{"gene":"TLE5","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2011,"finding":"AES (GRG5) inhibits Notch signaling by converting active RBPJ transcription complexes into repression complexes on the insoluble nuclear matrix, thereby suppressing transendothelial migration of colon cancer cells triggered by Notch ligands on blood vessels.","method":"Biochemical fractionation (nuclear matrix), genetic depletion in Apc-delta716 mice, Notch signaling inhibition rescue experiments","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (nuclear matrix fractionation, mouse genetics, pharmacological Notch inhibition rescue), replicated in both mouse and human tumor contexts","pmids":["21251616"],"is_preprint":false},{"year":2021,"finding":"CK1δ/ε phosphorylates AES at Ser121, which promotes SKP2-mediated ubiquitination and proteasomal degradation of AES via its Q domain interaction with CK1δ/ε and SKP2. The phosphorylation-deficient S121A mutant AES resists this degradation and retains its ability to suppress Wnt and Notch signaling in colon cancer cells.","method":"Co-immunoprecipitation, GST pull-down, Western blot, site-directed mutagenesis (S121A), in vivo tumor/metastasis models, PDTX models","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, GST pulldown, mutagenesis validation, and in vivo functional rescue, multiple orthogonal methods in single study","pmids":["33754069"],"is_preprint":false},{"year":2004,"finding":"GRG5 (AES) physically interacts with the transcription factor Runx2-Cbfa1, identified by yeast two-hybrid, and enhances Runx2 transcriptional activity in cell culture assays. Genetic interaction was confirmed in Runx2+/- Grg5-/- compound mutant mice, which showed more severe ossification defects and reduced Ihh expression than Runx2+/- alone.","method":"Yeast two-hybrid, cell culture transcriptional assay, compound knockout mouse genetics (epistasis)","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid interaction confirmed by genetic epistasis in vivo with defined skeletal phenotype, multiple orthogonal approaches","pmids":["15183720"],"is_preprint":false},{"year":2002,"finding":"Grg5 null mice exhibit reduced Indian hedgehog (Ihh) expression and signaling in growth plates, shorter zones of proliferative and hypertrophic chondrocytes, and decreased trabecular bone formation, consistent with Grg5 modulating Ihh signaling during skeletal development.","method":"Gene-targeted knockout mice, histological analysis of growth plates, Ihh expression analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with defined skeletal phenotype, single lab, pathway placement via Ihh expression reduction but no direct mechanistic reconstitution","pmids":["11984876"],"is_preprint":false},{"year":2013,"finding":"GRG5/AES interacts with TCF4 via a core region mapping to a 111-amino acid fragment of TCF4, and specifically requires a 4-amino acid LVPQ motif present only in TCF3 and some TCF4 isoforms (not shared with other GRGs). GRG5/AES represses Wnt-mediated transcription in human cells and in zebrafish embryos, and plays a role in dorsal-ventral patterning.","method":"Co-immunoprecipitation, deletion mapping, luciferase reporter assays (human cells), zebrafish overexpression/knockdown experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction mapped by deletion analysis and Co-IP, functional repression shown in two independent systems (human cells and zebrafish), single lab","pmids":["23840876"],"is_preprint":false},{"year":2011,"finding":"AES is upregulated by AML1/ETO in hematopoietic progenitor cells, and is required for AML1/ETO-induced self-renewal: RNAi knockdown of AES in AML1/ETO-expressing cell lines inhibited colony formation, and AES depletion in primary murine progenitors suppressed AML1/ETO-induced serial replating capacity.","method":"Expression microarray, RNAi knockdown in cell lines and primary murine progenitors, colony-forming unit assays, CFU-spleen assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with defined cellular phenotype across both cell lines and primary cells, multiple readouts, single lab","pmids":["21245488"],"is_preprint":false},{"year":2008,"finding":"HDRP (histone deacetylase-related protein) physically interacts with AES in the brain and blocks AES-induced neuronal apoptosis. Forced expression of AES in healthy cerebellar granule neurons causes cell death, which is prevented by co-expression of HDRP or TLE1.","method":"Yeast two-hybrid screen, in vitro binding assay, co-immunoprecipitation, co-localization, forced expression in cultured cerebellar granule neurons","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by three methods (yeast two-hybrid, in vitro binding, Co-IP), functional consequence in primary neurons, single lab","pmids":["18438919"],"is_preprint":false},{"year":2011,"finding":"AES physically interacts with the NUP98-HOXA9 oncoprotein (requiring the FG repeat region of NUP98-HOXA9) and with wild-type NUP98. AES augments NUP98-HOXA9 transcriptional activity and, in the presence of NUP98-HOXA9, increases long-term proliferation and primitive cell numbers in human CD34+ cells; these effects are not observed in the absence of NUP98-HOXA9.","method":"Cytoplasmic yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, immunofluorescence, primary human CD34+ cell proliferation assays, AES knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by three methods; functional consequence in primary human cells; single lab","pmids":["21937451"],"is_preprint":false},{"year":2015,"finding":"AES (Aes) forms nuclear foci in colorectal cancer cells together with TLE1. These foci dissolve during mitosis and reassemble after cytokinesis. HSC70 is an essential component of Aes nuclear foci; pharmacological inhibition of HSC70 ATPase activity with VER155008 reduces Aes focus formation.","method":"Electron microscopy, time-lapse cinematography, pharmacological inhibition (VER155008), subcellular fractionation","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live imaging and pharmacological intervention with defined structural phenotype; single lab","pmids":["26229111"],"is_preprint":false},{"year":2017,"finding":"AES suppresses transcriptional activities of androgen receptor (AR) and Notch signaling in prostate cancer cells. In AR-defective cells, AES overexpression reduces invasion and metastasis to lymph nodes and bones. Prostate epithelium-specific Aes knockout in Pten-flox mice increased Snail and MMP9 expression and accelerated tumor invasion and lymph node metastasis.","method":"Overexpression/knockdown in human PCa cell lines, luciferase reporter assays, xenograft mouse model, compound knockout mice (Aes/Pten), immunohistochemistry","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement