{"gene":"CCDC86","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2007,"finding":"Cyclon (CCDC86) is an immediate-early cytokine-responsive gene induced by IL-3 in hematopoietic cells. The encoded protein is a phosphorylated nuclear protein with repetitive sequences in the amino-terminus and a coiled-coil domain in the carboxyl-terminus. A reporter assay revealed that the mouse cyclon promoter contains redundant elements mediating IL-3-induced gene expression.","method":"Transient reporter assay, protein characterization (phosphorylation, domain analysis)","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, reporter assay plus protein characterization, two orthogonal methods but no functional epistasis","pmids":["17300783"],"is_preprint":false},{"year":2009,"finding":"Cyclon (CCDC86) is induced in T cells upon TCR ligation and promotes activation-induced cell death (AICD) by upregulating Fas expression. Targeted deletion of one Cyclon allele in activated CD4+ T cells reduced AICD and Fas expression, and transgenic Cyclon expression enhanced AICD and ameliorated autoimmune phenotype in IL-2R-deficient mice, placing Cyclon upstream of Fas in T-cell immune homeostasis.","method":"Conditional allele deletion (loss-of-function), transgenic overexpression, AICD assay, Fas expression measurement","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function genetics with defined molecular readout (Fas expression) and cellular phenotype (AICD), replicated in both transgenic and knockout models","pmids":["19528538"],"is_preprint":false},{"year":2021,"finding":"CCDC86 (CYCLON) physically interacts with NPM1 (nucleophosmin), and its protein interaction network connects it to the nucleolus, RNA processing, MYC signaling, and cell cycle progression. Alternative sub-cellular localizations (extra-nucleolar CYCLON and pan-cellular NPM1) were identified as independent predictive factors in DLBCL.","method":"Protein interaction network characterization (co-immunoprecipitation/proteomics implied), immunohistochemistry for sub-cellular localization","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction network characterization and localization data from single lab; abstract does not specify full Co-IP details","pmids":["34885010"],"is_preprint":false},{"year":2023,"finding":"CCDC86 is a chromosome periphery-associated protein that interacts with Ki-67 (MKI67). RNAi-mediated depletion of CCDC86 caused partial disorganisation of the chromosome periphery, altered localisation of Ki-67 and nucleolin (NCL), formation of abnormal cytoplasmic aggregates, errors in chromosome alignment, altered spindle length, and increased apoptosis. CCDC86, nucleolin, and B23 (NPM1) form subcomplexes required for mitotic spindle regulation and correct kinetochore-microtubule attachments.","method":"RNA interference (RNAi) depletion, fluorescence microscopy, biochemical fractionation, Co-immunoprecipitation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, microscopy, biochemistry/Co-IP) in a single rigorous study with defined mitotic phenotypes and partner identification","pmids":["36695333"],"is_preprint":false},{"year":2023,"finding":"CCDC86 promotes NPC cell proliferation, invasion, and migration by binding to NPM1 and thereby positively regulating EGFR expression and activating downstream PI3K/Akt signaling. CCDC86 does not directly bind EGFR but acts through NPM1 to upregulate EGFR transcriptionally/post-transcriptionally.","method":"In vitro proliferation/invasion/migration assays, in vivo xenograft, Co-immunoprecipitation (CCDC86-NPM1 interaction), siRNA knockdown, EGFR expression measurement, PI3K/Akt pathway analysis","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for CCDC86–NPM1 interaction, knockdown with defined molecular readout (EGFR, PI3K/Akt), single lab","pmids":["38247332"],"is_preprint":false},{"year":2025,"finding":"CCDC86 promotes aerobic glycolysis and glioma progression through interaction with BHLHE40, stabilizing ATF3 expression, which in turn activates the ERK signaling pathway to drive glycolysis and tumor development.","method":"CCDC86 knockdown functional assays (proliferation, migration, apoptosis, cell cycle), in vivo tumorigenesis assay, Co-immunoprecipitation (CCDC86–BHLHE40), ATF3 rescue experiment","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for CCDC86–BHLHE40 interaction plus knockdown/rescue with defined downstream pathway, single lab","pmids":["40837407"],"is_preprint":false}],"current_model":"CCDC86 (cyclon) is a phosphorylated nuclear/chromosome periphery protein that: (1) is induced by IL-3 and TCR stimulation and promotes T-cell AICD by upregulating Fas expression; (2) localizes to the chromosome periphery during mitosis where it interacts with Ki-67, nucleolin, and NPM1 to form subcomplexes required for mitotic spindle regulation and correct kinetochore-microtubule attachments; and (3) interacts with NPM1 and BHLHE40 to regulate downstream oncogenic signaling (EGFR/PI3K/Akt and ERK/glycolysis via ATF3) in cancer contexts."