{"gene":"KNTC1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2019,"finding":"shRNA-mediated knockdown of KNTC1 in human esophageal squamous cell carcinoma (ESCC) cell lines suppressed cell viability and induced apoptosis, demonstrating a required role for KNTC1 in ESCC cell survival. Gene set enrichment analysis of ESCC datasets indicated that KNTC1 overexpression correlates with increased mitotic spindle and hypoxia pathway activity.","method":"Lentivirus-mediated shRNA knockdown, MTT assay, Annexin V flow cytometry, high-content screening, GSEA of online datasets","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with phenotypic readout (viability/apoptosis) but no direct molecular mechanism or pathway placement beyond GSEA correlation; no rescue or epistasis experiment","pmids":["30628654"],"is_preprint":false},{"year":2022,"finding":"shRNA-mediated knockdown of KNTC1 in non-small-cell lung cancer (NSCLC) cell lines inhibited cell proliferation, migration, invasion, and tumor formation in xenograft models. Downstream mechanistic analysis indicated that KNTC1 depletion was positively associated with PSMB8 expression levels, suggesting KNTC1 acts upstream of PSMB8 in NSCLC progression.","method":"Lentivirus-delivered shRNA knockdown, MTT assay, wound-healing assay, transwell invasion assay, flow cytometry, nude mouse xenograft model, downstream gene expression analysis","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with multiple phenotypic readouts and partial pathway placement (PSMB8 association), but PSMB8 relationship is correlative rather than mechanistically validated by rescue or direct biochemical interaction","pmids":["35933405"],"is_preprint":false}],"current_model":"KNTC1 (ROD/KIAA0166) is a kinetochore-associated protein required for mitotic spindle checkpoint function and faithful chromosomal segregation; in cancer cell lines, its loss of function suppresses proliferation, migration, and survival, with partial evidence placing it upstream of the proteasome subunit PSMB8 in lung cancer, though the direct molecular mechanism of its kinetochore function remains uncharacterized in the available literature."},"narrative":{"mechanistic_narrative":"KNTC1 is required for cancer cell survival and proliferation, with loss-of-function studies in esophageal squamous cell carcinoma showing that its knockdown suppresses viability and induces apoptosis [PMID:30628654]. In non-small-cell lung cancer, KNTC1 depletion inhibits proliferation, migration, invasion, and xenograft tumor formation, and positions KNTC1 upstream of the proteasome subunit PSMB8 in driving tumor progression [PMID:35933405]. Pathway-level correlation links KNTC1 expression to mitotic spindle activity [PMID:30628654], but the direct molecular mechanism of KNTC1 function has not been characterized in the available corpus; all current evidence is phenotypic knockdown data without rescue, epistasis, or direct biochemical validation.","teleology":[{"year":2019,"claim":"Established that KNTC1 is functionally required for cancer cell survival rather than merely a correlate, by showing its depletion kills esophageal carcinoma cells.","evidence":"Lentiviral shRNA knockdown with MTT viability and Annexin V apoptosis assays in ESCC cell lines, plus GSEA of expression datasets","pmids":["30628654"],"confidence":"Low","gaps":["No rescue experiment to confirm on-target effect","Mitotic spindle association is correlative GSEA only, not a direct mechanistic link","No identification of KNTC1 molecular partners or substrates"]},{"year":2022,"claim":"Extended the requirement for KNTC1 to lung cancer proliferation, invasion, and in vivo tumor growth, and attempted to place it in a pathway upstream of PSMB8.","evidence":"Lentiviral shRNA knockdown with proliferation, wound-healing, transwell invasion, flow cytometry, and nude-mouse xenograft assays in NSCLC, with downstream PSMB8 expression analysis","pmids":["35933405"],"confidence":"Low","gaps":["PSMB8 relationship is correlative, not validated by rescue or direct interaction","No biochemical demonstration of how KNTC1 regulates PSMB8","Mechanism connecting KNTC1 to migration/invasion phenotypes unresolved"]},{"year":null,"claim":"The direct molecular function of KNTC1 — its biochemical activity, binding partners, and the mechanistic basis of its purported kinetochore/spindle role — remains undefined in the available corpus.","evidence":"No discovery in the timeline provides direct biochemical or structural characterization","pmids":[],"confidence":"Low","gaps":["No biochemical or structural characterization of KNTC1","No validated interaction partners identified","Causal mechanism linking KNTC1 to the proteasome and to mitotic phenotypes not established"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P50748","full_name":"Kinetochore-associated protein 1","aliases":["Rough deal homolog","HsROD","Rod","hRod"],"length_aa":2209,"mass_kda":250.7,"function":"Essential component of the mitotic checkpoint, which prevents cells from prematurely exiting mitosis. Required for the assembly of the dynein-dynactin and MAD1-MAD2 complexes onto kinetochores (PubMed:11146660, PubMed:11590237, PubMed:15824131). Its function related to the spindle assembly machinery is proposed to depend on its association in the mitotic RZZ complex","subcellular_location":"Cytoplasm; Nucleus; Chromosome, centromere, kinetochore; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/P50748/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KNTC1","classification":"Not Classified","n_dependent_lines":353,"n_total_lines":1208,"dependency_fraction":0.29221854304635764},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KNTC1","total_profiled":1310},"omim":[{"mim_id":"616401","title":"SPINDLE APPARATUS COILED-COIL PROTEIN 1; SPDL1","url":"https://www.omim.org/entry/616401"},{"mim_id":"609984","title":"ZWILCH KINETOCHORE PROTEIN; ZWILCH","url":"https://www.omim.org/entry/609984"},{"mim_id":"607363","title":"KINETOCHORE-ASSOCIATED PROTEIN 1; KNTC1","url":"https://www.omim.org/entry/607363"},{"mim_id":"603954","title":"ZW10 KINETOCHORE PROTEIN; ZW10","url":"https://www.omim.org/entry/603954"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":39.7}],"url":"https://www.proteinatlas.org/search/KNTC1"},"hgnc":{"alias_symbol":["KIAA0166","ROD"],"prev_symbol":[]},"alphafold":{"accession":"P50748","domains":[{"cath_id":"-","chopping":"403-462","consensus_level":"medium","plddt":74.833,"start":403,"end":462},{"cath_id":"-","chopping":"597-714","consensus_level":"medium","plddt":71.7761,"start":597,"end":714},{"cath_id":"1.25.40","chopping":"752-834","consensus_level":"high","plddt":56.0269,"start":752,"end":834}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50748","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50748-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50748-F1-predicted_aligned_error_v6.png","plddt_mean":71.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KNTC1","jax_strain_url":"https://www.jax.org/strain/search?query=KNTC1"},"sequence":{"accession":"P50748","fasta_url":"https://rest.uniprot.org/uniprotkb/P50748.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50748/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50748"}},"corpus_meta":[{"pmid":"11694879","id":"PMC_11694879","title":"Nrl 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Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28193819","citation_count":28,"is_preprint":false},{"pmid":"34974196","id":"PMC_34974196","title":"Molecular bases of rod and cone differences.","date":"2021","source":"Progress in retinal and eye research","url":"https://pubmed.ncbi.nlm.nih.gov/34974196","citation_count":28,"is_preprint":false},{"pmid":"16379027","id":"PMC_16379027","title":"RPE65 surface epitopes, protein interactions, and expression in rod- and cone-dominant species.","date":"2005","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/16379027","citation_count":28,"is_preprint":false},{"pmid":"24244730","id":"PMC_24244730","title":"Rod photoreceptors express GPR55 in the adult vervet monkey retina.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24244730","citation_count":28,"is_preprint":false},{"pmid":"26718442","id":"PMC_26718442","title":"Connexin 36 and rod bipolar cell independent rod pathways drive retinal ganglion cells and optokinetic reflexes.","date":"2016","source":"Vision research","url":"https://pubmed.ncbi.nlm.nih.gov/26718442","citation_count":27,"is_preprint":false},{"pmid":"12202366","id":"PMC_12202366","title":"Dynamic behavior of rod photoreceptor disks.","date":"2002","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12202366","citation_count":27,"is_preprint":false},{"pmid":"31635694","id":"PMC_31635694","title":"Extraocular, rod-like photoreceptors in a flatworm express xenopsin photopigment.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31635694","citation_count":27,"is_preprint":false},{"pmid":"29721965","id":"PMC_29721965","title":"Primary Rod and Cone Degeneration Is Prevented by HDAC Inhibition.","date":"2018","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/29721965","citation_count":26,"is_preprint":false},{"pmid":"29422031","id":"PMC_29422031","title":"Transcripts within rod photoreceptors of the Zebrafish retina.","date":"2018","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/29422031","citation_count":26,"is_preprint":false},{"pmid":"26626567","id":"PMC_26626567","title":"Circadian and light-driven regulation of rod dark adaptation.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26626567","citation_count":26,"is_preprint":false},{"pmid":"2991162","id":"PMC_2991162","title":"Lead and mercury toxicity and the rod light response.","date":"1985","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/2991162","citation_count":25,"is_preprint":false},{"pmid":"30628654","id":"PMC_30628654","title":"shRNA‑mediated knockdown of KNTC1 suppresses cell viability and induces apoptosis in esophageal squamous cell carcinoma.","date":"2019","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30628654","citation_count":24,"is_preprint":false},{"pmid":"31836805","id":"PMC_31836805","title":"Manipulating rod-shaped bacteria with optical tweezers.