via luciferase assays and in vivo genetic models, multiple readouts, single lab","pmids":["28178391"],"is_preprint":false},{"year":2016,"finding":"Transcription factor YY2 directly binds the YY element in the CpG-island promoter-enhancer of the AES gene and stimulates AES expression in human colonic epithelial cells; downregulation of YY2 in liver metastases reduces AES expression.","method":"Promoter-enhancer mapping, transcription factor binding assays, transplantation mouse model, correlation of YY2 and AES protein levels in human CRC metastases","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — binding to YY element shown, but the direct binding experiment is not fully described in the abstract; single lab, limited orthogonal validation","pmids":["27561171"],"is_preprint":false},{"year":2013,"finding":"AES knockdown downregulates RND3 expression at mRNA and protein levels in cancer cell lines, and AES overexpression enhances RND3 promoter activity as shown by luciferase assay, suggesting AES positively regulates RND3 transcription.","method":"RNAi knockdown, luciferase promoter assay, Western blot, RT-PCR","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single reporter assay for transcriptional mechanism; no direct binding or co-IP shown","pmids":["23546594"],"is_preprint":false},{"year":2015,"finding":"AES (Groucho protein) physically binds HNF1α and represses HNF1α-mediated transcription, with a direct functional link to glucose-stimulated insulin secretion in pancreatic beta-cells.","method":"Yeast two-hybrid (implied from 'identified as physical binding partner'), transcriptional reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction and repression function described but the abstract does not detail the binding assay method, single lab","pmids":["26549228"],"is_preprint":false},{"year":2018,"finding":"GRG5 (AES) ablation in embryonic stem cells deregulates pluripotency, while overexpression enhances self-renewal. GRG5 represses mesendodermal-related genes and promotes neuroectodermal specification via suppression of Wnt and BMP signaling. GRG5 also maintains Neural Stem Cell self-renewal by sustaining Notch/Hes and Stat3 signaling activities.","method":"Loss- and gain-of-function ESC experiments, transcriptomic analysis, cell differentiation assays, neuronal reprogramming assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — defined cellular phenotypes but pathway placements (Wnt, BMP, Notch, Stat3) inferred from transcriptomics without direct mechanistic reconstitution; single lab","pmids":["30214018"],"is_preprint":false},{"year":1993,"finding":"Mouse and human AES proteins (~202 and 197 amino acids, respectively) share approximately 50% amino acid identity with the N-terminal domain of Drosophila Groucho and full-length TLE/GRG proteins, establishing AES as a short, N-terminal fragment member of the Groucho family without the C-terminal WD-repeat domain.","method":"cDNA cloning, sequencing, sequence alignment","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Strong — direct molecular cloning and sequence determination, replicated for both mouse and human; foundational structural characterization","pmids":["8365415"],"is_preprint":false}],"current_model":"TLE5/AES/GRG5 is a short, N-terminal Groucho-family co-regulator that lacks a DNA-binding domain and acts as a functionally dynamic modulator of multiple transcription factors: it converts active RBPJ-Notch transcription complexes into repression complexes on the nuclear matrix to suppress metastasis; it is phosphorylated by CK1δ/ε at Ser121, triggering SKP2-mediated ubiquitin-proteasomal degradation; it enhances Runx2/Cbfa1 transcriptional activity and modulates Ihh signaling in bone; it represses Wnt-mediated transcription through a TCF4/LVPQ-motif-dependent interaction; it is required for AML1/ETO-induced hematopoietic self-renewal; it promotes neuronal apoptosis that is counteracted by direct binding of the neuroprotective protein HDRP; and it forms dynamic, HSC70-dependent nuclear foci that dissolve during mitosis."},"narrative":{"mechanistic_narrative":"TLE5/AES/GRG5 is a short, N-terminal Groucho-family transcriptional co-regulator that lacks the C-terminal WD-repeat domain present in full-length TLE/GRG proteins, functioning as a dynamic modulator that switches the output of multiple transcription factors rather than binding DNA itself [PMID:8365415]. In epithelial cancers it acts predominantly as a repressor: it converts active RBPJ-Notch transcription complexes into repression complexes on the insoluble nuclear matrix to suppress Notch-driven transendothelial migration and metastasis [PMID:21251616], and it represses Wnt-mediated transcription through an interaction with TCF4 that specifically requires a 4-amino-acid LVPQ motif [PMID:23840876]. This anti-metastatic activity extends to prostate cancer, where AES suppresses both androgen receptor and Notch transcriptional output and its epithelium-specific loss accelerates invasion and metastasis [PMID:28178391]. AES stability is gated by CK1δ/ε-mediated phosphorylation at Ser121, which licenses SKP2-dependent ubiquitination and proteasomal degradation through Q-domain contacts with both kinase and ligase; the S121A mutant resists turnover and retains Wnt/Notch suppression [PMID:33754069]. Beyond repression, AES enhances Runx2/Cbfa1 transcriptional activity and modulates Indian hedgehog signaling during skeletal development, with Grg5 loss reducing Ihh expression and impairing chondrocyte proliferation and bone formation [PMID:15183720, PMID:11984876]. In hematopoietic contexts AES is co-opted by the AML1/ETO and NUP98-HOXA9 oncoproteins to drive self-renewal and proliferation [PMID:21245488, PMID:21937451]. AES forms dynamic, HSC70-dependent nuclear foci together with TLE1 that dissolve during mitosis and reassemble after cytokinesis [PMID:26229111], and it promotes neuronal apoptosis that is counteracted by direct binding of the neuroprotective protein HDRP [PMID:18438919].","teleology":[{"year":1993,"claim":"Establishing the molecular identity of AES as a truncated Groucho-family member defined the structural basis for its non-DNA-binding co-regulatory behavior.","evidence":"cDNA cloning and sequence alignment of mouse and human AES against Drosophila Groucho and TLE/GRG proteins","pmids":["8365415"],"confidence":"Medium","gaps":["No functional consequence assigned to the absence of the WD-repeat domain at this stage","No interaction partners identified"]},{"year":2002,"claim":"Knockout phenotyping placed Grg5 in skeletal development, linking it to Indian hedgehog signaling and chondrocyte/bone formation.","evidence":"Gene-targeted knockout mice with