{"gene":"TACC1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1999,"finding":"Constitutive overexpression of TACC1 in mouse fibroblasts results in cellular transformation and anchorage-independent growth, demonstrating that inappropriate TACC1 expression can impart a proliferative advantage.","method":"CMV promoter-driven overexpression in mouse fibroblasts with anchorage-independent growth assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single functional assay with clear cellular phenotype but no pathway mechanism defined","pmids":["10435627"],"is_preprint":false},{"year":2002,"finding":"TACC1 protein localizes to the cytoplasm and is mainly perinuclear; it associates with the Sm-like RNA-binding proteins LSM7 and SmG (which associate with U6 snRNPs and function in mRNA processing), identified by yeast two-hybrid screen, GST pulldown, and co-immunoprecipitation.","method":"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, immunolocalization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal binding methods (Y2H, GST pulldown, Co-IP) in a single lab","pmids":["12165861"],"is_preprint":false},{"year":2002,"finding":"TACC1 interacts with the C-terminus of the microtubule-associated protein ch-TOG (ortholog of Drosophila MSPS/Xenopus XMAP215) and with the oncogenic transcription factor GAS41/NuBI1, suggesting TACC1 participates in multiple protein complexes.","method":"Yeast two-hybrid screen of human mammary epithelial cDNA library using full-length TACC1 as bait; interaction domain mapping","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus domain mapping, single lab, replicated for chTOG interaction by independent group (PMID:14603251)","pmids":["11903063"],"is_preprint":false},{"year":2003,"finding":"TACC1 forms a protein complex with chTOG, the adaptor protein TRAP, the mitotic kinase Aurora A, and the mRNA regulator LSM7; siRNA-mediated depletion of chTOG, and to a lesser extent TACC1, perturbs cell division.","method":"Co-immunoprecipitation, siRNA knockdown with cell division phenotype readout","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex identification plus functional siRNA knockdown, single lab, two orthogonal methods","pmids":["14603251"],"is_preprint":false},{"year":2004,"finding":"TACC1 localizes to the midzone spindle in anaphase and strongly to the midbody during cytokinesis, and relocates to the nucleolus in interphase; TACC1 and Aurora B kinase form a complex during cytokinesis. Knockdown of Aurora B by RNAi prevents midbody formation, mislocalizes TACC1, and leads to multinucleated cells, placing Aurora B upstream of TACC1 midbody localization.","method":"Immunofluorescence localization, co-immunoprecipitation, siRNA knockdown of Aurora B with multinucleation phenotype readout","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal complex identification by Co-IP, direct localization experiments, and genetic epistasis via RNAi with defined phenotype, single lab with multiple orthogonal methods","pmids":["15064709"],"is_preprint":false},{"year":2010,"finding":"TACC1 interacts with Thyroid Hormone Receptors (TR) and Retinoic Acid Receptors (RAR), preferentially binding unliganded receptors; endogenous TACC1 localizes to the chromatin-enriched nuclear fraction and interacts with RARα in the nucleus; TACC1 depletion reduces ligand-dependent transcriptional activity of RARα and TRα and causes delocalization of TR from nucleus to cytoplasm, indicating TACC1 functions as a nuclear receptor coregulator/scaffold.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, colocalization, subcellular fractionation, siRNA knockdown with transcriptional reporter assays","journal":"BMC molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, GST pulldown, Co-IP, fractionation, siRNA + transcriptional readout) in single lab establishing a functional mechanistic role","pmids":["20078863"],"is_preprint":false},{"year":2015,"finding":"Xenopus TACC1 acts as a microtubule plus-end tracking protein (+TIP) and regulates microtubule dynamics; the conserved C-terminal TACC domain is required for plus-end localization. TACC1 and TACC3 are each required for maintaining normal microtubule growth speed in Xenopus embryonic mesenchymal cells, with partial functional redundancy in regulating microtubule growth lifetime.","method":"Live