n      \"pmids\": [\"18519670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNA-binding factors recruiting TLE1 to these promoters not mapped\", \"Mechanism of growth inhibition downstream of targets incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetically dissected the WD40 domain to show partner-selective repression, separating Hes1-dependent anti-neurogenic activity from Eh1-motif binding.\",\n      \"evidence\": \"L743F mutagenesis with co-IP and cortical progenitor differentiation assays\",\n      \"pmids\": [\"18611861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of partner discrimination at this residue not crystallographically resolved\", \"Other WD40 surface residues governing partner choice untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined cofactor-activated SP-domain phosphorylation (Ser-286/289/298) as required for chromatin association distinct from partner recruitment.\",\n      \"evidence\": \"Mutagenesis plus mass-spectrometry phospho-mapping, ChIP, and neuron differentiation assays\",\n      \"pmids\": [\"19956621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase executing SP-domain phosphorylation not identified\", \"Chromatin contact mechanism (histone vs nucleosome) unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended TLE1 repression to rRNA genes via Runx2, linking the corepressor to ribosome biogenesis and proliferation control.\",\n      \"evidence\": \"Co-IP, rDNA ChIP, siRNA, histone modification, protein synthesis and proliferation assays\",\n      \"pmids\": [\"20160071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mitotic vs interphase rDNA association mechanism not fully separated\", \"Whether HDAC mediates the rDNA silencing not directly shown here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established TLE1 cooperation with HESX1/PROP1 in pituitary transcriptional repression, including HESX1-independent repression via direct contact.\",\n      \"evidence\": \"Co-IP, reporter assays, and transgenic pituitary expression with Eh1-domain mapping\",\n      \"pmids\": [\"20181723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological pituitary phenotype of TLE1 loss not tested\", \"Endogenous target promoters not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified TLE1 as a NOD2-interacting suppressor of NF-κB, opening a role in innate immune/inflammatory regulation.\",\n      \"evidence\": \"Yeast two-hybrid screen, co-IP, co-localization, and NF-κB reporter in HEK293\",\n      \"pmids\": [\"21699783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance not tested in this study\", \"Whether repression is transcriptional or signaling-level unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed TLE1 promotes anoikis resistance in breast cells by sequestering AES and antagonizing the Bit1 pathway, revealing a cytoplasmic regulatory crosstalk.\",\n      \"evidence\": \"Overexpression/knockdown, anoikis assays, Bit1-AES co-IP, and fractionation\",\n      \"pmids\": [\"22952044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for Bit1-driven TLE1 cytoplasmic translocation in physiological settings unclear\", \"Degradation machinery for cytoplasmic TLE1 not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated a pro-survival role for TLE1 in postmitotic neurons requiring CK2 phospho-sites, PI3K-Akt, and FoxG1, contrasting its anti-neurogenic role in progenitors.\",\n      \"evidence\": \"Ectopic expression/knockdown, inhibitors, Ser-239/253 mutants, and viability assays in cerebellar granule neurons\",\n      \"pmids\": [\"22354967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target genes mediating neuronal survival not identified\", \"Mechanistic link from PI3K-Akt to TLE1 not detailed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked TLE1 to EMT in lung cancer by HDAC-dependent E-cadherin repression, establishing an oncogenic transcriptional output.\",\n      \"evidence\": \"Overexpression/knockdown, migration assays, EMT marker analysis, ChIP, and TSA rescue in A549 cells\",\n      \"pmids\": [\"25446087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNA-binding factor recruiting TLE1 to E-cadherin not yet identified in this study\", \"Specific HDAC isoform unconfirmed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed TLE1 maintains pancreatic β-cell identity by repressing α-cell genes, defining a developmental/endocrine role.\",\n      \"evidence\": \"Human islet immunostaining and ectopic expression in α-cells with marker qRT-PCR\",\n      \"pmids\": [\"24487024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DNA-binding partner repressing glucagon/Arx not identified\", \"Loss-of-function in vivo β-cell phenotype not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided in vivo proof that TLE1 is a major negative regulator of NF-κB inflammation via knockout phenotypes in macrophages and skin.\",\n      \"evidence\": \"Tle1 knockout mice with cytokine quantification, NF-κB Western blots, LPS macrophage stimulation, and TPA model\",\n      \"pmids\": [\"26831087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular step at which TLE1 blocks NF-κB not fully defined\", \"Relationship between reduced Hes1 and NF-κB activation not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined Ras-ERK phosphorylation as the switch that excludes TLE1 from the nucleus and disables repression, integrating it into oncogenic signaling.\",\n      \"evidence\": \"Phosphorylation assays, fractionation, reporters, Drosophila phenotypes, and mouse tumor implantation with mutant TLE1\",\n      \"pmids\": [\"28192406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact ERK-targeted residues not pinpointed here\", \"Target gene set derepressed upon nuclear exclusion not enumerated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Delivered a structure-guided peptide inhibitor of the WD40 partner-binding site, validating the propeller as a druggable interface.