histological growth-plate analysis and Ihh expression profiling","pmids":["11984876"],"confidence":"Medium","gaps":["Pathway placement inferred from Ihh expression, not direct mechanistic reconstitution","No transcription factor partner identified to explain the Ihh effect"]},{"year":2004,"claim":"Identifying Runx2/Cbfa1 as a direct partner explained how AES exerts its skeletal role, as a positive co-activator confirmed by genetic epistasis.","evidence":"Yeast two-hybrid, transcriptional reporter assays, and Runx2+/- Grg5-/- compound mutant mice","pmids":["15183720"],"confidence":"High","gaps":["Mechanism by which a Groucho protein enhances rather than represses Runx2 not resolved","Whether the Runx2 link directly accounts for the Ihh effect not established"]},{"year":2008,"claim":"Discovery of the HDRP interaction revealed AES as a pro-apoptotic factor in neurons whose lethal activity is antagonized by binding partners.","evidence":"Yeast two-hybrid, in vitro binding, Co-IP, and forced expression in cerebellar granule neurons","pmids":["18438919"],"confidence":"Medium","gaps":["Transcriptional targets mediating AES-induced apoptosis unknown","Single lab; physiological relevance in vivo not tested"]},{"year":2011,"claim":"AES was defined as a Notch-pathway switch that suppresses cancer cell metastasis by remodeling RBPJ complexes on the nuclear matrix.","evidence":"Nuclear matrix fractionation, Apc-delta716 mouse genetics, and pharmacological Notch inhibition rescue","pmids":["21251616"],"confidence":"High","gaps":["Molecular basis of the active-to-repressive complex conversion not detailed","Nuclear matrix tethering partners not fully defined"]},{"year":2011,"claim":"Parallel hematopoietic studies showed AES is hijacked by leukemic fusion oncoproteins to drive aberrant self-renewal, contrasting with its tumor-suppressive role in epithelia.","evidence":"Expression microarray and RNAi knockdown in AML1/ETO and NUP98-HOXA9 systems with colony-forming and primary cell proliferation assays","pmids":["21245488","21937451"],"confidence":"Medium","gaps":["Transcriptional targets downstream of AES in leukemic self-renewal not mapped","How AES switches between repressive and oncogenic co-activator modes unresolved"]},{"year":2013,"claim":"Mapping the TCF4 interaction to an LVPQ motif explained the molecular specificity by which AES represses Wnt signaling.","evidence":"Co-IP, deletion mapping, luciferase reporters in human cells, and zebrafish gain/loss-of-function","pmids":["23840876"],"confidence":"Medium","gaps":["Structural basis of LVPQ recognition not resolved","Whether other TCF isoforms are differentially affected in vivo not established"]},{"year":2015,"claim":"Live imaging defined AES nuclear foci as dynamic, cell-cycle-regulated structures requiring HSC70 chaperone activity.","evidence":"Electron microscopy, time-lapse cinematography, VER155008 inhibition, and subcellular fractionation","pmids":["26229111"],"confidence":"Medium","gaps":["Functional consequence of focus formation for transcriptional output not established","Composition of foci beyond TLE1 and HSC70 unknown"]},{"year":2017,"claim":"Prostate cancer models extended AES anti-metastatic function to AR and Notch suppression, confirmed by tissue-specific knockout.","evidence":"Cell line over/knockdown, luciferase assays, xenograft and Aes/Pten compound knockout mice with IHC","pmids":["28178391"],"confidence":"Medium","gaps":["Direct AES-AR physical interaction not demonstrated","Mechanism linking AES loss to Snail/MMP9 induction not defined"]},{"year":2021,"claim":"Identification of CK1δ/ε–SKP2–driven degradation established how AES protein levels are post-translationally controlled, with Ser121 as the regulatory switch.","evidence":"Reciprocal Co-IP, GST pull-down, S121A mutagenesis, and in vivo tumor/metastasis and PDTX models","pmids":["33754069"],"confidence":"High","gaps":["Upstream signals activating CK1δ/ε toward AES not identified","Whether degradation is regulated differently across cell types not addressed"]},{"year":null,"claim":"How AES is toggled between transcriptional repressor (Notch/Wnt in epithelia) and co-activator/oncogenic effector (Runx2, AML1/ETO, NUP98-HOXA9) remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural or biochemical model distinguishes repressive from activating complexes","Context determinants (partner availability, modification state) not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,4,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,5,7,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3]}],"complexes":["RBPJ-Notch transcription complex","AES/TLE1 nuclear foci"],"partners":["RBPJ","TCF4","RUNX2","HDRP","TLE1","HSPA8","CSNK1D","SKP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q08117","full_name":"TLE family member 5","aliases":["Amino-terminal enhancer of split","Amino enhancer of split","Gp130-associated protein GAM","Grg-5","Groucho-related protein 5","Protein ESP1","Protein GRG","TLE family member 5, transcriptional modulator"],"length_aa":197,"mass_kda":22.0,"function":"Transcriptional corepressor. Acts as a dominant repressor towards other family members. Inhibits NF-kappa-B-regulated gene expression. May be required for the initiation and maintenance of the differentiated state. Essential for the transcriptional repressor activity of SIX3 during retina and lens development","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q08117/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TLE5","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TLE5","total_profiled":1310},"omim":[{"mim_id":"600188","title":"TLE FAMILY MEMBER 5, TRANSCRIPTIONAL MODULATOR; TLE5","url":"https://www.omim.org/entry/600188"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TLE5"},"hgnc":{"alias_symbol":["GRG5"],"prev_symbol":["AES"]},"alphafold":{"accession":"Q08117","domains":[{"cath_id":"-","chopping":"97-138","consensus_level":"medium","plddt":89.6469,"start":97,"end":138},{"cath_id":"1.20.5","chopping":"19-95","consensus_level":"medium","plddt":96.4226,"start":19,"end":95}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08117","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08117-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08117-F1-predicted_aligned_error_v6.png","plddt_mean":74.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TLE5","jax_strain_url":"https://www.jax.org/strain/search?query=TLE5"},"sequence":{"accession":"Q08117","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08117.