imaging of GFP-tagged TACC1 in Xenopus embryonic cells, domain-deletion mutants, morpholino knockdown with microtubule dynamics tracking","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with domain mutants and loss-of-function knockdown in a vertebrate model system, single lab, multiple orthogonal methods","pmids":["26012630"],"is_preprint":false},{"year":2021,"finding":"TACC1 variant25 (TACC1v25) overexpression in HNSCC cell lines inhibits proliferation and promotes autophagy; mechanistically, TACC1v25 decreases nuclear pERK and p-mTOR levels and increases Beclin-1 and LC3II/LC3I ratio; addition of AKT activator SC79 rescues autophagy suppression, placing TACC1v25 upstream of the AKT/mTOR pathway.","method":"Overexpression in Cal27 and Fadu cell lines, Western blotting, pharmacological rescue with SC79, proliferation and autophagy assays","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single approach per assay, no direct binding partner identified, pathway placement inferred from pharmacological rescue","pmids":["34897285"],"is_preprint":false},{"year":2026,"finding":"TACC1 binds directly to PARP1 (proline-rich acidic protein 1; identified by co-IP with mass spectrometry), inhibits apoptosis, and activates the AKT/mTOR signaling pathway; TACC1 expression is transcriptionally upregulated by NFE2L3, which itself is a transcriptional target of LEF1 (LEF1 binds the NFE2L3 promoter at positions 1321–1334 as shown by ChIP-seq).","method":"Co-immunoprecipitation with mass spectrometry (for TACC1-PARP1 interaction), ChIP-seq (for LEF1-NFE2L3), Western blotting, functional assays (proliferation, migration, invasion, apoptosis), xenograft mouse model","journal":"Journal of thoracic disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP/MS for binding partner, pathway placement based on correlative expression changes and rescue assays without reconstitution or mutagenesis","pmids":["42182760"],"is_preprint":false}],"current_model":"TACC1 is a centrosomal/cytoskeletal scaffold protein that (1) tracks microtubule plus-ends via its conserved C-terminal TACC domain to regulate microtubule dynamics; (2) forms mitotic complexes with chTOG and Aurora kinases (Aurora A at the centrosome/spindle, Aurora B at the midbody) to support cell division and cytokinesis — Aurora B is required for TACC1 midbody localization; (3) binds Sm-like mRNA-processing proteins (LSM7, SmG) suggesting a role in mRNA regulation; and (4) functions as a nuclear receptor coregulator, localizing to chromatin and scaffolding transcriptional complexes around unliganded thyroid and retinoic acid receptors to support their ligand-dependent transcriptional activity."},"narrative":{"mechanistic_narrative":"TACC1 is a centrosomal/cytoskeletal scaffold protein that couples microtubule dynamics to cell division and also functions in transcriptional regulation [PMID:15064709, PMID:26012630]. Through its conserved C-terminal TACC domain, TACC1 acts as a microtubule plus-end tracking protein that maintains normal microtubule growth speed, with partial functional redundancy with TACC3 [PMID:26012630]. During mitosis TACC1 assembles into complexes with the microtubule-associated protein chTOG and the adaptor TRAP, and partitions between Aurora kinase pools: it works with Aurora A and chTOG to support cell division, and forms a complex with Aurora B that drives its localization to the midbody during cytokinesis — Aurora B depletion mislocalizes TACC1 and produces multinucleated cells, placing Aurora B upstream of TACC1 [PMID:14603251, PMID:15064709]. TACC1 cycles to the nucleolus in interphase and into the chromatin-enriched nuclear fraction, where it serves as a nuclear receptor coregulator: it binds unliganded thyroid hormone and retinoic acid receptors and is required for their ligand-dependent transcriptional activity and proper nuclear retention [PMID:15064709, PMID:20078863]. TACC1 additionally associates with the Sm-like RNA-processing proteins LSM7 and SmG, linking it to mRNA regulation [PMID:12165861, PMID:14603251]. Inappropriate TACC1 overexpression transforms fibroblasts and confers anchorage-independent growth [PMID:10435627].","teleology":[{"year":1999,"claim":"Established that TACC1 dysregulation has oncogenic potential, motivating investigation of its normal cellular function.","evidence":"CMV-driven