{"gene":"CCT3","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1996,"finding":"Human CCT3 (Cctg) encodes the gamma subunit of the CCT/TRiC chaperonin complex, a ~60 kDa protein of 544 amino acids that shares conserved domains with other TF55/TCP-1 family chaperonins including GroEL and Hsp60. The gene is expressed ubiquitously across human and mouse tissues, with higher expression in testis.","method":"cDNA cloning, sequence analysis, Southern blot, mRNA expression analysis","journal":"The Biochemical Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular characterization with multiple methods (cloning, sequencing, expression analysis) in a single study","pmids":["8573069"],"is_preprint":false},{"year":1994,"finding":"The human CCT3 gene (TRIC5) maps to chromosome 1q23, demonstrating it is not syntenic with TCP1/CCT1 (which maps to chromosome 6 in humans), despite both encoding subunits of the same TRiC complex.","method":"Fluorescence in situ hybridization (FISH), cDNA cloning","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct FISH localization experiment, single lab","pmids":["8001976"],"is_preprint":false},{"year":2006,"finding":"The CCT3 subunit of yeast CCT/TRiC was used to develop an affinity-tagged purification via an internal calmodulin-binding peptide tag in the apical domain loop. Purified CCT/TRiC catalyzes actin folding in a quantitative in vitro assay following approximately first-order kinetics (rate constant ~0.03 min⁻¹). The reaction is consistent with a model where CCT and actin folding intermediate (Ac(I)) are in a binding pre-equilibrium with a rate-limiting binding step followed by ATP-driven processing to native actin.","method":"Affinity purification via CCT3 internal tag, quantitative in vitro actin folding assay, mutagenesis of actin (D244S, G150P)","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution assay with purified components, kinetic analysis, and mutagenesis validation in a single rigorous study","pmids":["16762366"],"is_preprint":false},{"year":1996,"finding":"The Drosophila Cctg gene is an ortholog of human CCT3, encoding a ~60 kDa protein of 545 amino acids sharing 70% sequence identity with human CCT gamma. The gene comprises four exons interrupted by three introns.","method":"Genomic clone sequence analysis, structural gene characterization","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single gene characterization by sequence analysis only, no functional assay","pmids":["8666276"],"is_preprint":false},{"year":1996,"finding":"Xenopus laevis CCT3 (XlCctg) encodes a 547-amino acid gamma subunit of the CCT chaperonin complex (~60 kDa), expressed ubiquitously in all tissues examined, with significantly higher mRNA levels in the ovary.","method":"Library screening, PCR, cDNA sequencing, mRNA expression analysis","journal":"Biochimica et Biophysica Acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — characterization by sequence analysis and expression; no functional mechanistic assay","pmids":["8950171"],"is_preprint":false},{"year":2012,"finding":"A point mutation in the ATP-binding site of the CCT3 subunit (Glu to Asp) induced cytoplasmic P-body formation in yeast cells. CCT3 interacts specifically with Gln/Asn-rich segments enriched in P-body proteins. An in vitro gel-shift assay showed that this mutation in CCT3 interferes with the ability of the CCT complex to bind a Gln/Asn-rich protein aggregate, establishing that CCT3 has a distinct substrate-binding specificity for Q/N-rich sequences.","method":"High-throughput microscopy of yeast cells, ATP-binding site mutagenesis, in vitro gel-shift assay, structural modeling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay plus mutagenesis plus cell-based imaging, single lab with multiple orthogonal methods","pmids":["23112166"],"is_preprint":false},{"year":2015,"finding":"CCT3 depletion in hepatocellular carcinoma (HCC) cells suppresses cell proliferation by inducing mitotic arrest at prometaphase and apoptosis. CCT3 is required for spindle integrity and proper kinetochore-microtubule attachment during mitosis.","method":"siRNA/shRNA knockdown, cell proliferation assay, immunofluorescence of spindle/kinetochore markers, flow cytometry","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotype (mitotic arrest, kinetochore-MT defects), single lab with multiple readouts","pmids":["26739059"],"is_preprint":false},{"year":2019,"finding":"CCT3 co-interacts with YAP and TFCP2 (identified by mass spectrometry and confirmed by Co-IP). CCT3 