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08117/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08117"}},"corpus_meta":[{"pmid":"26793994","id":"PMC_26793994","title":"Cutaneous 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AES-1R grown in a cystic fibrosis lung-like environment.","date":"2013","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/23991618","citation_count":22,"is_preprint":false},{"pmid":"610976","id":"PMC_610976","title":"Fast detoxification of heroin addicts by acupuncture and electrical stimulation (AES) in combination with naloxone.","date":"1977","source":"Comparative medicine East and West","url":"https://pubmed.ncbi.nlm.nih.gov/610976","citation_count":22,"is_preprint":false},{"pmid":"1822333","id":"PMC_1822333","title":"Contribution to Zn-speciation in human breast milk: fractionation of organic compounds by HPLC and subsequent Zn-determination by DCP-AES.","date":"1991","source":"Journal of trace elements and electrolytes in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/1822333","citation_count":18,"is_preprint":false},{"pmid":"32058289","id":"PMC_32058289","title":"Determination of heavy metals in cancerous and healthy colon tissues using 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Implications for the regulation of carbohydrate metabolism.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12374803","citation_count":12,"is_preprint":false},{"pmid":"17696396","id":"PMC_17696396","title":"A nanoparticle-based solution DNA sandwich assay using ICP-AES for readout.","date":"2007","source":"Biomacromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/17696396","citation_count":12,"is_preprint":false},{"pmid":"23840876","id":"PMC_23840876","title":"GRG5/AES interacts with T-cell factor 4 (TCF4) and downregulates Wnt signaling in human cells and zebrafish embryos.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23840876","citation_count":11,"is_preprint":false},{"pmid":"23546594","id":"PMC_23546594","title":"Suppression of RND3 activity by AES downregulation promotes cancer cell proliferation and invasion.","date":"2013","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23546594","citation_count":11,"is_preprint":false},{"pmid":"20040078","id":"PMC_20040078","title":"aes, the gene encoding the esterase B in Escherichia coli, is a powerful phylogenetic marker of the species.","date":"2009","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20040078","citation_count":11,"is_preprint":false},{"pmid":"21937451","id":"PMC_21937451","title":"Amino-terminal enhancer of split (AES) interacts with the oncoprotein NUP98-HOXA9 and enhances its transforming ability.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21937451","citation_count":11,"is_preprint":false},{"pmid":"36645286","id":"PMC_36645286","title":"Performance of the Vitek 2 Advanced Expert System (AES) as a Rapid Tool for Reporting Antimicrobial Susceptibility Testing (AST) in Enterobacterales from North and Latin America.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/36645286","citation_count":10,"is_preprint":false},{"pmid":"24458238","id":"PMC_24458238","title":"Simultaneous observation of the metabolism of cisplatin and NAMI-A in human plasma in vitro by SEC-ICP-AES.","date":"2014","source":"Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24458238","citation_count":10,"is_preprint":false},{"pmid":"30214018","id":"PMC_30214018","title":"Groucho related gene 5 (GRG5) is involved in embryonic and neural stem cell state decisions.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30214018","citation_count":9,"is_preprint":false},{"pmid":"28758353","id":"PMC_28758353","title":"Structural and SAXS analysis of Tle5-Tli5 complex reveals a novel inhibition mechanism of H2-T6SS in Pseudomonas aeruginosa.","date":"2017","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/28758353","citation_count":9,"is_preprint":false},{"pmid":"14621121","id":"PMC_14621121","title":"Oral glutamine (AES-14) supplementation inhibits PI-3k/Akt signaling in experimental breast cancer.","date":"2003","source":"JPEN. Journal of parenteral and enteral nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/14621121","citation_count":9,"is_preprint":false},{"pmid":"26229111","id":"PMC_26229111","title":"Characterization of Aes nuclear foci in colorectal cancer cells.","date":"2015","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26229111","citation_count":7,"is_preprint":false},{"pmid":"26219907","id":"PMC_26219907","title":"Autoinflammation Around AES Total Ankle Replacement Implants.","date":"2015","source":"Foot & ankle international","url":"https://pubmed.ncbi.nlm.nih.gov/26219907","citation_count":6,"is_preprint":false},{"pmid":"23934774","id":"PMC_23934774","title":"Structural and mutational analyses of Aes, an inhibitor of MalT in Escherichia coli.","date":"2013","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/23934774","citation_count":6,"is_preprint":false},{"pmid":"33950059","id":"PMC_33950059","title":"AES and ToF-SIMS combination for single cell chemical imaging of gold nanoparticle-labeled Escherichia coli.","date":"2021","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/33950059","citation_count":5,"is_preprint":false},{"pmid":"37642296","id":"PMC_37642296","title":"Can in vitro studies aid in the development and use of antiseizure therapies? A report of the ILAE/AES Joint Translational Task Force.","date":"2023","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/37642296","citation_count":5,"is_preprint":false},{"pmid":"33659389","id":"PMC_33659389","title":"Determination of the Cellular Ion Concentration in Saccharomyces cerevisiae Using ICP-AES.","date":"2020","source":"Bio-protocol","url":"https://pubmed.ncbi.nlm.nih.gov/33659389","citation_count":5,"is_preprint":false},{"pmid":"19248524","id":"PMC_19248524","title":"[Determination of mineral elements in brown rice of near-isogenic lines population for Japonica rice by ICP-AES].","date":"2008","source":"Guang pu xue yu guang pu fen xi = Guang pu","url":"https://pubmed.ncbi.nlm.nih.gov/19248524","citation_count":5,"is_preprint":false},{"pmid":"20939353","id":"PMC_20939353","title":"[Mineral elements analysis of Momordica charantiap seeds by ICP-AES and fatty acid profile identification of seed oil by GC-MS].","date":"2010","source":"Guang pu xue yu guang pu fen xi = Guang pu","url":"https://pubmed.ncbi.nlm.nih.gov/20939353","citation_count":4,"is_preprint":false},{"pmid":"14501134","id":"PMC_14501134","title":"Crystallization and preliminary X-ray diffraction studies of Aes acetyl-esterase from Escherichia coli.","date":"2003","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/14501134","citation_count":4,"is_preprint":false},{"pmid":"35498166","id":"PMC_35498166","title":"Optimization of AES-128 Encryption Algorithm for Security Layer in ZigBee Networking of Internet of Things.","date":"2022","source":"Computational