{"gene":"TCEAL7","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2005,"finding":"TCEAL7 promoter CpG methylation silences its expression in ovarian cancer; in vitro methylation of a CpG site within the promoter suppresses promoter activity, whereas selective demethylation attenuates this suppression. Re-expression of TCEAL7 in cancer cell lines induces cell death and reduces colony formation, identifying it as a cell death regulatory protein. TCEAL7 is also subject to X chromosome inactivation.","method":"Bisulfite sequencing of somatic cell hybrids, in vitro methylation/demethylation of promoter constructs, 5-aza-2'-deoxycytidine treatment, colony formation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (bisulfite sequencing, promoter methylation assay, demethylation rescue, functional cell death assay) in a single study","pmids":["15870691"],"is_preprint":false},{"year":2008,"finding":"TCEAL7 associates with the cyclin D1 promoter at Myc E-box sequences and transcriptionally represses cyclin D1 expression. TCEAL7 downregulation promotes Myc-Max DNA-binding activity and increases promoter activity of the c-Myc target gene ODC, while enhanced TCEAL7 expression inhibits Myc-induced ODC promoter activity, placing TCEAL7 as a repressor of c-Myc transcriptional activity.","method":"Chromatin immunoprecipitation (ChIP) at cyclin D1 promoter, Myc-Max DNA-binding assay, ODC promoter-luciferase reporter assay, anchorage-independent growth assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (ChIP, reporter assay, DNA-binding assay) establishing direct promoter association and functional repression","pmids":["18806825"],"is_preprint":false},{"year":2009,"finding":"TCEAL7 negatively regulates NF-κB signaling at the transcriptional level: shRNA-mediated knockdown of TCEAL7 increases NF-κB DNA-binding activity and transcriptional activity of NF-κB target gene promoters (IL-6, IL-8), while transient transfection of TCEAL7 inhibits NF-κB activation. ChIP assays show increased p65 and p300 recruitment to IL-8 and IL-6 promoters upon TCEAL7 knockdown. TCEAL7 inhibits p65 transcriptional activity without modulating cytoplasmic NF-κB signaling or IκB degradation.","method":"shRNA knockdown, NF-κB luciferase reporter assay, electrophoretic mobility shift assay (EMSA), ChIP for p65 and p300 at target promoters, IKK inhibitor rescue","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (reporter assay, EMSA, ChIP) with reciprocal gain/loss of function","pmids":["19966855"],"is_preprint":false},{"year":2010,"finding":"Myogenic regulatory factors (MRFs) directly transactivate the Tceal7 gene through conserved E-box motifs in a 0.7 kb upstream promoter fragment. Mutation of E-box motifs abolishes reporter expression in somites of transgenic embryos. Overexpression of Tceal7 in C2C12 myoblasts decreases proliferation, enhances differentiation, and upregulates p27 expression.","method":"Transgenic LacZ reporter analysis, E-box mutagenesis, transcriptional assays, EMSA, ChIP, C2C12 overexpression with proliferation/differentiation readouts","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (transgenic mouse, mutagenesis, EMSA, ChIP, functional cell assays) in a single study","pmids":["20307260"],"is_preprint":false},{"year":2010,"finding":"TCEAL7 acts as a competitive inhibitor of c-Myc activity in ALT (alternative lengthening of telomeres) cells, where its increased expression reduces c-Myc binding at the hTERT promoter and suppresses hTERT expression. Alteration of TCEAL7 expression levels in ALT and telomerase-positive cells correspondingly affects hTERT promoter activity.","method":"siRNA screen, c-Myc ChIP at hTERT promoter, TCEAL7 expression modulation with hTERT promoter activity readout","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and functional expression modulation, single study, moderate methods","pmids":["20454512"],"is_preprint":false},{"year":2019,"finding":"TCEAL7 negatively regulates the Wnt/β-catenin pathway by blocking β-catenin translocation from the cytoplasm to the nucleus. miR-301a (delivered via hypoxic glioma cell-secreted exosomes) directly targets the TCEAL7 3'UTR to repress its expression, thereby activating Wnt/β-catenin signaling and promoting radiation resistance. Overexpression of TCEAL7 reverses exo-miR-301a-mediated radioresistance.","method":"Luciferase 3'UTR reporter assay for miR-301a targeting, β-catenin subcellular fractionation/localization, TCEAL7 overexpression rescue of radioresistance","journal":"Molecular Therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct 3'UTR targeting validated, β-catenin localization assay, functional rescue; single lab study","pmids":["31402274"],"is_preprint":false},{"year":2021,"finding":"CAF-derived exosomal miR-18b promotes breast cancer invasion/metastasis by directly binding the 3'UTR of TCEAL7, repressing its expression; loss of TCEAL7 activates NF-κB signaling, promotes nuclear Snail ectopic