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31836805","citation_count":24,"is_preprint":false},{"pmid":"12675482","id":"PMC_12675482","title":"Why study rod cell death in retinal degenerations and how?","date":"2003","source":"Documenta ophthalmologica. Advances in ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/12675482","citation_count":23,"is_preprint":false},{"pmid":"27447117","id":"PMC_27447117","title":"Rod-cone crossover connectome of mammalian bipolar cells.","date":"2016","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/27447117","citation_count":23,"is_preprint":false},{"pmid":"23684654","id":"PMC_23684654","title":"A physiological role for the supramolecular organization of rhodopsin and transducin in rod photoreceptors.","date":"2013","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23684654","citation_count":23,"is_preprint":false},{"pmid":"19895810","id":"PMC_19895810","title":"Prox1 expression in rod precursors and Müller cells.","date":"2009","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/19895810","citation_count":21,"is_preprint":false},{"pmid":"23325348","id":"PMC_23325348","title":"Rod and cone pathway signaling and interaction under mesopic illumination.","date":"2013","source":"Journal of vision","url":"https://pubmed.ncbi.nlm.nih.gov/23325348","citation_count":21,"is_preprint":false},{"pmid":"7864751","id":"PMC_7864751","title":"Chromosome 19q cone-rod retinal dystrophy. Ocular phenotype.","date":"1995","source":"Archives of ophthalmology (Chicago, Ill. : 1960)","url":"https://pubmed.ncbi.nlm.nih.gov/7864751","citation_count":21,"is_preprint":false},{"pmid":"35363529","id":"PMC_35363529","title":"Genetic elimination of rod/cone coupling reveals the contribution of the secondary rod pathway to the retinal output.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/35363529","citation_count":20,"is_preprint":false},{"pmid":"29435986","id":"PMC_29435986","title":"Role of recoverin in rod photoreceptor light adaptation.","date":"2018","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29435986","citation_count":20,"is_preprint":false},{"pmid":"30201778","id":"PMC_30201778","title":"Assembly Order of Flagellar Rod Subunits in Bacillus subtilis.","date":"2018","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/30201778","citation_count":20,"is_preprint":false},{"pmid":"29184169","id":"PMC_29184169","title":"NMNAT1 variants cause cone and cone-rod dystrophy.","date":"2017","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/29184169","citation_count":20,"is_preprint":false},{"pmid":"35933405","id":"PMC_35933405","title":"shRNA‑mediated knockdown of KNTC1 inhibits non-small-cell lung cancer through regulating PSMB8.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35933405","citation_count":19,"is_preprint":false},{"pmid":"29721982","id":"PMC_29721982","title":"Maintaining Cone Function in Rod-Cone Dystrophies.","date":"2018","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/29721982","citation_count":18,"is_preprint":false},{"pmid":"2473730","id":"PMC_2473730","title":"Rod cell-specific antigens in retinoblastoma.","date":"1989","source":"Archives of ophthalmology (Chicago, Ill. : 1960)","url":"https://pubmed.ncbi.nlm.nih.gov/2473730","citation_count":18,"is_preprint":false},{"pmid":"2579769","id":"PMC_2579769","title":"Signal mechanisms of phototransduction in retinal rod.","date":"1985","source":"CRC critical reviews in biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2579769","citation_count":18,"is_preprint":false},{"pmid":"7635665","id":"PMC_7635665","title":"Intersegmental fusion in vertebrate rod photoreceptors. Rod cell structure revisited.","date":"1995","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/7635665","citation_count":18,"is_preprint":false},{"pmid":"17377979","id":"PMC_17377979","title":"Nr2e3 and Nrl can reprogram retinal precursors to the rod fate in Xenopus retina.","date":"2007","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/17377979","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42006,"output_tokens":991,"usd":0.070442,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7069,"output_tokens":1140,"usd":0.031922,"stage2_stop_reason":"end_turn"},"total_usd":0.102364,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about KNTC1 (also known as KIAA0166 or ROD), which is a kinetochore-associated protein involved in mitotic checkpoint/chromosomal segregation.\n\nThe vast majority of these papers are about \"rod\" photoreceptors, rod-shaped bacteria, or other unrelated uses of \"rod\" - these are symbol collisions and should be excluded.\n\nPapers directly about KNTC1 (the kinetochore protein):\n- PMID 30628654: shRNA knockdown of KNTC1 in esophageal squamous cell carcinoma\n- PMID 35933405: shRNA knockdown of KNTC1 in non-small-cell lung cancer, identifying PSMB8 as downstream\n\nLet me evaluate these carefully:\n\nPMID 30628654: KD of KNTC1 inhibits cell viability, increases apoptosis in ESCC. GSEA indicates association with mitotic spindle pathway. No direct molecular mechanism established beyond phenotypic readout.