intelligence and neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35498166","citation_count":3,"is_preprint":false},{"pmid":"26549228","id":"PMC_26549228","title":"Repression of HNF1α-mediated transcription by amino-terminal enhancer of split (AES).","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26549228","citation_count":3,"is_preprint":false},{"pmid":"31002973","id":"PMC_31002973","title":"Alkaline earth silicate (AES) wools: Evaluation of potential cyto-genotoxic and inflammatory effects on human respiratory cells.","date":"2019","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/31002973","citation_count":3,"is_preprint":false},{"pmid":"14993683","id":"PMC_14993683","title":"Crystallization and preliminary X-ray analysis of Aes, an acetyl-esterase from Escherichia coli.","date":"2004","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/14993683","citation_count":3,"is_preprint":false},{"pmid":"15760036","id":"PMC_15760036","title":"[Study on the determination of calcium in Chinese medicine by ICP-AES].","date":"2004","source":"Guang pu xue yu guang pu fen xi = Guang pu","url":"https://pubmed.ncbi.nlm.nih.gov/15760036","citation_count":3,"is_preprint":false},{"pmid":"26775392","id":"PMC_26775392","title":"Characterization of Klebsiella isolates by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and determination of antimicrobial resistance with VITEK 2 advanced expert system (AES).","date":"2015","source":"Turkish journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26775392","citation_count":3,"is_preprint":false},{"pmid":"38844554","id":"PMC_38844554","title":"Metabolism of alcohol ethoxylates (AEs) in rat, hamster, and human hepatocytes and liver S9: a pilot study for metabolic stability, metabolic pathway, and metabolites identification in vitro and in silico.","date":"2024","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38844554","citation_count":2,"is_preprint":false},{"pmid":"37878640","id":"PMC_37878640","title":"A double encryption protection algorithm for stem cell bank privacy data based on improved AES and chaotic encryption technology.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37878640","citation_count":2,"is_preprint":false},{"pmid":"17305603","id":"PMC_17305603","title":"Biochemical and thermostability features of acetyl esterase Aes from Escherichia coli.","date":"2007","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/17305603","citation_count":2,"is_preprint":false},{"pmid":"34992382","id":"PMC_34992382","title":"Clinical Impact of Switching to Ceritinib After Severe AEs Related to Crizotinib/Alectinib in a Novel PTH2R-ALK Fusion Lung Adenocarcinoma: A Case Report.","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34992382","citation_count":2,"is_preprint":false},{"pmid":"8673221","id":"PMC_8673221","title":"[Radiosensitivity and postradiation kinetics of megakaryocyte release of the bone marrow (analysis based on data of the Chernobyl AES accident sequelae)].","date":"1996","source":"Radiatsionnaia biologiia, radioecologiia","url":"https://pubmed.ncbi.nlm.nih.gov/8673221","citation_count":2,"is_preprint":false},{"pmid":"21365924","id":"PMC_21365924","title":"[Construction and pathogenic identification of aes-31 gene mutant of avian pathogenic Escherichia coli strain E058].","date":"2010","source":"Wei sheng wu xue bao = Acta microbiologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/21365924","citation_count":1,"is_preprint":false},{"pmid":"8069363","id":"PMC_8069363","title":"[Hydration and structural state of liver DNA of rats exposed to radiation in the Chernobyl AES zone].","date":"1994","source":"Radiatsionnaia biologiia, radioecologiia","url":"https://pubmed.ncbi.nlm.nih.gov/8069363","citation_count":1,"is_preprint":false},{"pmid":"9417309","id":"PMC_9417309","title":"[Health status of persons with acute radiation sickness caused by Chernobyl AES accident].","date":"1997","source":"Radiatsionnaia biologiia, radioecologiia","url":"https://pubmed.ncbi.nlm.nih.gov/9417309","citation_count":1,"is_preprint":false},{"pmid":"1719579","id":"PMC_1719579","title":"[Results of experimental radiobiological studies made within the 10-kilometer zone of the Chernobyl AES accident].","date":"1991","source":"Radiobiologiia","url":"https://pubmed.ncbi.nlm.nih.gov/1719579","citation_count":1,"is_preprint":false},{"pmid":"39253919","id":"PMC_39253919","title":"Investigating the Therapeutic Property of Galium verum L. (GV) for MSG induced Audiogenic Epilepsy (AEs) and Neuroprotection through In-Silico and In-Vitro Analysis.","date":"2025","source":"Central nervous system agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39253919","citation_count":0,"is_preprint":false},{"pmid":"9809752","id":"PMC_9809752","title":"Genomic organization and chromosome localization to band 19p13.3 of the human AES gene: gene product exhibits strong similarity to the N-terminal domain of Drosophila enhancer of Split Groucho protein.","date":"1998","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9809752","citation_count":0,"is_preprint":false},{"pmid":"9633619","id":"PMC_9633619","title":"[Determination of mutation frequency at loci of glycophorin A and T-cell receptor: study of Chernobyl AES accident cleanup workers].","date":"1998","source":"Radiatsionnaia biologiia, radioecologiia","url":"https://pubmed.ncbi.nlm.nih.gov/9633619","citation_count":0,"is_preprint":false},{"pmid":"19839351","id":"PMC_19839351","title":"[Study on ultrasonic nebulizer sample feeding system for ICP-AES].","date":"2009","source":"Guang pu xue yu guang pu fen xi = Guang pu","url":"https://pubmed.ncbi.nlm.nih.gov/19839351","citation_count":0,"is_preprint":false},{"pmid":"1448555","id":"PMC_1448555","title":"[Results of the cytogenetic examination of the people taking part in the clean-up of the accident at the Chernobyl AES].","date":"1992","source":"Radiobiologiia","url":"https://pubmed.ncbi.nlm.nih.gov/1448555","citation_count":0,"is_preprint":false},{"pmid":"15060947","id":"PMC_15060947","title":"[Evaluation of the consequences of stress factors on plant seeds growing in a 30-km zone of Balakovo AES].","date":"2004","source":"Radiatsionnaia biologiia, radioecologiia","url":"https://pubmed.ncbi.nlm.nih.gov/15060947","citation_count":0,"is_preprint":false},{"pmid":"7975418","id":"PMC_7975418","title":"[Actual nutrition of schoolchildren living in territories affected by the Chernobyl AES accident].","date":"1994","source":"Voprosy pitaniia","url":"https://pubmed.ncbi.nlm.nih.gov/7975418","citation_count":0,"is_preprint":false},{"pmid":"1950155","id":"PMC_1950155","title":"[Clinico-immunocytological characteristics of leukemia in persons exposed to ionizing radiation effects due to the Chernobyl