activation, and induces EMT.","method":"Luciferase 3'UTR reporter assay for miR-18b targeting TCEAL7, NF-κB pathway readout, Snail nuclear localization, EMT markers, mouse xenograft metastasis model","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct 3'UTR targeting validated, pathway activation demonstrated, in vivo metastasis model; single lab","pmids":["34853307"],"is_preprint":false},{"year":2022,"finding":"A triple complex of Mef2c, Creb1, and Myod synergistically transactivates the Tceal7 promoter through Mef2 and CRE motifs in the distal promoter region (Mef2#3-CRE#3-E#4 cluster). Protein-protein interaction between Mef2c and Creb1 was mapped, supporting cooperative transcriptional activation of Tceal7 during skeletal muscle differentiation.","method":"Transcriptional reporter assays, mutagenesis of Mef2/CRE binding motifs, protein-protein interaction mapping","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assays with mutagenesis and protein interaction mapping; single study","pmids":["35816819"],"is_preprint":false},{"year":2023,"finding":"Tceal7 physically interacts with Cdk1 (but not Cdk2, Cdk4, or Cdk6) in skeletal muscle. Transgenic overexpression of Tceal7 in vivo reduces phosphorylation of 4E-BP1 (Ser65), p70S6K1 (Thr389), and Cdk substrates, impairs postnatal muscle fiber growth, and reduces body weight. No direct interaction was detected between Tceal7 and Cyclin A2, B1, D1, or E1 despite the presence of four RxL motifs.","method":"Transgenic mouse overexpression model (MCK 6.5 kb-HA-Tceal7), co-immunoprecipitation for Tceal7–Cdk1 interaction, immunoblotting for phosphorylation of 4E-BP1/p70S6K1/Cdk substrates","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP demonstrating direct Cdk1 interaction, in vivo transgenic phosphorylation data; single study","pmids":["37047236"],"is_preprint":false},{"year":2026,"finding":"TCEAL7 expression in differentiating myoblasts is directly regulated by BRG1-containing mSWI/SNF complexes (not BRM) and calcineurin (Cn) signaling. BRG1 occupancy at the Tceal7 promoter increases during differentiation; Cn knockdown or pharmacological inhibition suppresses Tceal7 expression. TCEAL7 protein accumulates in the nucleus during differentiation. Tceal7 knockdown reduces Myogenin expression, alters cell proliferation, and broadly dysregulates myogenic, metabolic, and cell-cycle gene programs including cyclin-dependent kinase pathways.","method":"ChIP for BRG1 at Tceal7 promoter, siRNA knockdown of BRG1/BRM/calcineurin, pharmacological inhibition of mSWI/SNF bromodomains and calcineurin, RNA-seq, nuclear localization imaging, Myogenin expression readout","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, KD, pharmacological, RNA-seq); preprint, not yet peer-reviewed","pmids":["41648239"],"is_preprint":true}],"current_model":"TCEAL7 is a nuclear transcriptional regulatory protein that functions as a tumor suppressor and myogenic differentiation factor: it represses c-Myc transcriptional activity at E-box-containing promoters (including cyclin D1 and ODC), inhibits NF-κB p65 transcriptional activity at target gene promoters, blocks β-catenin nuclear translocation to suppress Wnt signaling, interacts with Cdk1 to modulate phosphorylation of cell-cycle and mTOR substrates in muscle, and is itself transcriptionally activated by MRFs (MyoD), Mef2c/Creb1 complexes, and BRG1-containing SWI/SNF complexes downstream of calcineurin signaling during skeletal muscle differentiation, while its expression is silenced in cancer by promoter CpG hypermethylation and by miR-301a/miR-18b targeting."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing TCEAL7 as a tumor suppressor silenced by epigenetic mechanisms resolved why this X-linked gene is lost in ovarian cancer: promoter CpG methylation directly suppresses transcription, and re-expression induces cell death.","evidence":"Bisulfite sequencing, in vitro methylation/demethylation of promoter constructs, 5-aza-2'-deoxycytidine treatment, and colony formation assays in ovarian cancer cell lines","pmids":["15870691"],"confidence":"High","gaps":["Mechanism by which TCEAL7 re-expression induces cell death was not identified","Whether methylation-mediated silencing extends to other cancer types was not tested","Direct transcriptional targets of TCEAL7 were unknown"]},{"year":2008,"claim":"Identification of TCEAL7 as a repressor of c-Myc transcriptional activity provided the first mechanistic link to a specific oncogenic transcription factor, showing TCEAL7 associates with Myc E-box sequences at the cyclin D1 promoter and inhibits Myc-Max DNA-binding activity.","evidence":"ChIP at cyclin D1 promoter, Myc-Max DNA-binding assay, ODC promoter-luciferase reporter, anchorage-independent growth assay","pmids":["18806825"],"confidence":"High","gaps":["Whether TCEAL7 directly binds DNA or acts through a co-repressor complex was unresolved","Physical interaction between TCEAL7 and Myc-Max was not