Affinage

TLE1

Transducin-like enhancer protein 1 · UniProt Q04724

Length
770 aa
Mass
83.2 kDa
Annotated
2026-06-10
82 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 33 steps
  1. 1996 High

    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

    PMID:8687460

    Open questions at the time
    • Did not resolve which TLE domain mediates binding
    • No promoter or repression readout in this study
  2. 1996 Medium

    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

    PMID:8713081

    Open questions at the time
    • No specific phospho-sites or kinases identified
    • Causal link between phosphorylation and nuclear targeting not yet tested by mutagenesis
  3. 2002 High

    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

    PMID:12057191

    Open questions at the time
    • Full-length and N-terminal domains not structurally resolved
    • Mechanism of induced-fit binding inferred, not directly captured with bound partner
  4. 2002 Medium

    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

    PMID:12030375

    Open questions at the time
    • Functional consequence for cytokine signaling not established
    • Single lab, no in vivo validation
  5. 2003 Medium

    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

    PMID:14651967

    Open questions at the time
    • Mechanism of the coactivator switch unresolved
    • No endogenous target gene validation
  6. 2003 Medium

    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

    PMID:12660810

    Open questions at the time
    • Direct repression targets driving transformation not identified
    • Mammalian relevance untested
  7. 2004 High

    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

    PMID:15607978

    Open questions at the time
    • Generality of PARP-1 dismissal beyond HES1 promoters unknown
    • Stoichiometry/timing of dismissal not quantified
  8. 2004 High

    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

    PMID:15367661

    Open questions at the time
    • Other CK2 or cofactor-dependent sites not yet mapped here
    • Direct chromatin binding consequence not measured
  9. 2005 Medium

    Revealed extranuclear TLE1 in postmitotic neuronal dendrites, implying functions beyond promoter repression.

    Evidence Immunolocalization in adult rat neocortical and Purkinje neurons

    PMID:16081186

    Open questions at the time
    • No functional role for dendritic TLE1 demonstrated
    • Interacting partners at this site unknown
  10. 2006 High

    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

    PMID:16452182

    Open questions at the time
    • Direct transcriptional targets linking TLE1 to ErbB upregulation not defined
    • Partner factor driving tumorigenesis unidentified in this model
  11. 2008 High

    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

    PMID:18258796

    Open questions at the time
    • Direct TLE1 target genes mediating apoptosis not fully resolved
    • Recruiting DNA-binding partner at relevant loci unspecified
  12. 2008 High

    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

    PMID:18519670

    Open questions at the time
    • DNA-binding factors recruiting TLE1 to these promoters not mapped
    • Mechanism of growth inhibition downstream of targets incomplete
  13. 2008 High

    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

    PMID:18611861

    Open questions at the time
    • Structural basis of partner discrimination at this residue not crystallographically resolved
    • Other WD40 surface residues governing partner choice untested
  14. 2009 High

    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

    PMID:19956621

    Open questions at the time
    • Kinase executing SP-domain phosphorylation not identified
    • Chromatin contact mechanism (histone vs nucleosome) unresolved
  15. 2010 High

    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

    PMID:20160071

    Open questions at the time
    • Mitotic vs interphase rDNA association mechanism not fully separated
    • Whether HDAC mediates the rDNA silencing not directly shown here
  16. 2010 Medium

    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

    PMID:20181723

    Open questions at the time
    • Physiological pituitary phenotype of TLE1 loss not tested
    • Endogenous target promoters not identified
  17. 2011 Medium

    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

    PMID:21699783

    Open questions at the time
    • In vivo relevance not tested in this study
    • Whether repression is transcriptional or signaling-level unresolved
  18. 2012 High

    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

    PMID:22952044

    Open questions at the time
    • Trigger for Bit1-driven TLE1 cytoplasmic translocation in physiological settings unclear
    • Degradation machinery for cytoplasmic TLE1 not defined
  19. 2012 High

    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

    PMID:22354967

    Open questions at the time
    • Target genes mediating neuronal survival not identified
    • Mechanistic link from PI3K-Akt to TLE1 not detailed
  20. 2014 High

    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

    PMID:25446087

    Open questions at the time
    • DNA-binding factor recruiting TLE1 to E-cadherin not yet identified in this study
    • Specific HDAC isoform unconfirmed
  21. 2014 Medium