\n\nPMID 35933405: KD of KNTC1 inhibits NSCLC proliferation/migration/invasion; identifies PSMB8 as positively associated downstream. This is a functional relationship but \"positively associated\" is correlative, not mechanistic reconstitution.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"shRNA-mediated knockdown of KNTC1 in human esophageal squamous cell carcinoma (ESCC) cell lines suppressed cell viability and induced apoptosis, demonstrating a required role for KNTC1 in ESCC cell survival. Gene set enrichment analysis of ESCC datasets indicated that KNTC1 overexpression correlates with increased mitotic spindle and hypoxia pathway activity.\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, MTT assay, Annexin V flow cytometry, high-content screening, GSEA of online datasets\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with phenotypic readout (viability/apoptosis) but no direct molecular mechanism or pathway placement beyond GSEA correlation; no rescue or epistasis experiment\",\n      \"pmids\": [\"30628654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"shRNA-mediated knockdown of KNTC1 in non-small-cell lung cancer (NSCLC) cell lines inhibited cell proliferation, migration, invasion, and tumor formation in xenograft models. Downstream mechanistic analysis indicated that KNTC1 depletion was positively associated with PSMB8 expression levels, suggesting KNTC1 acts upstream of PSMB8 in NSCLC progression.\",\n      \"method\": \"Lentivirus-delivered shRNA knockdown, MTT assay, wound-healing assay, transwell invasion assay, flow cytometry, nude mouse xenograft model, downstream gene expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with multiple phenotypic readouts and partial pathway placement (PSMB8 association), but PSMB8 relationship is correlative rather than mechanistically validated by rescue or direct biochemical interaction\",\n      \"pmids\": [\"35933405\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KNTC1 (ROD/KIAA0166) is a kinetochore-associated protein required for mitotic spindle checkpoint function and faithful chromosomal segregation; in cancer cell lines, its loss of function suppresses proliferation, migration, and survival, with partial evidence placing it upstream of the proteasome subunit PSMB8 in lung cancer, though the direct molecular mechanism of its kinetochore function remains uncharacterized in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KNTC1 is required for cancer cell survival and proliferation, with loss-of-function studies in esophageal squamous cell carcinoma showing that its knockdown suppresses viability and induces apoptosis [#0]. In non-small-cell lung cancer, KNTC1 depletion inhibits proliferation, migration, invasion, and xenograft tumor formation, and positions KNTC1 upstream of the proteasome subunit PSMB8 in driving tumor progression [#1]. Pathway-level correlation links KNTC1 expression to mitotic spindle activity [#0], but the direct molecular mechanism of KNTC1 function has not been characterized in the available corpus; all current evidence is phenotypic knockdown data without rescue, epistasis, or direct biochemical validation.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that KNTC1 is functionally required for cancer cell survival rather than merely a correlate, by showing its depletion kills esophageal carcinoma cells.\",\n      \"evidence\": \"Lentiviral shRNA knockdown with MTT viability and Annexin V apoptosis assays in ESCC cell lines, plus GSEA of expression datasets\",\n      \"pmids\": [\"30628654\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No rescue experiment to confirm on-target effect\",\n        \"Mitotic spindle association is correlative GSEA only, not a direct mechanistic link\",\n        \"No identification of KNTC1 molecular partners or substrates\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the requirement for KNTC1 to lung cancer proliferation, invasion, and in vivo tumor growth, and attempted to place it in a pathway upstream of PSMB8.\",\n      \"evidence\": \"Lentiviral shRNA knockdown with proliferation, wound-healing, transwell invasion, flow cytometry, and nude-mouse xenograft assays in NSCLC, with downstream PSMB8 expression analysis\",\n      \"pmids\": [\"35933405\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"PSMB8 relationship is correlative, not validated by rescue or direct interaction\",\n        \"No biochemical demonstration of how KNTC1 regulates PSMB8\",\n        \"Mechanism connecting KNTC1 to migration/invasion phenotypes unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular function of KNTC1 — its biochemical activity, binding partners, and the mechanistic basis of its purported kinetochore/spindle role — remains undefined in the available corpus.\",\n      \"evidence\": \"No discovery in the timeline provides direct biochemical or structural characterization\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No biochemical or structural characterization of KNTC1\",\n        \"No validated interaction partners identified\",\n        \"Causal mechanism linking KNTC1 to the proteasome and to mitotic phenotypes not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":2,"faith_total":2,"faith_pct":100.0}}