demonstrated"]},{"year":2009,"claim":"Discovery that TCEAL7 independently represses NF-κB signaling at the transcriptional level — reducing p65 and p300 recruitment to target promoters without affecting cytoplasmic IκB degradation — established a second major oncogenic pathway controlled by TCEAL7.","evidence":"shRNA knockdown, NF-κB luciferase reporter, EMSA, ChIP for p65 and p300 at IL-8/IL-6 promoters, IKK inhibitor rescue","pmids":["19966855"],"confidence":"High","gaps":["Whether TCEAL7 physically interacts with p65 or p300 was not determined","Mechanism by which TCEAL7 prevents p65/p300 recruitment to chromatin remained unclear"]},{"year":2010,"claim":"Demonstration that MRFs directly transactivate Tceal7 through conserved E-box motifs in vivo, and that Tceal7 overexpression promotes myoblast differentiation while reducing proliferation, placed TCEAL7 as a direct effector of the myogenic transcription program.","evidence":"Transgenic LacZ reporter in mouse embryos, E-box mutagenesis, EMSA, ChIP, C2C12 overexpression with proliferation/differentiation readouts","pmids":["20307260"],"confidence":"High","gaps":["Downstream transcriptional targets of TCEAL7 in muscle were not defined","Loss-of-function phenotype in muscle development was not tested"]},{"year":2010,"claim":"Extension of the c-Myc repressor function to hTERT regulation in ALT cells showed TCEAL7 competitively inhibits c-Myc binding at the hTERT promoter, broadening the set of Myc target genes subject to TCEAL7 repression.","evidence":"c-Myc ChIP at hTERT promoter, TCEAL7 expression modulation with hTERT promoter activity readout in ALT and telomerase-positive cells","pmids":["20454512"],"confidence":"Medium","gaps":["Direct physical competition between TCEAL7 and c-Myc at chromatin was not shown","Relevance to telomere maintenance in vivo was not tested"]},{"year":2019,"claim":"Identification of TCEAL7 as a negative regulator of Wnt/β-catenin signaling — blocking β-catenin nuclear translocation — added a third oncogenic pathway controlled by TCEAL7 and revealed exosomal miR-301a as a post-transcriptional silencing mechanism.","evidence":"Luciferase 3'UTR reporter for miR-301a, β-catenin subcellular fractionation, TCEAL7 overexpression rescue of radioresistance in glioma cells","pmids":["31402274"],"confidence":"Medium","gaps":["Molecular mechanism by which TCEAL7 prevents β-catenin nuclear import was not determined","Whether TCEAL7 physically interacts with β-catenin was not tested"]},{"year":2021,"claim":"Demonstration that exosomal miR-18b from cancer-associated fibroblasts represses TCEAL7 to activate NF-κB/Snail/EMT linked the NF-κB repressor function to an in vivo metastasis phenotype in breast cancer.","evidence":"Luciferase 3'UTR reporter for miR-18b, NF-κB pathway readout, Snail nuclear localization, EMT markers, mouse xenograft metastasis model","pmids":["34853307"],"confidence":"Medium","gaps":["Whether TCEAL7 directly regulates Snail transcription or acts solely through NF-κB was not resolved","Contribution of TCEAL7 versus other miR-18b targets to metastasis was not deconvolved"]},{"year":2022,"claim":"Mapping a Mef2c–Creb1–MyoD triple complex that synergistically transactivates the Tceal7 promoter through Mef2 and CRE motifs refined understanding of how Tceal7 is induced during skeletal muscle differentiation.","evidence":"Transcriptional reporter assays with Mef2/CRE motif mutagenesis, protein–protein interaction mapping between Mef2c and Creb1","pmids":["35816819"],"confidence":"Medium","gaps":["ChIP confirmation of Mef2c/Creb1 occupancy at the endogenous Tceal7 promoter was not shown","Functional requirement of each motif in vivo was not tested"]},{"year":2023,"claim":"Discovery that Tceal7 physically interacts with Cdk1 and that transgenic overexpression reduces phosphorylation of mTOR/Cdk substrates and impairs postnatal muscle fiber growth identified a non-transcriptional mechanism through which Tceal7 regulates cell growth.","evidence":"Co-immunoprecipitation for Tceal7–Cdk1 in skeletal muscle, transgenic MCK-HA-Tceal7 mouse, immunoblotting for p-4E-BP1/p-p70S6K1/Cdk substrates","pmids":["37047236"],"confidence":"Medium","gaps":["Reciprocal Co-IP or in vitro binding assay to confirm direct Tceal7–Cdk1 interaction was not provided","Whether Tceal7 inhibits Cdk1 kinase activity directly or acts as a scaffolding/sequestering factor is unknown","Loss-of-function muscle phenotype was not examined"]},{"year":null,"claim":"Key unresolved questions include the structural basis for TCEAL7's multi-pathway transcriptional repression (whether it directly binds DNA or acts exclusively through protein–protein interactions with Myc, p65, or β-catenin), the identity of a core TCEAL7-containing repressor complex, and the in vivo consequence of Tceal7 genetic loss in both tumor suppression and muscle development.