overexpression in mouse fibroblasts with anchorage-independent growth assay","pmids":["10435627"],"confidence":"Medium","gaps":["No molecular mechanism linking TACC1 to proliferation defined","No endogenous loss-of-function data"]},{"year":2002,"claim":"Identified TACC1's first physical partners, placing it in both an mRNA-processing context (LSM7, SmG) and a microtubule context (chTOG), and a transcription-factor context (GAS41), revealing its multi-complex scaffold nature.","evidence":"Yeast two-hybrid screens, GST pulldown, co-immunoprecipitation and domain mapping; immunolocalization to perinuclear cytoplasm","pmids":["12165861","11903063"],"confidence":"Medium","gaps":["Functional consequence of LSM7/SmG binding for mRNA processing not tested","chTOG and GAS41 interactions not yet linked to a cellular phenotype"]},{"year":2003,"claim":"Connected TACC1 to mitotic machinery by showing it forms a chTOG/TRAP/Aurora A/LSM7 complex and that its depletion perturbs cell division.","evidence":"Co-immunoprecipitation and siRNA knockdown with cell-division phenotype readout","pmids":["14603251"],"confidence":"Medium","gaps":["TACC1 knockdown effect weaker than chTOG, leaving its individual contribution unclear","Order of assembly within the complex not resolved"]},{"year":2004,"claim":"Defined TACC1's cell-cycle-dependent localization and placed Aurora B upstream of its midbody recruitment during cytokinesis.","evidence":"Immunofluorescence, reciprocal co-IP, and Aurora B RNAi with multinucleation readout","pmids":["15064709"],"confidence":"High","gaps":["Direct phosphorylation of TACC1 by Aurora B not demonstrated","Mechanism of nucleolar relocalization in interphase unknown"]},{"year":2010,"claim":"Established a nuclear function for TACC1 as a coregulator that scaffolds unliganded thyroid and retinoic acid receptors and supports their transcriptional output and nuclear retention.","evidence":"Yeast two-hybrid, GST pulldown, co-IP, subcellular fractionation, and siRNA with transcriptional reporter assays","pmids":["20078863"],"confidence":"High","gaps":["Identity of co-recruited transcriptional machinery not defined","How TACC1 switches between cytoplasmic/mitotic and nuclear roles is unknown"]},{"year":2015,"claim":"Demonstrated a direct cytoskeletal activity: TACC1 is a microtubule plus-end tracking protein whose TACC domain confers plus-end localization and regulates microtubule growth.","evidence":"Live imaging of GFP-TACC1 in Xenopus embryonic cells, domain-deletion mutants, and morpholino knockdown with microtubule dynamics tracking","pmids":["26012630"],"confidence":"Medium","gaps":["Mechanism of plus-end recognition by the TACC domain not resolved","Relationship between +TIP activity and mitotic complex function not integrated"]},{"year":2021,"claim":"Linked a TACC1 splice variant to suppression of proliferation and induction of autophagy via the AKT/mTOR axis.","evidence":"Overexpression of TACC1v25 in HNSCC cell lines, Western blotting, and pharmacological rescue with the AKT activator SC79","pmids":["34897285"],"confidence":"Low","gaps":["Pathway placement inferred from pharmacological rescue without direct binding partner","Single cell-line context; isoform-specific generality untested"]},{"year":2026,"claim":"Proposed a TACC1-PARP1 interaction and an upstream LEF1/NFE2L3 transcriptional axis activating AKT/mTOR and inhibiting apoptosis.","evidence":"Co-IP/mass spectrometry, ChIP-seq, Western blotting, functional assays, and xenograft model","pmids":["42182760"],"confidence":"Low","gaps":["Direct interaction not validated by reciprocal or reconstitution assays","Pathway placement based on correlative expression changes without mutagenesis"]},{"year":null,"claim":"How TACC1 partitions between its mitotic microtubule/Aurora roles, its nuclear receptor coregulator role, and its mRNA-processing associations — and what regulates these transitions — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the TACC domain bound to microtubule plus-ends or to nuclear receptors","Whether the mRNA-processing, mitotic, and transcriptional functions reflect distinct isoforms or a single regulated protein is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5]}],"complexes":[],"partners":["CHTOG","TRAP","AURKA","AURKB","LSM7","RARA","THRA","GAS41"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75410","full_name":"Transforming