    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

    PMID:24487024

    Open questions at the time
    • DNA-binding partner repressing glucagon/Arx not identified
    • Loss-of-function in vivo β-cell phenotype not tested
  22. 2016 High

    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

    PMID:26831087

    Open questions at the time
    • Direct molecular step at which TLE1 blocks NF-κB not fully defined
    • Relationship between reduced Hes1 and NF-κB activation not mechanistically dissected
  23. 2017 High

    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

    PMID:28192406

    Open questions at the time
    • Exact ERK-targeted residues not pinpointed here
    • Target gene set derepressed upon nuclear exclusion not enumerated
  24. 2017 High

    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

    PMID:28326635

    Open questions at the time
    • Cellular efficacy of the inhibitor not demonstrated
    • Affinity reduced relative to linear peptide
  25. 2017 High

    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

    PMID:29069783

    Open questions at the time
    • HDAC isoform recruited unspecified
    • Quantitative contribution of Bit1 regulation in vivo not resolved
  26. 2018 Medium

    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

    PMID:29316219

    Open questions at the time
    • Functional/therapeutic consequence of FOXG1:TLE1 targets not tested
    • Direct vs indirect NOTCH crosstalk unresolved
  27. 2020 Medium

    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

    PMID:32114961

    Open questions at the time
    • Mechanism of Tle1 downregulation during I/R unknown
    • Single lab, no rescue with TLE1 re-expression in vivo
  28. 2021 Medium

    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

    PMID:33571907

    Open questions at the time
    • Kinase responsible for the differential site not identified
    • Mechanistic link from this site to repression output incomplete
  29. 2023 Medium

    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

    PMID:37848553

    Open questions at the time
    • m6A reader interpreting TLE1 mRNA marks not identified
    • Direct vs indirect Akt/NF-κB effects not separated
  30. 2024 Medium

    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

    PMID:38857750

    Open questions at the time
    • Transcriptional targets mediating protection not identified
    • Whether TLE1 acts directly in PI3K/AKT pathway unresolved
  31. 2024 Medium

    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

    PMID:38574238

    Open questions at the time
    • Direct Foxq1-TLE1 physical interaction not demonstrated
    • Promoter targets driving the death phenotype unidentified
  32. 2025 Medium

    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

    PMID:40482589

    Open questions at the time
    • Clinical correlation of TLE1 with TKI resistance not established
    • Single lab, mechanism overlaps prior ZEB1 model
  33. 2026 Medium