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical data exist for TCEAL7 protein","No Tceal7 knockout mouse or genetic loss-of-function model has been reported","Whether the Myc-repressor, NF-κB-repressor, Wnt-inhibitory, and Cdk1-binding functions reflect a unified molecular mechanism is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,9]}],"pathway":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7]}],"complexes":[],"partners":["MYC","CDK1","RELA","MEF2C","CREB1","MYOD1","CTNNB1"],"other_free_text":[]},"mechanistic_narrative":"TCEAL7 is a nuclear transcriptional regulatory protein that functions as a tumor suppressor and myogenic differentiation factor by modulating multiple oncogenic and developmental signaling pathways. It represses c-Myc transcriptional activity at E-box-containing promoters (cyclin D1, ODC, hTERT) through association with Myc target promoter regions, and independently inhibits NF-κB p65 transcriptional activity at target gene promoters (IL-6, IL-8) without affecting cytoplasmic NF-κB signaling or IκB degradation [PMID:18806825, PMID:19966855, PMID:20454512]. TCEAL7 also blocks β-catenin nuclear translocation to suppress Wnt signaling, physically interacts with Cdk1 to reduce phosphorylation of mTOR pathway substrates (4E-BP1, p70S6K1) in skeletal muscle, and is transcriptionally activated by MRFs through conserved E-box motifs as well as by Mef2c/Creb1 complexes during myogenic differentiation [PMID:31402274, PMID:37047236, PMID:20307260, PMID:35816819]. Its expression is epigenetically silenced in cancer by promoter CpG hypermethylation and post-transcriptionally repressed by miR-301a and miR-18b delivered via exosomes, and re-expression induces cell death and reduces colony formation [PMID:15870691, PMID:34853307]."},"prefetch_data":{"uniprot":{"accession":"Q9BRU2","full_name":"Transcription elongation factor A protein-like 7","aliases":["Transcription elongation factor S-II protein-like 7"],"length_aa":100,"mass_kda":12.3,"function":"Plays a role in the negative regulation of NF-kappa-B signaling at the basal level by modulating transcriptional activity of NF-kappa-B on its target gene promoters. Associates with cyclin D1 promoter containing Myc E-box sequence and transcriptionally represses cyclin D1 expression. Regulates telomerase reverse transcriptase expression and telomerase activity in both ALT (alternative lengthening of telomeres)and telomerase-positive cell lines","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BRU2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TCEAL7","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TCEAL7","total_profiled":1310},"omim":[{"mim_id":"301155","title":"TRANSCRIPTION ELONGATION FACTOR A-LIKE 5; TCEAL5","url":"https://www.omim.org/entry/301155"},{"mim_id":"300771","title":"TRANSCRIPTION ELONGATION FACTOR A-LIKE 7; TCEAL7","url":"https://www.omim.org/entry/300771"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":120.5}],"url":"https://www.proteinatlas.org/search/TCEAL7"},"hgnc":{"alias_symbol":["MGC23947","WEX5"],"prev_symbol":[]},"alphafold":{"accession":"Q9BRU2","domains":[{"cath_id":"1.20.5","chopping":"43-92","consensus_level":"high","plddt":82.6866,"start":43,"end":92}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRU2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRU2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRU2-F1-predicted_aligned_error_v6.png","plddt_mean":71.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TCEAL7","jax_strain_url":"https://www.jax.org/strain/search?query=TCEAL7"},"sequence":{"accession":"Q9BRU2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BRU2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BRU2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRU2"}},"corpus_meta":[{"pmid":"31402274","id":"PMC_31402274","title":"Hypoxic Glioma Cell-Secreted Exosomal miR-301a Activates Wnt/β-catenin Signaling and Promotes Radiation Resistance by Targeting TCEAL7.","date":"2019","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31402274","citation_count":155,"is_preprint":false},{"pmid":"34853307","id":"PMC_34853307","title":"Cancer-associated fibroblast-derived exosomal miR-18b promotes breast cancer invasion and metastasis by regulating TCEAL7.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34853307","citation_count":69,"is_preprint":false},{"pmid":"15870691","id":"PMC_15870691","title":"Epigenetic silencing of TCEAL7 (Bex4) in ovarian cancer.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15870691","citation_count":57,"is_preprint":false},{"pmid":"19966855","id":"PMC_19966855","title":"TCEAL7, a putative tumor suppressor gene, negatively regulates NF-kappaB pathway.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19966855","citation_count":38,"is_preprint":false},{"pmid":"18806825","id":"PMC_18806825","title":"A role for candidate tumor-suppressor gene TCEAL7 in the regulation of c-Myc activity, cyclin D1 levels and cellular transformation.