acidic coiled-coil-containing protein 1","aliases":["Gastric cancer antigen Ga55","Taxin-1"],"length_aa":805,"mass_kda":87.8,"function":"Involved in transcription regulation induced by nuclear receptors, including in T3 thyroid hormone and all-trans retinoic acid pathways (PubMed:20078863). Might promote the nuclear localization of the receptors (PubMed:20078863). Likely involved in the processes that promote cell division prior to the formation of differentiated tissues","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O75410/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TACC1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RPN1","stoichiometry":0.2},{"gene":"TUBA1B","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TACC1","total_profiled":1310},"omim":[{"mim_id":"613446","title":"CENTROSOMAL PROTEIN, 120-KD; CEP120","url":"https://www.omim.org/entry/613446"},{"mim_id":"611142","title":"CYTOSKELETON-ASSOCIATED PROTEIN 5; CKAP5","url":"https://www.omim.org/entry/611142"},{"mim_id":"605303","title":"TRANSFORMING, ACIDIC, COILED-COIL-CONTAINING PROTEIN 3; TACC3","url":"https://www.omim.org/entry/605303"},{"mim_id":"605302","title":"TRANSFORMING, ACIDIC, COILED-COIL-CONTAINING PROTEIN 2; TACC2","url":"https://www.omim.org/entry/605302"},{"mim_id":"605301","title":"TRANSFORMING, ACIDIC, COILED-COIL-CONTAINING PROTEIN 1; TACC1","url":"https://www.omim.org/entry/605301"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TACC1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O75410","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75410","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75410-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75410-F1-predicted_aligned_error_v6.png","plddt_mean":56.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TACC1","jax_strain_url":"https://www.jax.org/strain/search?query=TACC1"},"sequence":{"accession":"O75410","fasta_url":"https://rest.uniprot.org/uniprotkb/O75410.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75410/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75410"}},"corpus_meta":[{"pmid":"10435627","id":"PMC_10435627","title":"Cloning of TACC1, an embryonically expressed, potentially transforming coiled coil containing gene, from the 8p11 breast cancer amplicon.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10435627","citation_count":101,"is_preprint":false},{"pmid":"14603251","id":"PMC_14603251","title":"TACC1-chTOG-Aurora A protein complex in breast cancer.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/14603251","citation_count":79,"is_preprint":false},{"pmid":"29978331","id":"PMC_29978331","title":"FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma.","date":"2018","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/29978331","citation_count":69,"is_preprint":false},{"pmid":"15918899","id":"PMC_15918899","title":"Aberrations of TACC1 and TACC3 are associated with ovarian cancer.","date":"2005","source":"BMC women's health","url":"https://pubmed.ncbi.nlm.nih.gov/15918899","citation_count":67,"is_preprint":false},{"pmid":"12165861","id":"PMC_12165861","title":"Carcinogenesis and translational controls: TACC1 is down-regulated in human cancers and associates with mRNA regulators.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12165861","citation_count":59,"is_preprint":false},{"pmid":"18984771","id":"PMC_18984771","title":"Identification of TACC1, NOV, and PTTG1 as new candidate genes associated with endocrine therapy resistance in breast cancer.","date":"2008","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18984771","citation_count":53,"is_preprint":false},{"pmid":"15064709","id":"PMC_15064709","title":"Aurora B -TACC1 protein complex in cytokinesis.