    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

    PMID:41810855

    Open questions at the time
    • Direct physical interaction with Ets/AP-1/Runx not biochemically validated
    • Endogenous Tle1 loss-of-function phenotype in T cells not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 3 GO:0005635 nuclear envelope 1 GO:0005730 nucleolus 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 2
Partners
FOXG1GP130HES1HESX1NOD2PARP1RUNX2ZEB1
Complex memberships
FOXG1:TLE1 repressor complexGroucho/TLE1 corepressor complex (with PARP-1)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Yeast two-hybrid assay; GST fusion protein pull-down assay Biochemical and biophysical research communications High 8687460
1996 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. Cell fractionation; SDS-PAGE mobility shift analysis; neural differentiation of P19 cells The Biochemical journal Medium 8713081
2002 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. X-ray crystallography (1.6 Å); comparative missense mutation analysis Structure High 12057191
2002 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. Yeast two-hybrid assay; GST pull-down assay; co-immunoprecipitation Molecular and cellular biochemistry Medium 12030375
2003 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. Yeast two-hybrid screen; mammalian two-hybrid assay; transformation assay in chicken embryo fibroblasts Oncogene Medium 12660810
2003 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. Phage display biopanning; GST pull-down; reporter gene assay Biochemical and biophysical research communications Medium 14651967
2004 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. Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); promoter reporter assays; dominant-negative/kinase assays Cell High 15607978
2004 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. Site-directed mutagenesis; in vivo phosphorylation assay; nuclear fractionation; transcription repression assay; primary cortical neural progenitor differentiation assay Molecular and cellular biology High 15367661
2005 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. Immunofluorescence/immunohistochemistry localization in adult rat brain sections Brain research. Molecular brain research Medium 16081186
2006 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. Transgenic mouse overexpression; tumor histology; Western blot for ErbB1/ErbB2/p53 Cancer research High 16452182
2008 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. shRNA knockdown; forced expression; cell-cycle and apoptosis assays; zebrafish Gro3 knockdown cooperating with AML1-ETO Blood High 18258796
2008 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. Bisulfite sequencing/methylation-specific PCR; colony and nude-mouse assays after reintroduction; shRNA knockdown Cancer research High 18519670
2008 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. Site-directed mutagenesis; co-immunoprecipitation; primary cortical neural progenitor differentiation assay The Journal of biological chemistry High 18611861
2009 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. Site-directed mutagenesis; mass spectrometry identification of phospho-sites; chromatin immunoprecipitation; primary cortical neuron differentiation assay PloS one High 19956621
2010 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. Co-immunoprecipitation; ChIP on rDNA; siRNA knockdown; histone modification analysis; protein synthesis assay; cell proliferation assay Proceedings of the National Academy of Sciences of the United States of America High 20160071
2010 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. Co-immunoprecipitation; transcriptional reporter assay; transgenic mouse pituitary expression Molecular endocrinology Medium 20181723
2011 TLE1 physically interacts with NOD2; both proteins co-localize around the nuclear membrane; TLE1 inhibits NF-κB activation by NOD2 in HEK293 cells. Yeast two-hybrid screen of intestinal epithelial library; co-immunoprecipitation in mammalian cells; co-localization imaging; NF-κB reporter assay Gastroenterology Medium 21699783
2012 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. TLE1 overexpression and siRNA knockdown; anoikis/apoptosis assays; co-immunoprecipitation (Bit1-AES complex); subcellular fractionation Molecular cancer research : MCR High 22952044
2012 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). Ectopic expression and knockdown in cerebellar granule neurons; pharmacological inhibitors; point mutants (Ser-239/253); cell viability/apoptosis assays The Journal of biological chemistry High 22354967
2014 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. TLE1 overexpression and siRNA knockdown; cell morphology/migration assays; RT-PCR/Western blot for EMT markers; chromatin immunoprecipitation; TSA pharmacological rescue Biochemical and biophysical research communications High 25446087
2014 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. Immunostaining in human islets; ectopic expression in α-cells; qRT-PCR for α/β-cell markers Diabetes Medium 24487024
2016 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. Tle1 knockout mice; cytokine/chemokine quantification; Western blot for NF-κB phosphorylation; macrophage LPS stimulation assays; skin TPA inflammation model Proceedings of the National Academy of Sciences of the United States of America High 26831087
2017 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. Phosphorylation assays; nuclear/cytoplasmic fractionation; transcriptional reporter assays; Drosophila transgenic phenotype analysis; tumor implantation in mice Oncogene High 28192406
2017 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. Isothermal titration calorimetry; thermal shift assay; X-ray co-crystallography Chemistry High 28326635
2017 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. TLE1 overexpression and siRNA knockdown; chromatin immunoprecipitation; in vivo tumorigenicity assay; ZEB1 siRNA epistasis Oncotarget High 29069783
2018 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. ChIP-Seq; RNA-Seq in patient-derived brain tumor-initiating cells Molecular oncology Medium 29316219
2020 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. Mouse I/R model; Tle1 siRNA knockdown; hypoxia/reoxygenation cell model; Western blot for NOD2/NF-κB; liver function assays Bioscience, biotechnology, and biochemistry Medium 32114961
2021 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. Site-directed mutagenesis of phosphorylation site; retroviral transduction; paclitaxel sensitivity assay; adipocyte differentiation assay Biochemical and biophysical research communications Medium 33571907
2023 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. FTO knockdown/overexpression; m6A methylation assay; mRNA stability assay; migration/invasion assays; Akt/NF-κB pathway Western blot Acta pharmacologica Sinica Medium 37848553
2024 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. AAV-mediated TLE1 overexpression/knockdown in rat MCAO model; PI3K inhibitor LY294002; infarct volume, BBB permeability, neuronal death assays Experimental neurology Medium 38857750
2024 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. Foxq1 knockdown and overexpression in MLE-12 cells; LPS ALI mouse model; Western blot for NF-κB/Bcl2/Bax; cell viability assays American journal of respiratory cell and molecular biology Medium 38574238
2025 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. TLE1 overexpression and knockdown in PC9/HCC827 and derived resistant lines; co-immunoprecipitation (TLE1-ZEB1); subcellular fractionation; apoptosis and viability assays; RNA-seq Biochemical and biophysical research communications Medium 40482589
2026 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. Retroviral Tle1 overexpression in CD8+ T cells; viral infection models; transcriptome analysis; ChIP-Seq/genome-wide binding profiles; PD-1 blockade experiments International immunology Medium 41810855