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18806825","citation_count":37,"is_preprint":false},{"pmid":"20307260","id":"PMC_20307260","title":"Myogenic regulatory factors transactivate the Tceal7 gene and modulate muscle differentiation.","date":"2010","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/20307260","citation_count":28,"is_preprint":false},{"pmid":"20454512","id":"PMC_20454512","title":"TCEAL7 inhibition of c-Myc activity in alternative lengthening of telomeres regulates hTERT expression.","date":"2010","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20454512","citation_count":24,"is_preprint":false},{"pmid":"31321645","id":"PMC_31321645","title":"Downregulation of TCEAL7 expression induces CCND1 expression in non-small cell lung cancer.","date":"2019","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31321645","citation_count":14,"is_preprint":false},{"pmid":"32952069","id":"PMC_32952069","title":"Long non-coding RNA HAND2-AS1 inhibits gastric cancer progression by suppressing TCEAL7 expression via targeting miR-769-5p.","date":"2020","source":"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/32952069","citation_count":11,"is_preprint":false},{"pmid":"35336819","id":"PMC_35336819","title":"Transcription Regulation of Tceal7 by the Triple Complex of Mef2c, Creb1 and Myod.","date":"2022","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35336819","citation_count":8,"is_preprint":false},{"pmid":"19419758","id":"PMC_19419758","title":"Polymorphisms in TCEAL7 and risk of epithelial ovarian cancer.","date":"2009","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19419758","citation_count":8,"is_preprint":false},{"pmid":"37047236","id":"PMC_37047236","title":"Tceal7 Regulates Skeletal Muscle Development through Its Interaction with Cdk1.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37047236","citation_count":5,"is_preprint":false},{"pmid":"35216152","id":"PMC_35216152","title":"Tceal5 and Tceal7 Function in C2C12 Myogenic Differentiation via Exosomes in Fetal Bovine Serum.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35216152","citation_count":4,"is_preprint":false},{"pmid":"41648239","id":"PMC_41648239","title":"Tceal7 is a BRG1-regulated target of calcineurin signaling that promotes myoblast differentiation.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41648239","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8246,"output_tokens":3028,"usd":0.035079},"stage2":{"model":"claude-opus-4-6","input_tokens":6404,"output_tokens":2971,"usd":0.159442},"total_usd":0.194521,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"TCEAL7 promoter CpG methylation silences its expression in ovarian cancer; in vitro methylation of a CpG site within the promoter suppresses promoter activity, whereas selective demethylation attenuates this suppression. Re-expression of TCEAL7 in cancer cell lines induces cell death and reduces colony formation, identifying it as a cell death regulatory protein. TCEAL7 is also subject to X chromosome inactivation.\",\n      \"method\": \"Bisulfite sequencing of somatic cell hybrids, in vitro methylation/demethylation of promoter constructs, 5-aza-2'-deoxycytidine treatment, colony formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (bisulfite sequencing, promoter methylation assay, demethylation rescue, functional cell death assay) in a single study\",\n      \"pmids\": [\"15870691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TCEAL7 associates with the cyclin D1 promoter at Myc E-box sequences and transcriptionally represses cyclin D1 expression. TCEAL7 downregulation promotes Myc-Max DNA-binding activity and increases promoter activity of the c-Myc target gene ODC, while enhanced TCEAL7 expression inhibits Myc-induced ODC promoter activity, placing TCEAL7 as a repressor of c-Myc transcriptional activity.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) at cyclin D1 promoter, Myc-Max DNA-binding assay, ODC promoter-luciferase reporter assay, anchorage-independent growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (ChIP, reporter assay, DNA-binding assay) establishing direct promoter association and functional repression\",\n      \"pmids\": [\"18806825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TCEAL7 negatively regulates NF-κB signaling at the transcriptional level: shRNA-mediated knockdown of TCEAL7 increases NF-κB DNA-binding activity and transcriptional activity of NF-κB target gene promoters (IL-6, IL-8), while transient transfection of TCEAL7 inhibits NF-κB activation. ChIP assays show increased p65 and p300 recruitment to IL-8 and IL-6 promoters upon TCEAL7 knockdown. TCEAL7 inhibits p65 transcriptional activity without modulating cytoplasmic NF-κB signaling or IκB degradation.