AES accident].","date":"1991","source":"Vestnik Akademii meditsinskikh nauk SSSR","url":"https://pubmed.ncbi.nlm.nih.gov/1950155","citation_count":0,"is_preprint":false},{"pmid":"9633624","id":"PMC_9633624","title":"[Study of immune status indices, levels of alpha-1-thymosin and autoantibodies to thymic epithelial cells in persons who worked in the 30-kilometer zone of the Chernobyl AES depending on the radiation dose].","date":"1998","source":"Radiatsionnaia biologiia, radioecologiia","url":"https://pubmed.ncbi.nlm.nih.gov/9633624","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.06.668327","title":"Robust CRISPR Screens Identify TPL1 as a Novel Long Noncoding RNA Driving Triple-Negative Breast Cancer Hallmarks","date":"2025-08-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.06.668327","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35029,"output_tokens":3691,"usd":0.080226,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11389,"output_tokens":3556,"usd":0.072923,"stage2_stop_reason":"end_turn"},"total_usd":0.153149,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"AES (GRG5) inhibits Notch signaling by converting active RBPJ transcription complexes into repression complexes on the insoluble nuclear matrix, thereby suppressing transendothelial migration of colon cancer cells triggered by Notch ligands on blood vessels.\",\n      \"method\": \"Biochemical fractionation (nuclear matrix), genetic depletion in Apc-delta716 mice, Notch signaling inhibition rescue experiments\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (nuclear matrix fractionation, mouse genetics, pharmacological Notch inhibition rescue), replicated in both mouse and human tumor contexts\",\n      \"pmids\": [\"21251616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CK1δ/ε phosphorylates AES at Ser121, which promotes SKP2-mediated ubiquitination and proteasomal degradation of AES via its Q domain interaction with CK1δ/ε and SKP2. The phosphorylation-deficient S121A mutant AES resists this degradation and retains its ability to suppress Wnt and Notch signaling in colon cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, Western blot, site-directed mutagenesis (S121A), in vivo tumor/metastasis models, PDTX models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, GST pulldown, mutagenesis validation, and in vivo functional rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33754069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GRG5 (AES) physically interacts with the transcription factor Runx2-Cbfa1, identified by yeast two-hybrid, and enhances Runx2 transcriptional activity in cell culture assays. Genetic interaction was confirmed in Runx2+/- Grg5-/- compound mutant mice, which showed more severe ossification defects and reduced Ihh expression than Runx2+/- alone.\",\n      \"method\": \"Yeast two-hybrid, cell culture transcriptional assay, compound knockout mouse genetics (epistasis)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid interaction confirmed by genetic epistasis in vivo with defined skeletal phenotype, multiple orthogonal approaches\",\n      \"pmids\": [\"15183720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Grg5 null mice exhibit reduced Indian hedgehog (Ihh) expression and signaling in growth plates, shorter zones of proliferative and hypertrophic chondrocytes, and decreased trabecular bone formation, consistent with Grg5 modulating Ihh signaling during skeletal development.\",\n      \"method\": \"Gene-targeted knockout mice, histological analysis of growth plates, Ihh expression analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with defined skeletal phenotype, single lab, pathway placement via Ihh expression reduction but no direct mechanistic reconstitution\",\n      \"pmids\": [\"11984876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GRG5/AES interacts with TCF4 via a core region mapping to a 111-amino acid fragment of TCF4, and specifically requires a 4-amino acid LVPQ motif present only in TCF3 and some TCF4 isoforms (not shared with other GRGs). GRG5/AES represses Wnt-mediated transcription in human cells and in zebrafish embryos, and plays a role in dorsal-ventral patterning.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, luciferase reporter assays (human cells), zebrafish overexpression/knockdown experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction mapped by deletion analysis and Co-IP, functional repression shown in two independent systems (human cells and zebrafish), single lab\",\n      \"pmids\": [\"23840876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AES is upregulated by AML1/ETO in hematopoietic progenitor cells, and is required for AML1/ETO-induced self-renewal: RNAi knockdown of AES in AML1/ETO-expressing cell lines inhibited colony formation, and AES depletion in primary murine progenitors suppressed AML1/ETO-induced serial replating capacity.\",\n      \"method\": \"Expression microarray, RNAi knockdown in cell lines and primary murine progenitors, colony-forming unit assays, CFU-spleen assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with defined cellular phenotype across both cell lines and primary cells, multiple readouts, single lab\",\n      \"pmids\": [\"21245488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HDRP (histone deacetylase-related protein) physically interacts with AES in the brain and blocks AES-induced neuronal apoptosis. Forced expression of AES in healthy cerebellar granule neurons causes cell death, which is prevented by co-expression of HDRP or TLE1.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay, co-immunoprecipitation, co-localization, forced expression in cultured cerebellar granule neurons\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by three methods (yeast two-hybrid, in vitro binding, Co-IP), functional consequence in primary neurons, single lab\",\n      \"pmids\": [\"18438919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AES physically interacts with the NUP98-HOXA9 oncoprotein (requiring the FG repeat region of NUP98-HOXA9) and with wild-type NUP98. AES augments NUP98-HOXA9 transcriptional activity and, in the presence of NUP98-HOXA9, increases long-term proliferation and primitive cell numbers in human CD34+ cells; these effects are not observed in the absence of NUP98-HOXA9.\",\n      \"method\": \"Cytoplasmic yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, immunofluorescence, primary human CD34+ cell proliferation assays, AES knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by three methods; functional consequence in primary human cells; single lab\",\n      \"pmids\": [\"21937451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AES (Aes) forms nuclear foci in colorectal cancer cells together with TLE1. These foci dissolve during mitosis and reassemble after cytokinesis. HSC70 is an essential component of Aes nuclear foci; pharmacological inhibition of HSC70 ATPase activity with VER155008 reduces Aes focus formation.