\",\n      \"evidence\": \"ITC, thermal shift, and X-ray co-crystallography of the cycFWRPW stapled peptide\",\n      \"pmids\": [\"28326635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular efficacy of the inhibitor not demonstrated\", \"Affinity reduced relative to linear peptide\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified ZEB1 as the DNA-binding partner recruiting TLE1 to the E-cadherin promoter, mechanistically grounding TLE1-driven anoikis resistance and tumorigenicity in lung cancer.\",\n      \"evidence\": \"Overexpression/knockdown, ChIP co-occupancy, ZEB1 epistasis, and in vivo tumorigenicity assays\",\n      \"pmids\": [\"29069783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HDAC isoform recruited unspecified\", \"Quantitative contribution of Bit1 regulation in vivo not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped genome-wide FOXG1:TLE1 repressor occupancy in glioblastoma-initiating cells, connecting the complex to NOTCH-regulatory targets.\",\n      \"evidence\": \"ChIP-Seq and RNA-Seq in patient-derived brain tumor-initiating cells\",\n      \"pmids\": [\"29316219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional/therapeutic consequence of FOXG1:TLE1 targets not tested\", \"Direct vs indirect NOTCH crosstalk unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned Tle1 upstream of NOD2 in liver ischemia/reperfusion, extending its NF-κB-suppressive role to organ injury.\",\n      \"evidence\": \"Mouse I/R model, Tle1 siRNA, hypoxia/reoxygenation cells, and epistasis Western blots\",\n      \"pmids\": [\"32114961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Tle1 downregulation during I/R unknown\", \"Single lab, no rescue with TLE1 re-expression in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a TLE1-specific N-terminal phospho-site distinguishing it functionally from TLE3, demonstrating site-swapping converts paralog behavior.\",\n      \"evidence\": \"Mutagenesis and reconstitution with paclitaxel sensitivity and adipocyte differentiation readouts\",\n      \"pmids\": [\"33571907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for the differential site not identified\", \"Mechanistic link from this site to repression output incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed TLE1 mRNA is controlled by FTO-mediated m6A demethylation, adding a post-transcriptional regulatory layer relevant to NSCLC migration.\",\n      \"evidence\": \"FTO knockdown/overexpression, m6A and mRNA stability assays, migration assays, and Akt/NF-κB Western blots\",\n      \"pmids\": [\"37848553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A reader interpreting TLE1 mRNA marks not identified\", \"Direct vs indirect Akt/NF-κB effects not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated TLE1 in PI3K/AKT-dependent blood-brain barrier protection and PANoptosis reduction after cerebral ischemia/reperfusion.\",\n      \"evidence\": \"AAV TLE1 overexpression/knockdown in rat MCAO with LY294002 and BBB/neuronal death readouts\",\n      \"pmids\": [\"38857750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets mediating protection not identified\", \"Whether TLE1 acts directly in PI3K/AKT pathway unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed TLE1 downstream of Foxq1 in NF-κB suppression governing alveolar epithelial cell death in acute lung injury.\",\n      \"evidence\": \"Foxq1 knockdown/overexpression in MLE-12 cells, LPS ALI model, and NF-κB/Bcl2/Bax analyses\",\n      \"pmids\": [\"38574238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Foxq1-TLE1 physical interaction not demonstrated\", \"Promoter targets driving the death phenotype unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated TLE1-ZEB1-driven EMT as a mechanism of EGFR-TKI resistance, with Bit1-AES-mediated nuclear exclusion modulating drug response.\",\n      \"evidence\": \"Overexpression/knockdown in PC9/HCC827 and resistant lines, TLE1-ZEB1 co-IP, fractionation, and RNA-seq\",\n      \"pmids\": [\"40482589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical correlation of TLE1 with TKI resistance not established\", \"Single lab, mechanism overlaps prior ZEB1 model\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a CD8+ T-cell role where Tle1 enhances effector responses and checkpoint-blockade efficacy via TCF-1 repression and cooperation with Ets/AP-1/Runx factors.\",\n      \"evidence\": \"Retroviral Tle1 overexpression, viral infection models, transcriptomics, ChIP-Seq, and PD-1 blockade experiments\",\n      \"pmids\": [\"41810855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction with Ets/AP-1/Runx not biochemically validated\", \"Endogenous Tle1 loss-of-function phenotype in T cells not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single corepressor toggles between tumor-suppressive and oncogenic outputs, and how phosphorylation/partner choice deterministically dictates this in a given tissue, remains unresolved.\",\n      \"evidence\": \"No single study integrates the phosphorylation code, partner selection, and context-specific functional outcome\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking specific phospho-states to specific partner-recruited repression outputs\", \"Kinases for several functional phospho-sites unidentified\", \"Determinants of corepressor-to-coactivator switching incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6, 14, 19, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 16, 21, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 12, 14, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 7, 13, 17, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17, 22, 31]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 14, 19, 24]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 21, 26, 30, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11, 19, 24, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 12, 18, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [22, 29]}\n    ],\n    \"complexes\": [\n      \"Groucho/TLE1 corepressor complex (with PARP-1)\",\n      \"FOXG1:TLE1 repressor complex\"\n    ],\n    \"partners\": [\n      \"HES1\",\n      \"ZEB1\",\n      \"FoxG1\",\n      \"Runx2\",\n      \"NOD2\",\n      \"PARP1\",\n      \"HESX1\",\n      \"gp130\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}