\",\n      \"method\": \"shRNA knockdown, NF-κB luciferase reporter assay, electrophoretic mobility shift assay (EMSA), ChIP for p65 and p300 at target promoters, IKK inhibitor rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (reporter assay, EMSA, ChIP) with reciprocal gain/loss of function\",\n      \"pmids\": [\"19966855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Myogenic regulatory factors (MRFs) directly transactivate the Tceal7 gene through conserved E-box motifs in a 0.7 kb upstream promoter fragment. Mutation of E-box motifs abolishes reporter expression in somites of transgenic embryos. Overexpression of Tceal7 in C2C12 myoblasts decreases proliferation, enhances differentiation, and upregulates p27 expression.\",\n      \"method\": \"Transgenic LacZ reporter analysis, E-box mutagenesis, transcriptional assays, EMSA, ChIP, C2C12 overexpression with proliferation/differentiation readouts\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (transgenic mouse, mutagenesis, EMSA, ChIP, functional cell assays) in a single study\",\n      \"pmids\": [\"20307260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TCEAL7 acts as a competitive inhibitor of c-Myc activity in ALT (alternative lengthening of telomeres) cells, where its increased expression reduces c-Myc binding at the hTERT promoter and suppresses hTERT expression. Alteration of TCEAL7 expression levels in ALT and telomerase-positive cells correspondingly affects hTERT promoter activity.\",\n      \"method\": \"siRNA screen, c-Myc ChIP at hTERT promoter, TCEAL7 expression modulation with hTERT promoter activity readout\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and functional expression modulation, single study, moderate methods\",\n      \"pmids\": [\"20454512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TCEAL7 negatively regulates the Wnt/β-catenin pathway by blocking β-catenin translocation from the cytoplasm to the nucleus. miR-301a (delivered via hypoxic glioma cell-secreted exosomes) directly targets the TCEAL7 3'UTR to repress its expression, thereby activating Wnt/β-catenin signaling and promoting radiation resistance. Overexpression of TCEAL7 reverses exo-miR-301a-mediated radioresistance.\",\n      \"method\": \"Luciferase 3'UTR reporter assay for miR-301a targeting, β-catenin subcellular fractionation/localization, TCEAL7 overexpression rescue of radioresistance\",\n      \"journal\": \"Molecular Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct 3'UTR targeting validated, β-catenin localization assay, functional rescue; single lab study\",\n      \"pmids\": [\"31402274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAF-derived exosomal miR-18b promotes breast cancer invasion/metastasis by directly binding the 3'UTR of TCEAL7, repressing its expression; loss of TCEAL7 activates NF-κB signaling, promotes nuclear Snail ectopic activation, and induces EMT.\",\n      \"method\": \"Luciferase 3'UTR reporter assay for miR-18b targeting TCEAL7, NF-κB pathway readout, Snail nuclear localization, EMT markers, mouse xenograft metastasis model\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct 3'UTR targeting validated, pathway activation demonstrated, in vivo metastasis model; single lab\",\n      \"pmids\": [\"34853307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A triple complex of Mef2c, Creb1, and Myod synergistically transactivates the Tceal7 promoter through Mef2 and CRE motifs in the distal promoter region (Mef2#3-CRE#3-E#4 cluster). Protein-protein interaction between Mef2c and Creb1 was mapped, supporting cooperative transcriptional activation of Tceal7 during skeletal muscle differentiation.\",\n      \"method\": \"Transcriptional reporter assays, mutagenesis of Mef2/CRE binding motifs, protein-protein interaction mapping\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assays with mutagenesis and protein interaction mapping; single study\",\n      \"pmids\": [\"35816819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Tceal7 physically interacts with Cdk1 (but not Cdk2, Cdk4, or Cdk6) in skeletal muscle. Transgenic overexpression of Tceal7 in vivo reduces phosphorylation of 4E-BP1 (Ser65), p70S6K1 (Thr389), and Cdk substrates, impairs postnatal muscle fiber growth, and reduces body weight. No direct interaction was detected between Tceal7 and Cyclin A2, B1, D1, or E1 despite the presence of four RxL motifs.\",\n      \"method\": \"Transgenic mouse overexpression model (MCK 6.5 kb-HA-Tceal7), co-immunoprecipitation for Tceal7–Cdk1 interaction, immunoblotting for phosphorylation of 4E-BP1/p70S6K1/Cdk substrates\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP demonstrating direct Cdk1 interaction, in vivo transgenic phosphorylation data; single study\",\n      \"pmids\": [\"37047236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TCEAL7 expression in differentiating myoblasts is directly regulated by BRG1-containing mSWI/SNF complexes (not BRM) and calcineurin (Cn) signaling. BRG1 occupancy at the Tceal7 promoter increases during differentiation; Cn knockdown or pharmacological inhibition suppresses Tceal7 expression. TCEAL7 protein accumulates in the nucleus during differentiation. Tceal7 knockdown reduces Myogenin expression, alters cell proliferation, and broadly dysregulates myogenic, metabolic, and cell-cycle gene programs including cyclin-dependent kinase pathways.