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15064709","citation_count":43,"is_preprint":false},{"pmid":"12547166","id":"PMC_12547166","title":"Altered splicing pattern of TACC1 mRNA in gastric cancer.","date":"2002","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/12547166","citation_count":42,"is_preprint":false},{"pmid":"11903063","id":"PMC_11903063","title":"Interaction of the transforming acidic coiled-coil 1 (TACC1) protein with ch-TOG and GAS41/NuBI1 suggests multiple TACC1-containing protein complexes in human cells.","date":"2002","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11903063","citation_count":40,"is_preprint":false},{"pmid":"33481389","id":"PMC_33481389","title":"Neurofibrosarcoma Revisited: An Institutional Case Series of Uterine Sarcomas Harboring Kinase-related Fusions With Report of a Novel FGFR1-TACC1 Fusion.","date":"2021","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33481389","citation_count":32,"is_preprint":false},{"pmid":"20078863","id":"PMC_20078863","title":"The transforming acidic coiled coil (TACC1) protein modulates the transcriptional activity of the nuclear receptors TR and RAR.","date":"2010","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20078863","citation_count":20,"is_preprint":false},{"pmid":"26012630","id":"PMC_26012630","title":"Xenopus TACC1 is a microtubule plus-end tracking protein that can regulate microtubule dynamics during embryonic development.","date":"2015","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/26012630","citation_count":12,"is_preprint":false},{"pmid":"16496324","id":"PMC_16496324","title":"Temporal and spatial expression of TACC1 in the mouse and human.","date":"2006","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/16496324","citation_count":11,"is_preprint":false},{"pmid":"36302190","id":"PMC_36302190","title":"Uterine Sarcoma With FGFR1-TACC1 Gene Fusion: A Case Report and Review of the Literature.","date":"2021","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/36302190","citation_count":10,"is_preprint":false},{"pmid":"35307914","id":"PMC_35307914","title":"LINC01140 inhibits nonsmall cell lung cancer progression and cisplatin resistance through the miR-4742-5p/TACC1 axis.","date":"2022","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35307914","citation_count":10,"is_preprint":false},{"pmid":"35064610","id":"PMC_35064610","title":"The novel finding of an FGFR1::TACC1 fusion in an undifferentiated spindle cell sarcoma of soft tissue with aggressive clinical course.","date":"2022","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35064610","citation_count":8,"is_preprint":false},{"pmid":"34734147","id":"PMC_34734147","title":"FGFR1-TACC1 fusion associated with malignant transformation in a primary spinal cord glioma: a case report.","date":"2021","source":"Journal of spine surgery (Hong Kong)","url":"https://pubmed.ncbi.nlm.nih.gov/34734147","citation_count":5,"is_preprint":false},{"pmid":"23354013","id":"PMC_23354013","title":"Efficient downregulation of ErbB-2 induces TACC1 upregulation in breast cancer cell lines.","date":"2013","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23354013","citation_count":4,"is_preprint":false},{"pmid":"34897285","id":"PMC_34897285","title":"Loss of TACC1 variant25 inducing cell proliferation and suppressing autophagy in head and neck squamous carcinoma.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34897285","citation_count":3,"is_preprint":false},{"pmid":"34749374","id":"PMC_34749374","title":"Leptomeningeal Dissemination of Low-Grade Neuroepithelial Tumor with FGFR1_TACC1 Fusion with Clinical and Radiographic Response to Pazopanib and Topotecan.","date":"2021","source":"Pediatric neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/34749374","citation_count":1,"is_preprint":false},{"pmid":"42182760","id":"PMC_42182760","title":"LEF1/NFE2L3/TACC1 axis activates the AKT-mTOR pathway to promote the progression of esophageal squamous cell carcinoma.","date":"2026","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/42182760","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12593,"output_tokens":2450,"usd":0.037264,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9583,"output_tokens":2968,"usd":0.061058,"stage2_stop_reason":"end_turn"},"total_usd":0.098322,"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\": 1999,\n      \"finding\": \"Constitutive overexpression of TACC1 in mouse fibroblasts results in cellular transformation and anchorage-independent growth, demonstrating that inappropriate TACC1 expression can impart a proliferative advantage.