},"narrative":{"mechanistic_narrative":"CCDC86 (cyclon) is a phosphorylated nuclear protein with an N-terminal repetitive region and a C-terminal coiled-coil domain that operates in two distinct contexts: immune cell death regulation and the mitotic chromosome periphery [PMID:17300783, PMID:36695333]. It was first identified as an immediate-early gene induced by IL-3 in hematopoietic cells [PMID:17300783], and in T cells its induction following TCR ligation drives activation-induced cell death by upregulating Fas expression, placing CCDC86 upstream of Fas in immune homeostasis as shown by reciprocal allele deletion and transgenic overexpression [PMID:19528538]. During mitosis, CCDC86 associates with the chromosome periphery and, together with nucleolin (NCL) and NPM1/B23, forms subcomplexes required for spindle regulation and correct kinetochore-microtubule attachments; its depletion disorganizes the chromosome periphery, mislocalizes Ki-67 (MKI67) and nucleolin, and produces chromosome alignment errors and increased apoptosis [PMID:36695333]. CCDC86 physically interacts with NPM1, linking it to the nucleolus, RNA processing, MYC signaling, and cell cycle progression [PMID:34885010]. In cancer contexts, CCDC86 acts through partner proteins to drive oncogenic signaling: it binds NPM1 to upregulate EGFR and activate PI3K/Akt in nasopharyngeal carcinoma [PMID:38247332], and binds BHLHE40 to stabilize ATF3 and activate ERK-driven aerobic glycolysis in glioma [PMID:40837407].","teleology":[{"year":2007,"claim":"Established CCDC86/cyclon as a cytokine-responsive immediate-early gene and defined its basic protein architecture, framing it as a regulated nuclear factor rather than a constitutive housekeeping protein.","evidence":"Transient reporter assay of the mouse cyclon promoter plus protein characterization (phosphorylation, domain analysis) in IL-3-responsive hematopoietic cells","pmids":["17300783"],"confidence":"Medium","gaps":["No molecular function assigned to the protein","Coiled-coil binding partners not identified","Phosphorylation sites and responsible kinases unknown"]},{"year":2009,"claim":"Answered what cyclon does functionally in immune cells, showing it promotes T-cell activation-induced cell death by upregulating Fas and contributes to immune homeostasis.","evidence":"Conditional allele deletion (loss-of-function), transgenic overexpression, AICD assays, and Fas expression measurement in mouse CD4+ T cells and IL-2R-deficient mice","pmids":["19528538"],"confidence":"High","gaps":["Molecular mechanism by which CCDC86 controls Fas expression unresolved","Direct DNA or protein targets not identified","Link between nuclear localization and Fas regulation unestablished"]},{"year":2021,"claim":"Identified NPM1 as a physical partner and connected CCDC86 to the nucleolus, RNA processing, MYC signaling, and cell cycle, while linking its subcellular localization to disease prognosis.","evidence":"Protein interaction network characterization and immunohistochemistry for subcellular localization in DLBCL","pmids":["34885010"],"confidence":"Medium","gaps":["Full Co-IP/proteomics validation details not specified","Functional consequence of the NPM1 interaction not tested here","Mechanism linking extra-nucleolar localization to outcome unknown"]},{"year":2023,"claim":"Defined a concrete mitotic role: CCDC86 is a chromosome periphery component that, with nucleolin and NPM1, forms subcomplexes required for spindle regulation and kinetochore-microtubule attachment fidelity.","evidence":"RNAi depletion, fluorescence microscopy, biochemical fractionation, and Co-immunoprecipitation identifying Ki-67/MKI67, NCL, and NPM1 partners","pmids":["36695333"],"confidence":"High","gaps":["Structural basis of subcomplex assembly unknown","How CCDC86 is recruited to the chromosome periphery unresolved","Direct molecular activity at the kinetochore not defined"]},{"year":2023,"claim":"Showed CCDC86 drives carcinoma cell proliferation and invasion indirectly, acting through NPM1 to upregulate EGFR and activate PI3K/Akt rather than binding EGFR directly.","evidence":"In vitro proliferation/invasion/migration assays, xenograft, Co-IP of CCDC86-NPM1, siRNA knockdown, and EGFR/PI3K-Akt pathway analysis in nasopharyngeal carcinoma","pmids":["38247332"],"confidence":"Medium","gaps":["Mechanism by which the NPM1 complex regulates EGFR expression unclear","Single lab, single tumor type","Whether mitotic and oncogenic NPM1 complexes are the same