\",\n      \"method\": \"ChIP for BRG1 at Tceal7 promoter, siRNA knockdown of BRG1/BRM/calcineurin, pharmacological inhibition of mSWI/SNF bromodomains and calcineurin, RNA-seq, nuclear localization imaging, Myogenin expression readout\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, KD, pharmacological, RNA-seq); preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41648239\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TCEAL7 is a nuclear transcriptional regulatory protein that functions as a tumor suppressor and myogenic differentiation factor: it represses c-Myc transcriptional activity at E-box-containing promoters (including cyclin D1 and ODC), inhibits NF-κB p65 transcriptional activity at target gene promoters, blocks β-catenin nuclear translocation to suppress Wnt signaling, interacts with Cdk1 to modulate phosphorylation of cell-cycle and mTOR substrates in muscle, and is itself transcriptionally activated by MRFs (MyoD), Mef2c/Creb1 complexes, and BRG1-containing SWI/SNF complexes downstream of calcineurin signaling during skeletal muscle differentiation, while its expression is silenced in cancer by promoter CpG hypermethylation and by miR-301a/miR-18b targeting.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TCEAL7 is a nuclear transcriptional regulatory protein that functions as a tumor suppressor and myogenic differentiation factor by modulating multiple oncogenic and developmental signaling pathways. It represses c-Myc transcriptional activity at E-box-containing promoters (cyclin D1, ODC, hTERT) through association with Myc target promoter regions, and independently inhibits NF-κB p65 transcriptional activity at target gene promoters (IL-6, IL-8) without affecting cytoplasmic NF-κB signaling or IκB degradation [PMID:18806825, PMID:19966855, PMID:20454512]. TCEAL7 also blocks β-catenin nuclear translocation to suppress Wnt signaling, physically interacts with Cdk1 to reduce phosphorylation of mTOR pathway substrates (4E-BP1, p70S6K1) in skeletal muscle, and is transcriptionally activated by MRFs through conserved E-box motifs as well as by Mef2c/Creb1 complexes during myogenic differentiation [PMID:31402274, PMID:37047236, PMID:20307260, PMID:35816819]. Its expression is epigenetically silenced in cancer by promoter CpG hypermethylation and post-transcriptionally repressed by miR-301a and miR-18b delivered via exosomes, and re-expression induces cell death and reduces colony formation [PMID:15870691, PMID:34853307].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing TCEAL7 as a tumor suppressor silenced by epigenetic mechanisms resolved why this X-linked gene is lost in ovarian cancer: promoter CpG methylation directly suppresses transcription, and re-expression induces cell death.\",\n      \"evidence\": \"Bisulfite sequencing, in vitro methylation/demethylation of promoter constructs, 5-aza-2'-deoxycytidine treatment, and colony formation assays in ovarian cancer cell lines\",\n      \"pmids\": [\"15870691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which TCEAL7 re-expression induces cell death was not identified\",\n        \"Whether methylation-mediated silencing extends to other cancer types was not tested\",\n        \"Direct transcriptional targets of TCEAL7 were unknown\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of TCEAL7 as a repressor of c-Myc transcriptional activity provided the first mechanistic link to a specific oncogenic transcription factor, showing TCEAL7 associates with Myc E-box sequences at the cyclin D1 promoter and inhibits Myc-Max DNA-binding activity.\",\n      \"evidence\": \"ChIP at cyclin D1 promoter, Myc-Max DNA-binding assay, ODC promoter-luciferase reporter, anchorage-independent growth assay\",\n      \"pmids\": [\"18806825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TCEAL7 directly binds DNA or acts through a co-repressor complex was unresolved\",\n        \"Physical interaction between TCEAL7 and Myc-Max was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that TCEAL7 independently represses NF-κB signaling at the transcriptional level — reducing p65 and p300 recruitment to target promoters without affecting cytoplasmic IκB degradation — established a second major oncogenic pathway controlled by TCEAL7.\",\n      \"evidence\": \"shRNA knockdown, NF-κB luciferase reporter, EMSA, ChIP for p65 and p300 at IL-8/IL-6 promoters, IKK inhibitor rescue\",\n      \"pmids\": [\"19966855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TCEAL7 physically interacts with p65 or p300 was not determined\",\n        \"Mechanism by which TCEAL7 prevents p65/p300 recruitment to chromatin remained unclear\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that MRFs directly transactivate Tceal7 through conserved E-box motifs in vivo, and that Tceal7 overexpression promotes myoblast differentiation while reducing proliferation, placed TCEAL7 as a direct effector of the myogenic transcription program.