\",\n      \"method\": \"Electron microscopy, time-lapse cinematography, pharmacological inhibition (VER155008), subcellular fractionation\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live imaging and pharmacological intervention with defined structural phenotype; single lab\",\n      \"pmids\": [\"26229111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AES suppresses transcriptional activities of androgen receptor (AR) and Notch signaling in prostate cancer cells. In AR-defective cells, AES overexpression reduces invasion and metastasis to lymph nodes and bones. Prostate epithelium-specific Aes knockout in Pten-flox mice increased Snail and MMP9 expression and accelerated tumor invasion and lymph node metastasis.\",\n      \"method\": \"Overexpression/knockdown in human PCa cell lines, luciferase reporter assays, xenograft mouse model, compound knockout mice (Aes/Pten), immunohistochemistry\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement via luciferase assays and in vivo genetic models, multiple readouts, single lab\",\n      \"pmids\": [\"28178391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Transcription factor YY2 directly binds the YY element in the CpG-island promoter-enhancer of the AES gene and stimulates AES expression in human colonic epithelial cells; downregulation of YY2 in liver metastases reduces AES expression.\",\n      \"method\": \"Promoter-enhancer mapping, transcription factor binding assays, transplantation mouse model, correlation of YY2 and AES protein levels in human CRC metastases\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — binding to YY element shown, but the direct binding experiment is not fully described in the abstract; single lab, limited orthogonal validation\",\n      \"pmids\": [\"27561171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AES knockdown downregulates RND3 expression at mRNA and protein levels in cancer cell lines, and AES overexpression enhances RND3 promoter activity as shown by luciferase assay, suggesting AES positively regulates RND3 transcription.\",\n      \"method\": \"RNAi knockdown, luciferase promoter assay, Western blot, RT-PCR\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single reporter assay for transcriptional mechanism; no direct binding or co-IP shown\",\n      \"pmids\": [\"23546594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AES (Groucho protein) physically binds HNF1α and represses HNF1α-mediated transcription, with a direct functional link to glucose-stimulated insulin secretion in pancreatic beta-cells.\",\n      \"method\": \"Yeast two-hybrid (implied from 'identified as physical binding partner'), transcriptional reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction and repression function described but the abstract does not detail the binding assay method, single lab\",\n      \"pmids\": [\"26549228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GRG5 (AES) ablation in embryonic stem cells deregulates pluripotency, while overexpression enhances self-renewal. GRG5 represses mesendodermal-related genes and promotes neuroectodermal specification via suppression of Wnt and BMP signaling. GRG5 also maintains Neural Stem Cell self-renewal by sustaining Notch/Hes and Stat3 signaling activities.\",\n      \"method\": \"Loss- and gain-of-function ESC experiments, transcriptomic analysis, cell differentiation assays, neuronal reprogramming assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — defined cellular phenotypes but pathway placements (Wnt, BMP, Notch, Stat3) inferred from transcriptomics without direct mechanistic reconstitution; single lab\",\n      \"pmids\": [\"30214018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Mouse and human AES proteins (~202 and 197 amino acids, respectively) share approximately 50% amino acid identity with the N-terminal domain of Drosophila Groucho and full-length TLE/GRG proteins, establishing AES as a short, N-terminal fragment member of the Groucho family without the C-terminal WD-repeat domain.\",\n      \"method\": \"cDNA cloning, sequencing, sequence alignment\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct molecular cloning and sequence determination, replicated for both mouse and human; foundational structural characterization\",\n      \"pmids\": [\"8365415\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TLE5/AES/GRG5 is a short, N-terminal Groucho-family co-regulator that lacks a DNA-binding domain and acts as a functionally dynamic modulator of multiple transcription factors: it converts active RBPJ-Notch transcription complexes into repression complexes on the nuclear matrix to suppress metastasis; it is phosphorylated by CK1δ/ε at Ser121, triggering SKP2-mediated ubiquitin-proteasomal degradation; it enhances Runx2/Cbfa1 transcriptional activity and modulates Ihh signaling in bone; it represses Wnt-mediated transcription through a TCF4/LVPQ-motif-dependent interaction; it is required for AML1/ETO-induced hematopoietic self-renewal; it promotes neuronal apoptosis that is counteracted by direct binding of the neuroprotective protein HDRP; and it forms dynamic, HSC70-dependent nuclear foci that dissolve during mitosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TLE5/AES/GRG5 is a short, N-terminal Groucho-family transcriptional co-regulator that lacks the C-terminal WD-repeat domain present in full-length TLE/GRG proteins, functioning as a dynamic modulator that switches the output of multiple transcription factors rather than binding DNA itself [#14]. In epithelial cancers it acts predominantly as a repressor: it converts active RBPJ-Notch transcription complexes into repression complexes on the insoluble nuclear matrix to suppress Notch-driven transendothelial migration and metastasis [#0], and it represses Wnt-mediated transcription through an interaction with TCF4 that specifically requires a 4-amino-acid LVPQ motif [#4]. This anti-metastatic activity extends to prostate cancer, where AES suppresses both androgen receptor and Notch transcriptional output and its epithelium-specific loss accelerates invasion and metastasis [#9]. AES stability is gated by CK1\\u03b4/\\u03b5-mediated phosphorylation at Ser121, which licenses SKP2-dependent ubiquitination and proteasomal degradation through Q-domain contacts with both kinase and ligase; the S121A mutant resists turnover and retains Wnt/Notch suppression [#1]. Beyond repression, AES enhances Runx2/Cbfa1 transcriptional activity and modulates Indian hedgehog signaling during skeletal development, with Grg5 loss reducing Ihh expression and impairing chondrocyte proliferation and bone formation [#2, #3]. In hematopoietic contexts AES is co-opted by the AML1/ETO and NUP98-HOXA9 oncoproteins to drive self-renewal and proliferation [#5, #7]. AES forms dynamic, HSC70-dependent nuclear foci together with TLE1 that dissolve during mitosis and reassemble after cytokinesis [#8], and it promotes neuronal apoptosis that is counteracted by direct binding of the neuroprotective protein HDRP [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the molecular identity of AES as a truncated Groucho-family member defined the structural basis for its non-DNA-binding co-regulatory behavior.