is untested"]},{"year":2025,"claim":"Extended the oncogenic role to glioma via a distinct partner, showing CCDC86 binds BHLHE40 to stabilize ATF3 and activate ERK-driven aerobic glycolysis.","evidence":"Knockdown functional assays, in vivo tumorigenesis, Co-IP of CCDC86-BHLHE40, and ATF3 rescue experiments in glioma cells","pmids":["40837407"],"confidence":"Medium","gaps":["Direct biochemical basis of ATF3 stabilization unknown","Relationship between BHLHE40 and NPM1 pathways unresolved","Single lab finding"]},{"year":null,"claim":"The intrinsic molecular activity of CCDC86 and how a single coiled-coil protein bridges chromosome periphery assembly, Fas-mediated apoptosis, and multiple oncogenic partner complexes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No enzymatic or defined biochemical activity established","No structure of CCDC86 or its complexes","Mechanism unifying immune, mitotic, and oncogenic roles unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[2]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]}],"complexes":[],"partners":["NPM1","MKI67","NCL","BHLHE40"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H6F5","full_name":"Coiled-coil domain-containing protein 86","aliases":["Cytokine-induced protein with coiled-coil domain"],"length_aa":360,"mass_kda":40.2,"function":"Required for proper chromosome segregation during mitosis and error-free mitotic progression","subcellular_location":"Nucleus; Chromosome; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9H6F5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC86","classification":"Common Essential","n_dependent_lines":1094,"n_total_lines":1208,"dependency_fraction":0.9056291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000110104","cell_line_id":"CID001930","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGB2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"TPT1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001930","total_profiled":1310},"omim":[{"mim_id":"611293","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 86; CCDC86","url":"https://www.omim.org/entry/611293"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Nucleoli rim","reliability":"Enhanced"},{"location":"Mitotic chromosome","reliability":"Enhanced"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"parathyroid gland","ntpm":355.2}],"url":"https://www.proteinatlas.org/search/CCDC86"},"hgnc":{"alias_symbol":["MGC2574","cyclon","Cgr1"],"prev_symbol":[]},"alphafold":{"accession":"Q9H6F5","domains":[{"cath_id":"1.20.5","chopping":"269-316","consensus_level":"medium","plddt":94.0481,"start":269,"end":316}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6F5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6F5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6F5-F1-predicted_aligned_error_v6.png","plddt_mean":61.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC86","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC86"},"sequence":{"accession":"Q9H6F5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H6F5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H6F5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6F5"}},"corpus_meta":[{"pmid":"12672226","id":"PMC_12672226","title":"A novel N-terminal cyclic dynorphin A analogue cyclo(N,5)[Trp(3),Trp(4),Glu(5)] dynorphin A-(1-11)NH(2) that lacks the basic N-terminus.","date":"2003","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12672226","citation_count":29,"is_preprint":false},{"pmid":"17300783","id":"PMC_17300783","title":"Redundant promoter elements mediate IL-3-induced expression of a novel cytokine-inducible gene, cyclon.","date":"2007","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/17300783","citation_count":20,"is_preprint":false},{"pmid":"19528538","id":"PMC_19528538","title":"Regulation of Fas-mediated immune homeostasis by an activation-induced protein, Cyclon.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19528538","citation_count":16,"is_preprint":false},{"pmid":"31231525","id":"PMC_31231525","title":"Cgr1, a ripe rot resistance QTL in Vitis amurensis 'Shuang Hong' grapevine.","date":"2019","source":"Horticulture research","url":"https://pubmed.ncbi.nlm.nih.gov/31231525","citation_count":15,"is_preprint":false},{"pmid":"36695333","id":"PMC_36695333","title":"CCDC86 is a novel Ki-67-interacting protein important for cell division.","date":"2023","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/36695333","citation_count":9,"is_preprint":false},{"pmid":"38247332","id":"PMC_38247332","title":"CCDC86 promotes the aggressive behavior of nasopharyngeal carcinoma by positively regulating EGFR and activating the PI3K/Akt signaling.","date":"2023","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/38247332","citation_count":7,"is_preprint":false},{"pmid":"11342110","id":"PMC_11342110","title":"Isolation