prolongs the half-life of YAP and TFCP2 by blocking their ubiquitination mediated by PCBP2 in a βTrCP-independent manner. PCBP2 directly interacts with YAP via a WB motif–WW domain interaction, and CCT3 disrupts PCBP2-YAP interactions, thereby preventing YAP and TFCP2 from PCBP2-induced ubiquitination and degradation.","method":"Mass spectrometry, Co-IP, ubiquitination assay, protein half-life assay, epistasis by overexpression/knockdown","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and mass spectrometry identification with functional ubiquitination assay, single lab","pmids":["31501420"],"is_preprint":false},{"year":2022,"finding":"CCT3 regulates LINC00326 in a chaperonin-independent manner (as a non-canonical RNA-binding protein). Perturbation of the CCT3-LINC00326 regulatory network leads to decreased lipid accumulation, increased lipid degradation in cells, and diminished tumor growth in vivo.","method":"RBP knockdown, RNA sequencing, CRISPRa overexpression, lipid accumulation assays, in vivo tumor models","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (sequencing, cell assays, in vivo), single lab","pmids":["35022268"],"is_preprint":false},{"year":2018,"finding":"Drosophila CCT3 physically and genetically interacts with MTGO (the FNDC3 ortholog). Heterozygous mutation in CCT3 reducing binding between CCT3 and MTGO causes abnormal NMJ development (reduced branching, fewer synaptic boutons) similar to mtgo null mutants, establishing that CCT3 and MTGO form a macromolecular complex required for NMJ development.","method":"Co-IP (physical interaction), genetic epistasis in Drosophila, confocal microscopy of NMJ morphology","journal":"Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — physical interaction confirmed by Co-IP and genetic interaction confirmed by epistasis, single lab","pmids":["30539716"],"is_preprint":false},{"year":2020,"finding":"CCT3 knockdown in breast cancer cells reduces proliferation and migration. A rescue experiment showed that overexpression of NF-κB p65 rescued cell proliferation and migration impaired by CCT3 knockdown, placing CCT3 upstream of the NF-κB pathway in breast cancer cell growth.","method":"Lentiviral shRNA knockdown, proliferation assay, Transwell migration, flow cytometry, western blot, rescue overexpression","journal":"Cancer Cell International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pathway rescue, single lab, two orthogonal methods","pmids":["32518527"],"is_preprint":false},{"year":2021,"finding":"CCT3 knockdown in cisplatin-resistant lung adenocarcinoma cells re-sensitizes them to cisplatin by inhibiting the JAK2/STAT3 signaling pathway, establishing that CCT3 acts upstream of JAK2/STAT3 to promote cisplatin resistance.","method":"shRNA knockdown, cell viability/proliferation/invasion assays, in vivo xenograft, western blot of JAK2/STAT3 pathway","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with in vitro and in vivo validation, pathway identified by western blot, single lab","pmids":["34612768"],"is_preprint":false},{"year":2022,"finding":"CCT3 suppression inhibits glycolytic function and reduces total intracellular ATP levels by at least 25% in lung adenocarcinoma cells. CCT3 was found to interact with eukaryotic translation initiation factor 3 subunit G (EIF3G) by Co-IP, and EIF3G knockdown phenocopies CCT3 knockdown in impairing protein synthesis and cell growth.","method":"siRNA knockdown, Co-IP, ATP measurement, protein translation assay, in vivo tumor growth","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding partner identified, functional assays in vitro and in vivo, single lab","pmids":["35409343"],"is_preprint":false},{"year":2021,"finding":"CCT3 suppression in breast and prostate cancer cells via miRNA mimics (miR-24-3p, miR-128-3p, miR-149-5p) causes G0/G1 cell cycle arrest, impaired mitochondrial membrane potential, increased intracellular ROS, and apoptosis, with shifts in intracellular free amino acid profiles (glutamine, beta-alanine, glycine, serine, asparagine, sarcosine), suggesting CCT3 maintains energy metabolism homeostasis.","method":"miRNA mimic-mediated knockdown, acridine orange/ethidium bromide staining, Annexin V/PI flow cytometry, ROS measurement, mitochondria membrane potential analysis, free amino acid profiling","journal":"Free Radical Biology & Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal cellular readouts, single lab","pmids":["33508424"],"is_preprint":false},{"year":2024,"finding":"CCT3 interacts with ACTN4 