\",\n      \"evidence\": \"cDNA cloning and sequence alignment of mouse and human AES against Drosophila Groucho and TLE/GRG proteins\",\n      \"pmids\": [\"8365415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence assigned to the absence of the WD-repeat domain at this stage\", \"No interaction partners identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Knockout phenotyping placed Grg5 in skeletal development, linking it to Indian hedgehog signaling and chondrocyte/bone formation.\",\n      \"evidence\": \"Gene-targeted knockout mice with histological growth-plate analysis and Ihh expression profiling\",\n      \"pmids\": [\"11984876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway placement inferred from Ihh expression, not direct mechanistic reconstitution\", \"No transcription factor partner identified to explain the Ihh effect\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying Runx2/Cbfa1 as a direct partner explained how AES exerts its skeletal role, as a positive co-activator confirmed by genetic epistasis.\",\n      \"evidence\": \"Yeast two-hybrid, transcriptional reporter assays, and Runx2+/- Grg5-/- compound mutant mice\",\n      \"pmids\": [\"15183720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a Groucho protein enhances rather than represses Runx2 not resolved\", \"Whether the Runx2 link directly accounts for the Ihh effect not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery of the HDRP interaction revealed AES as a pro-apoptotic factor in neurons whose lethal activity is antagonized by binding partners.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, Co-IP, and forced expression in cerebellar granule neurons\",\n      \"pmids\": [\"18438919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets mediating AES-induced apoptosis unknown\", \"Single lab; physiological relevance in vivo not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"AES was defined as a Notch-pathway switch that suppresses cancer cell metastasis by remodeling RBPJ complexes on the nuclear matrix.\",\n      \"evidence\": \"Nuclear matrix fractionation, Apc-delta716 mouse genetics, and pharmacological Notch inhibition rescue\",\n      \"pmids\": [\"21251616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the active-to-repressive complex conversion not detailed\", \"Nuclear matrix tethering partners not fully defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Parallel hematopoietic studies showed AES is hijacked by leukemic fusion oncoproteins to drive aberrant self-renewal, contrasting with its tumor-suppressive role in epithelia.\",\n      \"evidence\": \"Expression microarray and RNAi knockdown in AML1/ETO and NUP98-HOXA9 systems with colony-forming and primary cell proliferation assays\",\n      \"pmids\": [\"21245488\", \"21937451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets downstream of AES in leukemic self-renewal not mapped\", \"How AES switches between repressive and oncogenic co-activator modes unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping the TCF4 interaction to an LVPQ motif explained the molecular specificity by which AES represses Wnt signaling.\",\n      \"evidence\": \"Co-IP, deletion mapping, luciferase reporters in human cells, and zebrafish gain/loss-of-function\",\n      \"pmids\": [\"23840876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of LVPQ recognition not resolved\", \"Whether other TCF isoforms are differentially affected in vivo not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Live imaging defined AES nuclear foci as dynamic, cell-cycle-regulated structures requiring HSC70 chaperone activity.\",\n      \"evidence\": \"Electron microscopy, time-lapse cinematography, VER155008 inhibition, and subcellular fractionation\",\n      \"pmids\": [\"26229111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of focus formation for transcriptional output not established\", \"Composition of foci beyond TLE1 and HSC70 unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Prostate cancer models extended AES anti-metastatic function to AR and Notch suppression, confirmed by tissue-specific knockout.\",\n      \"evidence\": \"Cell line over/knockdown, luciferase assays, xenograft and Aes/Pten compound knockout mice with IHC\",\n      \"pmids\": [\"28178391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AES-AR physical interaction not demonstrated\", \"Mechanism linking AES loss to Snail/MMP9 induction not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of CK1\\u03b4/\\u03b5\\u2013SKP2\\u2013driven degradation established how AES protein levels are post-translationally controlled, with Ser121 as the regulatory switch.\",\n      \"evidence\": \"Reciprocal Co-IP, GST pull-down, S121A mutagenesis, and in vivo tumor/metastasis and PDTX models\",\n      \"pmids\": [\"33754069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating CK1\\u03b4/\\u03b5 toward AES not identified\", \"Whether degradation is regulated differently across cell types not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AES is toggled between transcriptional repressor (Notch/Wnt in epithelia) and co-activator/oncogenic effector (Runx2, AML1/ETO, NUP98-HOXA9) remains the central unresolved question.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural or biochemical model distinguishes repressive from activating complexes\", \"Context determinants (partner availability, modification state) not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 4, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0016604\", \"supporting_discovery_ids\": []}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 5, 7, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\"RBPJ-Notch transcription complex\", \"AES/TLE1 nuclear foci\"],\n    \"partners\": [\"RBPJ\", \"TCF4\", \"RUNX2\", \"HDRP\", \"TLE1\", \"HSPA8\", \"CSNK1D\", \"SKP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}