Source papers

Stage 0 corpus · 82 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Activating the PARP-1 sensor component of the groucho/ TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway. Cell 255 15607978
2009 TLE1 expression is not specific for synovial sarcoma: a whole section study of 163 soft tissue and bone neoplasms. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 165 19363472
2011 Immunohistochemical staining for TLE1 distinguishes synovial sarcoma from histologic mimics. American journal of clinical pathology 160 21571956
1996 Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif. Biochemical and biophysical research communications 131 8687460
2009 Prospective evaluation of TLE1 as a diagnostic immunohistochemical marker in synovial sarcoma. The American journal of surgical pathology 106 19809272
2010 TLE1 is a robust diagnostic biomarker for synovial sarcomas and correlates with t(X;18): analysis of 319 cases. European journal of cancer (Oxford, England : 1990) 83 20189377
2008 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. Blood 78 18258796
2016 Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway. Proceedings of the National Academy of Sciences of the United States of America 64 26831087
2002 Crystal structure of the C-terminal WD40 repeat domain of the human Groucho/TLE1 transcriptional corepressor. Structure (London, England : 1993) 59 12057191
2006 Modelling transcriptional feedback loops: the role of Gro/TLE1 in Hes1 oscillations. Philosophical transactions. Series A, Mathematical, physical, and engineering sciences 58 16608701
2004 Phosphorylation of serine 239 of Groucho/TLE1 by protein kinase CK2 is important for inhibition of neuronal differentiation. Molecular and cellular biology 54 15367661
2006 Grg1 acts as a lung-specific oncogene in a transgenic mouse model. Cancer research 49 16452182
2008 Epigenetic inactivation of the Groucho homologue gene TLE1 in hematologic malignancies. Cancer research 47 18519670
1996 Affinity for the nuclear compartment and expression during cell differentiation implicate phosphorylated Groucho/TLE1 forms of higher molecular mass in nuclear functions. The Biochemical journal 47 8713081
2010 Transcriptional corepressor TLE1 functions with Runx2 in epigenetic repression of ribosomal RNA genes. Proceedings of the National Academy of Sciences of the United States of America 41 20160071
2014 TLE1 promotes EMT in A549 lung cancer cells through suppression of E-cadherin. Biochemical and biophysical research communications 40 25446087
2012 TLE1 is an anoikis regulator and is downregulated by Bit1 in breast cancer cells. Molecular cancer research : MCR 40 22952044
2010 TLE1 expression in malignant mesothelioma. Virchows Archiv : an international journal of pathology 40 20857142
2012 Immunohistochemical validation of TLE1, a novel marker, for synovial sarcomas. The Indian journal of medical research 37 23287123
2014 Structure of the type VI secretion phospholipase effector Tle1 provides insight into its hydrolysis and membrane targeting. Acta crystallographica. Section D, Biological crystallography 33 25084336
2011 TLE1 modifies the effects of NOD2 in the pathogenesis of Crohn's disease. Gastroenterology 31 21699783
2008 Inhibition of cortical neuron differentiation by Groucho/TLE1 requires interaction with WRPW, but not Eh1, repressor peptides. The Journal of biological chemistry 31 18611861
1994 A cis-acting region required for the regulated expression of grg-1, a Neurospora glucose-repressible gene. Two regulatory sites (CRE and NRS) are required to repress grg-1 expression. Journal of molecular biology 31 8133521
2011 The role of TLE1 in synovial sarcoma. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 30 21319215
2003 Binding of the corepressor TLE1 to Qin enhances Qin-mediated transformation of chicken embryo fibroblasts. Oncogene 29 12660810
2013 Reappraisal of TLE-1 immunohistochemical staining and molecular detection of SS18-SSX fusion transcripts for synovial sarcoma. Pathology international 27 24422953
2012 Transducin-like enhancer of Split-1 (TLE1) combines with Forkhead box protein G1 (FoxG1) to promote neuronal survival. The Journal of biological chemistry 27 22354967
2003 Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERRgamma. Biochemical and biophysical research communications 27 14651967