\",\n      \"method\": \"CMV promoter-driven overexpression in mouse fibroblasts with anchorage-independent growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single functional assay with clear cellular phenotype but no pathway mechanism defined\",\n      \"pmids\": [\"10435627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TACC1 protein localizes to the cytoplasm and is mainly perinuclear; it associates with the Sm-like RNA-binding proteins LSM7 and SmG (which associate with U6 snRNPs and function in mRNA processing), identified by yeast two-hybrid screen, GST pulldown, and co-immunoprecipitation.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, immunolocalization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal binding methods (Y2H, GST pulldown, Co-IP) in a single lab\",\n      \"pmids\": [\"12165861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TACC1 interacts with the C-terminus of the microtubule-associated protein ch-TOG (ortholog of Drosophila MSPS/Xenopus XMAP215) and with the oncogenic transcription factor GAS41/NuBI1, suggesting TACC1 participates in multiple protein complexes.\",\n      \"method\": \"Yeast two-hybrid screen of human mammary epithelial cDNA library using full-length TACC1 as bait; interaction domain mapping\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus domain mapping, single lab, replicated for chTOG interaction by independent group (PMID:14603251)\",\n      \"pmids\": [\"11903063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TACC1 forms a protein complex with chTOG, the adaptor protein TRAP, the mitotic kinase Aurora A, and the mRNA regulator LSM7; siRNA-mediated depletion of chTOG, and to a lesser extent TACC1, perturbs cell division.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with cell division phenotype readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex identification plus functional siRNA knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"14603251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TACC1 localizes to the midzone spindle in anaphase and strongly to the midbody during cytokinesis, and relocates to the nucleolus in interphase; TACC1 and Aurora B kinase form a complex during cytokinesis. Knockdown of Aurora B by RNAi prevents midbody formation, mislocalizes TACC1, and leads to multinucleated cells, placing Aurora B upstream of TACC1 midbody localization.\",\n      \"method\": \"Immunofluorescence localization, co-immunoprecipitation, siRNA knockdown of Aurora B with multinucleation phenotype readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal complex identification by Co-IP, direct localization experiments, and genetic epistasis via RNAi with defined phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15064709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TACC1 interacts with Thyroid Hormone Receptors (TR) and Retinoic Acid Receptors (RAR), preferentially binding unliganded receptors; endogenous TACC1 localizes to the chromatin-enriched nuclear fraction and interacts with RARα in the nucleus; TACC1 depletion reduces ligand-dependent transcriptional activity of RARα and TRα and causes delocalization of TR from nucleus to cytoplasm, indicating TACC1 functions as a nuclear receptor coregulator/scaffold.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, colocalization, subcellular fractionation, siRNA knockdown with transcriptional reporter assays\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, GST pulldown, Co-IP, fractionation, siRNA + transcriptional readout) in single lab establishing a functional mechanistic role\",\n      \"pmids\": [\"20078863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Xenopus TACC1 acts as a microtubule plus-end tracking protein (+TIP) and regulates microtubule dynamics; the conserved C-terminal TACC domain is required for plus-end localization. TACC1 and TACC3 are each required for maintaining normal microtubule growth speed in Xenopus embryonic mesenchymal cells, with partial functional redundancy in regulating microtubule growth lifetime.\",\n      \"method\": \"Live imaging of GFP-tagged TACC1 in Xenopus embryonic cells, domain-deletion mutants, morpholino knockdown with microtubule dynamics tracking\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with domain mutants and loss-of-function knockdown in a vertebrate model system, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26012630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TACC1 variant25 (TACC1v25) overexpression in HNSCC cell lines inhibits proliferation and promotes autophagy; mechanistically, TACC1v25 decreases nuclear pERK and p-mTOR levels and increases Beclin-1 and LC3II/LC3I ratio; addition of AKT activator SC79 rescues autophagy suppression, placing TACC1v25 upstream of the AKT/mTOR pathway.