to hinder the recycling of transferrin receptor protein 1 (TFRC) to the cell membrane, thus obstructing iron endocytosis and inhibiting ferroptosis. CCT3-mediated ferroptosis inhibition depends on deubiquitination of K6-linked non-degradative ubiquitination at lysine 21 (K21), which occurs upon Sorafenib treatment.","method":"Co-IP, CRISPR/Cas9 knockout screening, PTM omics, xenograft model, western blot","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed interaction, PTM omics identified K21 ubiquitination, in vivo validation, single lab","pmids":["39210442"],"is_preprint":false},{"year":2024,"finding":"CCT3 promotes nuclear export of tumor suppressors RB1 and p21 by enhancing the stability of XPO1 through correct folding, confirmed by Co-IP and GST pull-down. This suppresses cellular senescence in clear cell renal carcinoma, causing G1 phase arrest upon CCT3 depletion.","method":"Co-IP, GST pull-down, SA-β-gal activity assay, cell cycle analysis, xenograft tumor model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct binding confirmed by reciprocal Co-IP and GST pull-down, functional consequence validated in vitro and in vivo, single lab","pmids":["41732260"],"is_preprint":false},{"year":2025,"finding":"The isolated apical domain of CCT3 (human) strongly inhibits tau aggregation in vitro. Kinetic analysis and negative-stain electron microscopy indicate that in the presence of the CCT3 apical domain, tau aggregation fits a saturating elongation and fragmentation mechanism, mechanistically distinct from CCT7's apical domain (which follows a fragmentation model alone). Coarse-grained molecular dynamics simulations show tau interacts with different regions of CCT3 versus CCT7 apical domains.","method":"In vitro tau aggregation kinetics, negative-stain electron microscopy, coarse-grained molecular dynamics simulations","journal":"Protein Science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with structural analysis and simulation, single study, single lab","pmids":["40400346"],"is_preprint":false},{"year":2026,"finding":"Loss of cct3 function in zebrafish causes failure to form normal myelin sheaths due to early apoptotic death of Schwann cells, abnormal NMJ refinement, cytoskeletal alterations (tubulin/microtubules), and severely disturbed microtubule-dependent axonal transport of organelles in peripheral motor axons, establishing Cct3/TRiC as essential for myelination, Schwann cell survival, NMJ development, and axonal transport.","method":"CRISPR/Cas9 loss-of-function in zebrafish, confocal microscopy, electron microscopy, immunostaining, comparison with human patient-derived tissue","journal":"Cell Death & Disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo methods (CRISPR KO, confocal, EM, transgenic lines), multiple phenotypic readouts, validated against human patient tissue","pmids":["41680121"],"is_preprint":false},{"year":2022,"finding":"CCT3 knockdown in melanoma cells inhibits proliferation and cell cycle progression and induces apoptosis. Rescue experiments showed that CDK1 overexpression rescues decreased proliferation caused by CCT3 silencing, placing CCT3 upstream of CDK1 in melanoma cell cycle regulation.","method":"shRNA knockdown, gene array analysis, proliferation/apoptosis assays, CDK1 overexpression rescue, in vivo xenograft","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue experiment, in vitro and in vivo validation, single lab","pmids":["35399722"],"is_preprint":false},{"year":2021,"finding":"CCT3 knockdown in cervical cancer cells suppresses proliferation, migration, invasion, and promotes apoptosis and cell cycle arrest. Rescue assays demonstrated that CCT3 promotes CESC proliferation and migration via fibronectin 1 (FN1), as FN1 protein expression is suppressed after CCT3 knockdown and restoration of FN1 rescues the phenotype.","method":"siRNA knockdown, Transwell assay, flow cytometry, western blot, rescue overexpression of FN1","journal":"Molecular Medicine Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue placing CCT3 upstream of FN1, single lab with multiple assays","pmids":["34651664"],"is_preprint":false}],"current_model":"CCT3 is the gamma subunit of the ATP-dependent CCT/TRiC chaperonin complex that folds cytoskeletal proteins (actin, tubulin) and other substrates; its apical domain has subunit-specific binding affinity for Gln/Asn-rich sequences and can inhibit tau aggregation, while in cells CCT3 supports mitotic spindle integrity, kinetochore-microtubule attachment, axonal transport, myelination, and NMJ refinement, and acts as a non-canonical chaperone that stabilizes client proteins (YAP, TFCP2, XPO1) by blocking their ubiquitin-mediated degradation, placing it upstream of multiple oncogenic pathways including NF-κB, JAK2/STAT3, YAP/TFCP2, and CDK1-dependent cell cycle regulation."