\",\n      \"evidence\": \"Transgenic LacZ reporter in mouse embryos, E-box mutagenesis, EMSA, ChIP, C2C12 overexpression with proliferation/differentiation readouts\",\n      \"pmids\": [\"20307260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream transcriptional targets of TCEAL7 in muscle were not defined\",\n        \"Loss-of-function phenotype in muscle development was not tested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extension of the c-Myc repressor function to hTERT regulation in ALT cells showed TCEAL7 competitively inhibits c-Myc binding at the hTERT promoter, broadening the set of Myc target genes subject to TCEAL7 repression.\",\n      \"evidence\": \"c-Myc ChIP at hTERT promoter, TCEAL7 expression modulation with hTERT promoter activity readout in ALT and telomerase-positive cells\",\n      \"pmids\": [\"20454512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical competition between TCEAL7 and c-Myc at chromatin was not shown\",\n        \"Relevance to telomere maintenance in vivo was not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of TCEAL7 as a negative regulator of Wnt/β-catenin signaling — blocking β-catenin nuclear translocation — added a third oncogenic pathway controlled by TCEAL7 and revealed exosomal miR-301a as a post-transcriptional silencing mechanism.\",\n      \"evidence\": \"Luciferase 3'UTR reporter for miR-301a, β-catenin subcellular fractionation, TCEAL7 overexpression rescue of radioresistance in glioma cells\",\n      \"pmids\": [\"31402274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism by which TCEAL7 prevents β-catenin nuclear import was not determined\",\n        \"Whether TCEAL7 physically interacts with β-catenin was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstration that exosomal miR-18b from cancer-associated fibroblasts represses TCEAL7 to activate NF-κB/Snail/EMT linked the NF-κB repressor function to an in vivo metastasis phenotype in breast cancer.\",\n      \"evidence\": \"Luciferase 3'UTR reporter for miR-18b, NF-κB pathway readout, Snail nuclear localization, EMT markers, mouse xenograft metastasis model\",\n      \"pmids\": [\"34853307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether TCEAL7 directly regulates Snail transcription or acts solely through NF-κB was not resolved\",\n        \"Contribution of TCEAL7 versus other miR-18b targets to metastasis was not deconvolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping a Mef2c–Creb1–MyoD triple complex that synergistically transactivates the Tceal7 promoter through Mef2 and CRE motifs refined understanding of how Tceal7 is induced during skeletal muscle differentiation.\",\n      \"evidence\": \"Transcriptional reporter assays with Mef2/CRE motif mutagenesis, protein–protein interaction mapping between Mef2c and Creb1\",\n      \"pmids\": [\"35816819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"ChIP confirmation of Mef2c/Creb1 occupancy at the endogenous Tceal7 promoter was not shown\",\n        \"Functional requirement of each motif in vivo was not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that Tceal7 physically interacts with Cdk1 and that transgenic overexpression reduces phosphorylation of mTOR/Cdk substrates and impairs postnatal muscle fiber growth identified a non-transcriptional mechanism through which Tceal7 regulates cell growth.\",\n      \"evidence\": \"Co-immunoprecipitation for Tceal7–Cdk1 in skeletal muscle, transgenic MCK-HA-Tceal7 mouse, immunoblotting for p-4E-BP1/p-p70S6K1/Cdk substrates\",\n      \"pmids\": [\"37047236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reciprocal Co-IP or in vitro binding assay to confirm direct Tceal7–Cdk1 interaction was not provided\",\n        \"Whether Tceal7 inhibits Cdk1 kinase activity directly or acts as a scaffolding/sequestering factor is unknown\",\n        \"Loss-of-function muscle phenotype was not examined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for TCEAL7's multi-pathway transcriptional repression (whether it directly binds DNA or acts exclusively through protein–protein interactions with Myc, p65, or β-catenin), the identity of a core TCEAL7-containing repressor complex, and the in vivo consequence of Tceal7 genetic loss in both tumor suppression and muscle development.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical data exist for TCEAL7 protein\",\n        \"No Tceal7 knockout mouse or genetic loss-of-function model has been reported\",\n        \"Whether the Myc-repressor, NF-κB-repressor, Wnt-inhibitory, and Cdk1-binding functions reflect a unified molecular mechanism is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MYC\", \"CDK1\", \"RELA\", \"MEF2C\", \"CREB1\", \"MYOD1\", \"CTNNB1\"],\n    \"other_free_text\": []\n  }\n}\n```"}