\",\n      \"method\": \"Overexpression in Cal27 and Fadu cell lines, Western blotting, pharmacological rescue with SC79, proliferation and autophagy assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single approach per assay, no direct binding partner identified, pathway placement inferred from pharmacological rescue\",\n      \"pmids\": [\"34897285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TACC1 binds directly to PARP1 (proline-rich acidic protein 1; identified by co-IP with mass spectrometry), inhibits apoptosis, and activates the AKT/mTOR signaling pathway; TACC1 expression is transcriptionally upregulated by NFE2L3, which itself is a transcriptional target of LEF1 (LEF1 binds the NFE2L3 promoter at positions 1321–1334 as shown by ChIP-seq).\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry (for TACC1-PARP1 interaction), ChIP-seq (for LEF1-NFE2L3), Western blotting, functional assays (proliferation, migration, invasion, apoptosis), xenograft mouse model\",\n      \"journal\": \"Journal of thoracic disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP/MS for binding partner, pathway placement based on correlative expression changes and rescue assays without reconstitution or mutagenesis\",\n      \"pmids\": [\"42182760\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TACC1 is a centrosomal/cytoskeletal scaffold protein that (1) tracks microtubule plus-ends via its conserved C-terminal TACC domain to regulate microtubule dynamics; (2) forms mitotic complexes with chTOG and Aurora kinases (Aurora A at the centrosome/spindle, Aurora B at the midbody) to support cell division and cytokinesis — Aurora B is required for TACC1 midbody localization; (3) binds Sm-like mRNA-processing proteins (LSM7, SmG) suggesting a role in mRNA regulation; and (4) functions as a nuclear receptor coregulator, localizing to chromatin and scaffolding transcriptional complexes around unliganded thyroid and retinoic acid receptors to support their ligand-dependent transcriptional activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TACC1 is a centrosomal/cytoskeletal scaffold protein that couples microtubule dynamics to cell division and also functions in transcriptional regulation [#4, #6]. Through its conserved C-terminal TACC domain, TACC1 acts as a microtubule plus-end tracking protein that maintains normal microtubule growth speed, with partial functional redundancy with TACC3 [#6]. During mitosis TACC1 assembles into complexes with the microtubule-associated protein chTOG and the adaptor TRAP, and partitions between Aurora kinase pools: it works with Aurora A and chTOG to support cell division, and forms a complex with Aurora B that drives its localization to the midbody during cytokinesis — Aurora B depletion mislocalizes TACC1 and produces multinucleated cells, placing Aurora B upstream of TACC1 [#3, #4]. TACC1 cycles to the nucleolus in interphase and into the chromatin-enriched nuclear fraction, where it serves as a nuclear receptor coregulator: it binds unliganded thyroid hormone and retinoic acid receptors and is required for their ligand-dependent transcriptional activity and proper nuclear retention [#4, #5]. TACC1 additionally associates with the Sm-like RNA-processing proteins LSM7 and SmG, linking it to mRNA regulation [#1, #3]. Inappropriate TACC1 overexpression transforms fibroblasts and confers anchorage-independent growth [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that TACC1 dysregulation has oncogenic potential, motivating investigation of its normal cellular function.\",\n      \"evidence\": \"CMV-driven overexpression in mouse fibroblasts with anchorage-independent growth assay\",\n      \"pmids\": [\"10435627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism linking TACC1 to proliferation defined\", \"No endogenous loss-of-function data\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified TACC1's first physical partners, placing it in both an mRNA-processing context (LSM7, SmG) and a microtubule context (chTOG), and a transcription-factor context (GAS41), revealing its multi-complex scaffold nature.