},"narrative":{"mechanistic_narrative":"CCT3 is the gamma subunit of the ATP-dependent CCT/TRiC chaperonin, a complex that catalyzes the folding of cytoskeletal substrates such as actin through a binding pre-equilibrium followed by ATP-driven processing to the native state [PMID:8573069, PMID:16762366]. The CCT3 subunit contributes subunit-specific substrate recognition: its apical domain binds Gln/Asn-rich sequences, a specificity disrupted by an ATP-site point mutation [PMID:23112166], and the isolated CCT3 apical domain inhibits tau aggregation through a saturating elongation-and-fragmentation mechanism distinct from that of CCT7 [PMID:40400346]. Consistent with its folding role, CCT3 is required in cells for mitotic spindle integrity and proper kinetochore-microtubule attachment [PMID:26739059], and its loss in vivo causes cytoskeletal/microtubule alterations, defective microtubule-dependent axonal transport, Schwann cell death with myelination failure, and abnormal neuromuscular junction development [PMID:41680121], the last of which it supports through a physical and genetic interaction with the FNDC3 ortholog MTGO [PMID:30539716]. Beyond canonical folding, CCT3 acts as a non-canonical chaperone and RNA-binding protein that stabilizes client proteins by opposing their ubiquitin-mediated turnover: it prolongs the half-life of YAP and TFCP2 by disrupting PCBP2-mediated ubiquitination [PMID:31501420], stabilizes XPO1 to drive nuclear export of RB1 and p21 and suppress senescence [PMID:41732260], regulates the lncRNA LINC00326 to control lipid metabolism and tumor growth [PMID:35022268], and restrains ferroptosis by interacting with ACTN4 to block transferrin receptor recycling [PMID:39210442]. Through these activities CCT3 functions upstream of multiple growth and survival pathways in cancer, including NF-κB [PMID:32518527], JAK2/STAT3 [PMID:34612768], CDK1-dependent cell-cycle progression [PMID:35399722], and FN1-dependent proliferation and migration [PMID:34651664], and supports tumor cell energy metabolism and protein synthesis in part via interaction with EIF3G [PMID:35409343, PMID:33508424].","teleology":[{"year":1996,"claim":"Establishing the molecular identity of CCT3 as the gamma subunit of the CCT/TRiC chaperonin was the foundational step, defining it as a TF55/TCP-1 family chaperonin expressed ubiquitously.","evidence":"cDNA cloning, sequence analysis, and tissue expression profiling of human CCT3, with FISH mapping to chromosome 1q23","pmids":["8573069","8001976"],"confidence":"Medium","gaps":["No functional folding assay in these studies","Substrate range and complex assembly not addressed"]},{"year":2006,"claim":"Reconstitution with CCT3-tagged purified chaperonin demonstrated the complex catalyzes actin folding with defined kinetics, establishing the canonical chaperonin activity quantitatively.","evidence":"Affinity purification via a CCT3 internal tag and a quantitative in vitro actin folding assay with actin mutagenesis","pmids":["16762366"],"confidence":"High","gaps":["CCT3-specific contribution to substrate recognition not isolated here","Folding of non-actin substrates not tested"]},{"year":2012,"claim":"Mutagenesis of the CCT3 ATP-binding site revealed that this subunit confers a distinct substrate-binding specificity for Gln/Asn-rich sequences, explaining subunit-level division of labor within the complex.","evidence":"Yeast ATP-site mutagenesis with P-body imaging, in vitro gel-shift binding to Q/N-rich aggregates, and structural modeling","pmids":["23112166"],"confidence":"High","gaps":["Mammalian Q/N substrate repertoire not enumerated","Link to disease aggregation not addressed in this study"]},{"year":2025,"claim":"The isolated CCT3 apical domain was shown to inhibit tau aggregation by a mechanism distinct from CCT7, mechanistically linking CCT3 substrate-binding to control of amyloidogenic proteins.","evidence":"In vitro tau aggregation kinetics, negative-stain EM, and coarse-grained molecular dynamics simulations","pmids":["40400346"],"confidence":"Medium","gaps":["Effect within the intact CCT/TRiC complex not tested","No cellular or in vivo validation of tau protection"]},{"year":2015,"claim":"Loss-of-function