and expression of a gene (CGR1) regulated during the yeast-hyphal transition in Candida albicans.","date":"2001","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11342110","citation_count":7,"is_preprint":false},{"pmid":"23528659","id":"PMC_23528659","title":"Expression of Cyclon/CCDC86, a novel nuclear protein, in the hippocampus of adult non-human primates.","date":"2013","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/23528659","citation_count":6,"is_preprint":false},{"pmid":"34885010","id":"PMC_34885010","title":"CYCLON and NPM1 Cooperate within an Oncogenic Network Predictive of R-CHOP Response in DLBCL.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34885010","citation_count":6,"is_preprint":false},{"pmid":"23439384","id":"PMC_23439384","title":"Expression and differential response to haloperidol treatment of Cyclon/CCDC86 mRNA in schizophrenia patients.","date":"2013","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/23439384","citation_count":5,"is_preprint":false},{"pmid":"26521698","id":"PMC_26521698","title":"Complete genome sequence of Microbacterium sp. CGR1, bacterium tolerant to wide abiotic conditions isolated from the Atacama Desert.","date":"2015","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26521698","citation_count":5,"is_preprint":false},{"pmid":"16219793","id":"PMC_16219793","title":"The CRAL/TRIO and GOLD domain protein CGR-1 promotes induction of vulval cell fates in Caenorhabditis elegans and interacts genetically with the Ras signaling pathway.","date":"2005","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16219793","citation_count":5,"is_preprint":false},{"pmid":"11381331","id":"PMC_11381331","title":"Molecular cloning of cgrA, the gene encoding the Aspergillus nidulans ortholog of Saccharomyces cerevisiae CGR1.","date":"2001","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11381331","citation_count":4,"is_preprint":false},{"pmid":"40837407","id":"PMC_40837407","title":"CCDC86-BHLHE40-ATF3 axis promotes aerobic glycolysis and tumor development in glioma.","date":"2025","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40837407","citation_count":2,"is_preprint":false},{"pmid":"40729033","id":"PMC_40729033","title":"Establishment of an Assay with Ultrahigh Sensitivity for Detecting sEV-Derived PD-L1 as a Serum Biomarker for Lung Cancer-A Pilot Study Using TN-cyclon™.","date":"2025","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40729033","citation_count":2,"is_preprint":false},{"pmid":"41467918","id":"PMC_41467918","title":"CCDC86 modulates immune cell infiltration and disease progression in head and neck squamous cell carcinoma.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41467918","citation_count":0,"is_preprint":false},{"pmid":"41661401","id":"PMC_41661401","title":"Single-cell RNA sequencing unveils CCDC86-driven immune modulation and antigen-presenting cell dynamics in head and neck squamous cell carcinoma.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41661401","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9264,"output_tokens":1686,"usd":0.026541,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8545,"output_tokens":2564,"usd":0.053413,"stage2_stop_reason":"end_turn"},"total_usd":0.079954,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Cyclon (CCDC86) is an immediate-early cytokine-responsive gene induced by IL-3 in hematopoietic cells. The encoded protein is a phosphorylated nuclear protein with repetitive sequences in the amino-terminus and a coiled-coil domain in the carboxyl-terminus. A reporter assay revealed that the mouse cyclon promoter contains redundant elements mediating IL-3-induced gene expression.\",\n      \"method\": \"Transient reporter assay, protein characterization (phosphorylation, domain analysis)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, reporter assay plus protein characterization, two orthogonal methods but no functional epistasis\",\n      \"pmids\": [\"17300783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cyclon (CCDC86) is induced in T cells upon TCR ligation and promotes activation-induced cell death (AICD) by upregulating Fas expression. Targeted deletion of one Cyclon allele in activated CD4+ T cells reduced AICD and Fas expression, and transgenic Cyclon expression enhanced AICD and ameliorated autoimmune phenotype in IL-2R-deficient mice, placing Cyclon upstream of Fas in T-cell immune homeostasis.