2018 Characterization of a FOXG1:TLE1 transcriptional network in glioblastoma-initiating cells. Molecular oncology 26 29316219
2018 Expression of TLE-1 and CD99 in Carcinoma: Pitfalls in Diagnosis of Synovial Sarcoma. Applied immunohistochemistry & molecular morphology : AIMM 25 27753659
2010 Corepressors TLE1 and TLE3 interact with HESX1 and PROP1. Molecular endocrinology (Baltimore, Md.) 25 20181723
2013 Specificity of TLE1 expression in unclassified high-grade sarcomas for the diagnosis of synovial sarcoma. Applied immunohistochemistry & molecular morphology : AIMM 24 23197007
2014 Grg3/TLE3 and Grg1/TLE1 induce monohormonal pancreatic β-cells while repressing α-cell functions. Diabetes 21 24487024
2011 TLE1 is expressed in the majority of primary pleuropulmonary synovial sarcomas. Virchows Archiv : an international journal of pathology 21 22071579
2009 Cofactor-activated phosphorylation is required for inhibition of cortical neuron differentiation by Groucho/TLE1. PloS one 20 19956621
2010 Dynamic expression of Groucho-related genes Grg1 and Grg3 in foregut endoderm and antagonism of differentiation. Developmental dynamics : an official publication of the American Association of Anatomists 19 20108349
2024 Esculentoside H reduces the PANoptosis and protects the blood-brain barrier after cerebral ischemia/reperfusion through the TLE1/PI3K/AKT signaling pathway. Experimental neurology 18 38857750
2017 TLE1 inhibits anoikis and promotes tumorigenicity in human lung cancer cells through ZEB1-mediated E-cadherin repression. Oncotarget 18 29069783
2016 The Anoikis Effector Bit1 Inhibits EMT through Attenuation of TLE1-Mediated Repression of E-Cadherin in Lung Cancer Cells. PloS one 15 27655370
2020 lncRNA RASSF8‑AS1 suppresses the progression of laryngeal squamous cell carcinoma via targeting the miR‑664b‑3p/TLE1 axis. Oncology reports 14 33000257
2023 GRg1 inhibits the TLR4/NF-kB signaling pathway by upregulating miR-216a-5p to reduce growth factors and inflammatory cytokines in DR. Molecular biology reports 13 37819496
2023 Unusual Aspects of Small Cell Carcinoma of the Ovary of Hypercalcaemic Type: Retained SMARCA4 Immunohistochemical Staining and Positive Staining With TLE1. The American journal of surgical pathology 12 37345679
2023 Phenethyl isothiocyanate inhibits metastasis potential of non-small cell lung cancer cells through FTO mediated TLE1 m6A modification. Acta pharmacologica Sinica 12 37848553
2018 Expression of TLE1 in Malignant Melanoma With Spindle Cell Morphology: A Potential Diagnostic Pitfall. International journal of surgical pathology 11 30301396
2020 Tle1 attenuates hepatic ischemia/reperfusion injury by suppressing NOD2/NF-κB signaling. Bioscience, biotechnology, and biochemistry 10 32114961
2015 Trichostatin A suppresses lung adenocarcinoma development in Grg1 overexpressing transgenic mice. Biochemical and biophysical research communications 10 26086099
2024 Foxq1 Promotes Alveolar Epithelial Cell Death through Tle1-mediated Inhibition of the NF-κB Signaling Pathway. American journal of respiratory cell and molecular biology 9 38574238
2021 Gene of the month: TLE 1. Journal of clinical pathology 9 33441390
2020 Reduced Expression of the Co-regulator TLE1 in Type 2 Diabetes Is Associated with Increased Islet α-Cell Number. Endocrinology 9 32065829
2019 Frequent TLE1 Expression in Cutaneous Neoplasms. The American Journal of dermatopathology 8 30608261
2019 Is TLE1 Expression Limited to Synovial Sarcoma? Our Experience at Shifa International Hospital, Pakistan. Cureus 8 31893185
2017 Ras-Erk signaling induces phosphorylation of human TLE1 and downregulates its repressor function. Oncogene 8 28192406
2017 Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1. Chemistry (Weinheim an der Bergstrasse, Germany) 8 28326635
2018 TLE1, a key player in neurogenesis, a new candidate gene for autosomal recessive postnatal microcephaly. European journal of medical genetics 7 29758293
2016 Transducer-like enhancer of split 1 (TLE1) expression as a diagnostic immunohistochemical marker for synovial sarcoma and its association with morphological features. The Malaysian journal of pathology 7 27568668
2023 The utility of TLE1 and BCOR as immunohistochemical markers for angiomatoid fibrous histiocytoma. International journal of clinical and experimental pathology 6 36910892