in cancer cells connected CCT3 to mitotic fidelity, showing it is required for spindle integrity and kinetochore-microtubule attachment.","evidence":"siRNA/shRNA knockdown with spindle/kinetochore immunofluorescence and flow cytometry in HCC cells","pmids":["26739059"],"confidence":"Medium","gaps":["Whether the phenotype reflects tubulin folding versus a non-canonical role not distinguished","Direct mitotic substrates not identified"]},{"year":2026,"claim":"In vivo zebrafish loss-of-function established CCT3/TRiC as essential for cytoskeletal integrity, axonal transport, Schwann cell survival, myelination, and NMJ development, extending its role to the nervous system.","evidence":"CRISPR/Cas9 knockout with confocal/electron microscopy and immunostaining, compared against human patient-derived tissue","pmids":["41680121"],"confidence":"High","gaps":["Causative human mutation/genetics not fully defined here","Molecular link between folding defect and Schwann cell apoptosis unresolved"]},{"year":2018,"claim":"A physical and genetic interaction between CCT3 and MTGO (FNDC3 ortholog) in Drosophila defined a specific developmental complex required for NMJ morphogenesis.","evidence":"Co-IP and genetic epistasis with confocal NMJ morphology analysis in Drosophila","pmids":["30539716"],"confidence":"Medium","gaps":["Whether MTGO is a folding client or a partner unresolved","Conservation of the interaction in mammals not tested"]},{"year":2019,"claim":"Identification of YAP and TFCP2 as CCT3-stabilized clients revealed a non-canonical chaperone function in which CCT3 blocks PCBP2-mediated, βTrCP-independent ubiquitination.","evidence":"Mass spectrometry, reciprocal Co-IP, ubiquitination and half-life assays with epistasis","pmids":["31501420"],"confidence":"Medium","gaps":["Whether stabilization requires the full chaperonin or folding activity not resolved","Structural basis of PCBP2 displacement unknown"]},{"year":2024,"claim":"CCT3 was shown to stabilize XPO1 by promoting its correct folding, driving nuclear export of RB1 and p21 and suppressing senescence, linking the chaperone activity to tumor suppressor inactivation.","evidence":"Co-IP, GST pull-down, SA-β-gal and cell-cycle assays, and xenograft models in clear cell renal carcinoma","pmids":["41732260"],"confidence":"Medium","gaps":["Direct demonstration of XPO1 misfolding upon CCT3 loss limited","Generality across cell types not established"]},{"year":2022,"claim":"CCT3 was found to act as a non-canonical RNA-binding protein regulating LINC00326 to control lipid metabolism and tumor growth, broadening its function beyond protein folding.","evidence":"RBP knockdown, RNA-seq, CRISPRa overexpression, lipid assays, and in vivo tumor models","pmids":["35022268"],"confidence":"Medium","gaps":["RNA-binding mode and sequence specificity not defined","Relation to chaperonin complex unclear"]},{"year":2024,"claim":"CCT3 was shown to restrain ferroptosis by interacting with ACTN4 to block transferrin receptor recycling, a mechanism dependent on K6-linked K21 ubiquitination, defining a role in iron handling and drug response.","evidence":"Co-IP, CRISPR/Cas9 screening, PTM omics, and xenograft models under Sorafenib treatment","pmids":["39210442"],"confidence":"Medium","gaps":["Enzyme controlling K21 ubiquitination not identified","Whether ACTN4 is a folding client unresolved"]},{"year":2022,"claim":"Multiple cancer studies placed CCT3 upstream of growth and survival pathways and metabolism, defining its oncogenic significance across tumor types.","evidence":"Knockdown with pathway-rescue epistasis (NF-κB p65, JAK2/STAT3, CDK1, FN1), EIF3G Co-IP, ATP/translation and metabolic profiling, in vitro and in vivo","pmids":["32518527","34612768","35409343","33508424","35399722","34651664"],"confidence":"Medium","gaps":["Whether these pathway effects are direct chaperone clients or downstream consequences not resolved","Common upstream mechanism across tumor types not unified"]},{"year":null,"claim":"How CCT3's canonical folding activity, its subunit-specific Q/N substrate recognition, and its chaperonin-independent roles (RNA binding, client stabilization, ubiquitination control) are mechanistically integrated remains unresolved.","evidence":"No single study reconciles the folding-dependent and folding-independent functions","pmids":[],"confidence":"Low","gaps":["No structure of CCT3 engaging non-canonical clients","Boundary between free CCT3 and complex-assembled CCT3 functions undefined","No human Mendelian disease