\",\n      \"method\": \"Conditional allele deletion (loss-of-function), transgenic overexpression, AICD assay, Fas expression measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function genetics with defined molecular readout (Fas expression) and cellular phenotype (AICD), replicated in both transgenic and knockout models\",\n      \"pmids\": [\"19528538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCDC86 (CYCLON) physically interacts with NPM1 (nucleophosmin), and its protein interaction network connects it to the nucleolus, RNA processing, MYC signaling, and cell cycle progression. Alternative sub-cellular localizations (extra-nucleolar CYCLON and pan-cellular NPM1) were identified as independent predictive factors in DLBCL.\",\n      \"method\": \"Protein interaction network characterization (co-immunoprecipitation/proteomics implied), immunohistochemistry for sub-cellular localization\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction network characterization and localization data from single lab; abstract does not specify full Co-IP details\",\n      \"pmids\": [\"34885010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC86 is a chromosome periphery-associated protein that interacts with Ki-67 (MKI67). RNAi-mediated depletion of CCDC86 caused partial disorganisation of the chromosome periphery, altered localisation of Ki-67 and nucleolin (NCL), formation of abnormal cytoplasmic aggregates, errors in chromosome alignment, altered spindle length, and increased apoptosis. CCDC86, nucleolin, and B23 (NPM1) form subcomplexes required for mitotic spindle regulation and correct kinetochore-microtubule attachments.\",\n      \"method\": \"RNA interference (RNAi) depletion, fluorescence microscopy, biochemical fractionation, Co-immunoprecipitation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, microscopy, biochemistry/Co-IP) in a single rigorous study with defined mitotic phenotypes and partner identification\",\n      \"pmids\": [\"36695333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC86 promotes NPC cell proliferation, invasion, and migration by binding to NPM1 and thereby positively regulating EGFR expression and activating downstream PI3K/Akt signaling. CCDC86 does not directly bind EGFR but acts through NPM1 to upregulate EGFR transcriptionally/post-transcriptionally.\",\n      \"method\": \"In vitro proliferation/invasion/migration assays, in vivo xenograft, Co-immunoprecipitation (CCDC86-NPM1 interaction), siRNA knockdown, EGFR expression measurement, PI3K/Akt pathway analysis\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for CCDC86–NPM1 interaction, knockdown with defined molecular readout (EGFR, PI3K/Akt), single lab\",\n      \"pmids\": [\"38247332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC86 promotes aerobic glycolysis and glioma progression through interaction with BHLHE40, stabilizing ATF3 expression, which in turn activates the ERK signaling pathway to drive glycolysis and tumor development.\",\n      \"method\": \"CCDC86 knockdown functional assays (proliferation, migration, apoptosis, cell cycle), in vivo tumorigenesis assay, Co-immunoprecipitation (CCDC86–BHLHE40), ATF3 rescue experiment\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for CCDC86–BHLHE40 interaction plus knockdown/rescue with defined downstream pathway, single lab\",\n      \"pmids\": [\"40837407\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC86 (cyclon) is a phosphorylated nuclear/chromosome periphery protein that: (1) is induced by IL-3 and TCR stimulation and promotes T-cell AICD by upregulating Fas expression; (2) localizes to the chromosome periphery during mitosis where it interacts with Ki-67, nucleolin, and NPM1 to form subcomplexes required for mitotic spindle regulation and correct kinetochore-microtubule attachments; and (3) interacts with NPM1 and BHLHE40 to regulate downstream oncogenic signaling (EGFR/PI3K/Akt and ERK/glycolysis via ATF3) in cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCDC86 (cyclon) is a phosphorylated nuclear protein with an N-terminal repetitive region and a C-terminal coiled-coil domain that operates in two distinct contexts: immune cell death regulation and the mitotic chromosome periphery [#0, #3]. It was first identified as an immediate-early gene induced by IL-3 in hematopoietic cells [#0], and in T cells its induction following TCR ligation drives activation-induced cell death by upregulating Fas expression, placing CCDC86 upstream of Fas in immune homeostasis as shown by reciprocal allele deletion and transgenic overexpression [#1]. During mitosis, CCDC86 associates with the chromosome periphery and, together with nucleolin (NCL) and NPM1/B23, forms subcomplexes required for spindle regulation and correct kinetochore-microtubule attachments; its depletion disorganizes the chromosome periphery, mislocalizes Ki-67 (MKI67) and nucleolin, and produces chromosome alignment errors and increased apoptosis [#3]. CCDC86 physically interacts with NPM1, linking it to the nucleolus, RNA processing, MYC signaling, and cell cycle progression [#2]. In cancer contexts, CCDC86 acts through partner proteins to drive oncogenic signaling: it binds NPM1 to upregulate EGFR and activate PI3K/Akt in nasopharyngeal carcinoma [#4], and binds BHLHE40 to stabilize ATF3 and activate ERK-driven aerobic glycolysis in glioma [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established CCDC86/cyclon as a cytokine-responsive immediate-early gene and defined its basic protein architecture, framing it as a regulated nuclear factor rather than a constitutive housekeeping protein.