\",\n      \"evidence\": \"Yeast two-hybrid screens, GST pulldown, co-immunoprecipitation and domain mapping; immunolocalization to perinuclear cytoplasm\",\n      \"pmids\": [\"12165861\", \"11903063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of LSM7/SmG binding for mRNA processing not tested\", \"chTOG and GAS41 interactions not yet linked to a cellular phenotype\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected TACC1 to mitotic machinery by showing it forms a chTOG/TRAP/Aurora A/LSM7 complex and that its depletion perturbs cell division.\",\n      \"evidence\": \"Co-immunoprecipitation and siRNA knockdown with cell-division phenotype readout\",\n      \"pmids\": [\"14603251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TACC1 knockdown effect weaker than chTOG, leaving its individual contribution unclear\", \"Order of assembly within the complex not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined TACC1's cell-cycle-dependent localization and placed Aurora B upstream of its midbody recruitment during cytokinesis.\",\n      \"evidence\": \"Immunofluorescence, reciprocal co-IP, and Aurora B RNAi with multinucleation readout\",\n      \"pmids\": [\"15064709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation of TACC1 by Aurora B not demonstrated\", \"Mechanism of nucleolar relocalization in interphase unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established a nuclear function for TACC1 as a coregulator that scaffolds unliganded thyroid and retinoic acid receptors and supports their transcriptional output and nuclear retention.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, co-IP, subcellular fractionation, and siRNA with transcriptional reporter assays\",\n      \"pmids\": [\"20078863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of co-recruited transcriptional machinery not defined\", \"How TACC1 switches between cytoplasmic/mitotic and nuclear roles is unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a direct cytoskeletal activity: TACC1 is a microtubule plus-end tracking protein whose TACC domain confers plus-end localization and regulates microtubule growth.\",\n      \"evidence\": \"Live imaging of GFP-TACC1 in Xenopus embryonic cells, domain-deletion mutants, and morpholino knockdown with microtubule dynamics tracking\",\n      \"pmids\": [\"26012630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of plus-end recognition by the TACC domain not resolved\", \"Relationship between +TIP activity and mitotic complex function not integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked a TACC1 splice variant to suppression of proliferation and induction of autophagy via the AKT/mTOR axis.\",\n      \"evidence\": \"Overexpression of TACC1v25 in HNSCC cell lines, Western blotting, and pharmacological rescue with the AKT activator SC79\",\n      \"pmids\": [\"34897285\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement inferred from pharmacological rescue without direct binding partner\", \"Single cell-line context; isoform-specific generality untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Proposed a TACC1-PARP1 interaction and an upstream LEF1/NFE2L3 transcriptional axis activating AKT/mTOR and inhibiting apoptosis.\",\n      \"evidence\": \"Co-IP/mass spectrometry, ChIP-seq, Western blotting, functional assays, and xenograft model\",\n      \"pmids\": [\"42182760\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct interaction not validated by reciprocal or reconstitution assays\", \"Pathway placement based on correlative expression changes without mutagenesis\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TACC1 partitions between its mitotic microtubule/Aurora roles, its nuclear receptor coregulator role, and its mRNA-processing associations — and what regulates these transitions — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the TACC domain bound to microtubule plus-ends or to nuclear receptors\", \"Whether the mRNA-processing, mitotic, and transcriptional functions reflect distinct isoforms or a single regulated protein is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"chTOG\", \"TRAP\", \"AURKA\", \"AURKB\", \"LSM7\", \"RARA\", \"THRA\", \"GAS41\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}