2021 Diagnostic Utility of TLE1 (Transducer-Like Enhancer of Split 1) in Distinguishing Synovial Sarcoma from Mimicking Tumors. International journal of general medicine 6 34880656
2019 Transducer-like enhancer of split 1 (TLE1) as a novel biomarker for diagnosis of synovial sarcoma correlates with translocation t(X;18): a study of 155 cases in China. International journal of clinical and experimental pathology 6 31933740
2005 Dendritic localization of the transcriptional co-repressor Groucho/TLE1 in cortical and cerebellar neurons. Brain research. Molecular brain research 6 16081186
2002 The transcription co-repressor TLE1 interacted with the intracellular region of gpl30 through its Q domain. Molecular and cellular biochemistry 5 12030375
2019 TLE-1-Positive Angiomatoid Fibrous Histiocytoma Mimicking Synovial Sarcoma. Applied immunohistochemistry & molecular morphology : AIMM 4 28248724
2021 Differential functions of TLE1 and TLE3 depending on a specific phosphorylation site. Biochemical and biophysical research communications 3 33571907
2021 Tissue microarray based immunohistochemical study of TLE1 in synovial sarcoma and its histologic mimics. Indian journal of pathology & microbiology 3 33851625
2017 Epigenetic modification of TLE1 induce abnormal differentiation in diabetic mice intestinal epithelium. Molecular and cellular biochemistry 3 28744818
2013 A Case of Distal Epithelioid Sarcoma of the Thumb Expressing Podoplanin, TLE1 and Ca 125. Case reports in pathology 3 23691400
2023 Expression of TLE1 in a Carcinoid Tumor of the Lung With Spindle Cell Morphology-A Potential Diagnostic Pitfall. Applied immunohistochemistry & molecular morphology : AIMM 2 37668410
2021 Expression of TLE1, INI1, β-catenin, Claudin1, CK7, CK19, SS18 and calponin in synovial sarcoma. Indian journal of pathology & microbiology 2 34673590
2019 A rare case of TLE1-positive sclerosing epithelioid fibrosarcoma expanding the differential diagnosis of TLE1-positive tumors: a case report. AME case reports 2 31020273
2019 TLE1 expression fails to distinguish between synovial sarcoma, atypical fibroxanthoma, and dermatofibrosarcoma protuberans. Journal of cutaneous pathology 2 31614009
2018 TLE1 Positive Clear Cell Sarcoma of the Kidney: A Case Report and Review of the Literature. Case reports in pathology 2 30410809
2016 Generation of a TLE1 homozygous knockout human embryonic stem cell line using CRISPR-Cas9. Stem cell research 2 27879218
2025 TLE1 drives EGFR-TKI resistance in EGFR-mutant lung adenocarcinoma through epithelial to mesenchymal transition. Biochemical and biophysical research communications 1 40482589
2024 TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing. Biomedical reports 1 39781042
2023 Expression of TLE-1 in Gastrointestinal Stromal Tumour and Its Relationship to Clinicopathological Parameters. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP 1 36945158
2018 TLE1 Expression in Malignant Rhabdoid Tumor and Atypical Teratoid/Rhabdoid Tumor. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 1 29490565
2026 Overexpression of the transcriptional corepressor Tle1 enhances effector proliferation of CD8+ T cells during acute and chronic viral infections. International immunology 0 41810855
2026 BIT1 as an Effector of EGFR-TKI-induced Apoptosis via TLE1 Inhibition in Lung Adenocarcinoma Cells. Anticancer research 0 41895783
2026 "Molecular insights into the bactericidal toxin Tle1 of Pseudomonas aeruginosa: Interaction with VgrG, its adaptor, and its immunity protein". The Journal of biological chemistry 0 41933729
2025 Differential Expression of TLE1 in Small Round Cell Tumors: A Proposed Solution for Challenging Differentials Impacting Treatment Strategies. International journal of surgical pathology 0 40335446
2024 TLE1 Expression in NUT Carcinoma: A Case Report Highlighting a Potential Diagnostic Pitfall for the Pathologist. International journal of surgical pathology 0 38233028
2010 [Prokaryotic expression and purification of human TLE1 N-terminal Q domain fragment and production of its polyclonal antibody]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 0 21081038
2010 Expression, purification, crystallization, and preliminary X-ray diffraction analysis of the human TLE1 Q domain. Acta biochimica et biophysica Sinica 0 21183761

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