\",\n      \"evidence\": \"Transient reporter assay of the mouse cyclon promoter plus protein characterization (phosphorylation, domain analysis) in IL-3-responsive hematopoietic cells\",\n      \"pmids\": [\"17300783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function assigned to the protein\", \"Coiled-coil binding partners not identified\", \"Phosphorylation sites and responsible kinases unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Answered what cyclon does functionally in immune cells, showing it promotes T-cell activation-induced cell death by upregulating Fas and contributes to immune homeostasis.\",\n      \"evidence\": \"Conditional allele deletion (loss-of-function), transgenic overexpression, AICD assays, and Fas expression measurement in mouse CD4+ T cells and IL-2R-deficient mice\",\n      \"pmids\": [\"19528538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which CCDC86 controls Fas expression unresolved\", \"Direct DNA or protein targets not identified\", \"Link between nuclear localization and Fas regulation unestablished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified NPM1 as a physical partner and connected CCDC86 to the nucleolus, RNA processing, MYC signaling, and cell cycle, while linking its subcellular localization to disease prognosis.\",\n      \"evidence\": \"Protein interaction network characterization and immunohistochemistry for subcellular localization in DLBCL\",\n      \"pmids\": [\"34885010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full Co-IP/proteomics validation details not specified\", \"Functional consequence of the NPM1 interaction not tested here\", \"Mechanism linking extra-nucleolar localization to outcome unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a concrete mitotic role: CCDC86 is a chromosome periphery component that, with nucleolin and NPM1, forms subcomplexes required for spindle regulation and kinetochore-microtubule attachment fidelity.\",\n      \"evidence\": \"RNAi depletion, fluorescence microscopy, biochemical fractionation, and Co-immunoprecipitation identifying Ki-67/MKI67, NCL, and NPM1 partners\",\n      \"pmids\": [\"36695333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of subcomplex assembly unknown\", \"How CCDC86 is recruited to the chromosome periphery unresolved\", \"Direct molecular activity at the kinetochore not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed CCDC86 drives carcinoma cell proliferation and invasion indirectly, acting through NPM1 to upregulate EGFR and activate PI3K/Akt rather than binding EGFR directly.\",\n      \"evidence\": \"In vitro proliferation/invasion/migration assays, xenograft, Co-IP of CCDC86-NPM1, siRNA knockdown, and EGFR/PI3K-Akt pathway analysis in nasopharyngeal carcinoma\",\n      \"pmids\": [\"38247332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the NPM1 complex regulates EGFR expression unclear\", \"Single lab, single tumor type\", \"Whether mitotic and oncogenic NPM1 complexes are the same is untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the oncogenic role to glioma via a distinct partner, showing CCDC86 binds BHLHE40 to stabilize ATF3 and activate ERK-driven aerobic glycolysis.\",\n      \"evidence\": \"Knockdown functional assays, in vivo tumorigenesis, Co-IP of CCDC86-BHLHE40, and ATF3 rescue experiments in glioma cells\",\n      \"pmids\": [\"40837407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical basis of ATF3 stabilization unknown\", \"Relationship between BHLHE40 and NPM1 pathways unresolved\", \"Single lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic molecular activity of CCDC86 and how a single coiled-coil protein bridges chromosome periphery assembly, Fas-mediated apoptosis, and multiple oncogenic partner complexes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic or defined biochemical activity established\", \"No structure of CCDC86 or its complexes\", \"Mechanism unifying immune, mitotic, and oncogenic roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NPM1\", \"MKI67\", \"NCL\", \"BHLHE40\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}