mechanism established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,2,5,15,16]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[2,5]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7,15]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6,17]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,10,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,17]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14,17]}],"complexes":["CCT/TRiC chaperonin"],"partners":["YAP1","TFCP2","PCBP2","XPO1","ACTN4","EIF3G","MTGO"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49368","full_name":"T-complex protein 1 subunit gamma","aliases":["CCT-gamma","Chaperonin containing T-complex polypeptide 1 subunit 3","hTRiC5"],"length_aa":545,"mass_kda":60.5,"function":"Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis (PubMed:25467444, PubMed:36493755, PubMed:35449234, PubMed:37193829). The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance (PubMed:25467444). As part of the TRiC complex may play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia (PubMed:20080638)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P49368/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCT3","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000163468","cell_line_id":"CID000208","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"ACTB","stoichiometry":10.0},{"gene":"CCT2","stoichiometry":10.0},{"gene":"CCT5","stoichiometry":10.0},{"gene":"CCT6A","stoichiometry":10.0},{"gene":"CCT4","stoichiometry":10.0},{"gene":"CCT8","stoichiometry":10.0},{"gene":"TCP1","stoichiometry":10.0},{"gene":"CCT7","stoichiometry":10.0},{"gene":"PPP2CA","stoichiometry":10.0},{"gene":"PPP2CB","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000208","total_profiled":1310},"omim":[{"mim_id":"621034","title":"NEURODEVELOPMENTAL DISORDER WITH SPEECH OR VISUAL IMPAIRMENT AND BRAIN HYPOMYELINATION; NEDSVH","url":"https://www.omim.org/entry/621034"},{"mim_id":"615794","title":"FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 3A; FNDC3A","url":"https://www.omim.org/entry/615794"},{"mim_id":"605139","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 2; CCT2","url":"https://www.omim.org/entry/605139"},{"mim_id":"600114","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 3; CCT3","url":"https://www.omim.org/entry/600114"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCT3"},"hgnc":{"alias_symbol":["Cctg"],"prev_symbol":["TRIC5"]},"alphafold":{"accession":"P49368","domains":[{"cath_id":"1.10.560.10","chopping":"13-142_408-524","consensus_level":"high","plddt":91.7309,"start":13,"end":524},{"cath_id":"3.30.260.10","chopping":"148-215_375-404","consensus_level":"medium","plddt":87.6941,"start":148,"end":404},{"cath_id":"3.50.7.10","chopping":"217-249_265-368","consensus_level":"medium","plddt":93.5155,"start":217,"end":368}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49368","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49368-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49368-F1-predicted_aligned_error_v6.png","plddt_mean":89.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCT3","jax_strain_url":"https://www.jax.org/strain/search?query=CCT3"},"sequence":{"accession":"P49368","fasta_url":"https://rest.uniprot.org/uniprotkb/P49368.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49368/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49368"}},"corpus_meta":[{"pmid":"11486088","id":"PMC_11486088","title":"Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9.","date":"2001","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11486088","citation_count":937,"is_preprint":false},{"pmid":"36028483","id":"PMC_36028483","title":"The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36028483","citation_count":118,"is_preprint":false},{"pmid":"12970845","id":"PMC_12970845","title":"Confirmation of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: a single shared haplotype indicates an ancestral founder effect.","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12970845","citation_count":111,"is_preprint":false},{"pmid":"35750695","id":"PMC_35750695","title":"Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35750695","citation_count":106,"is_preprint":false},{"pmid":"26739059","id":"PMC_26739059","title":"Molecular chaperone CCT3 supports proper mitotic progression and cell proliferation in hepatocellular carcinoma cells.","date":"2015","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/26739059","citation_count":69,"is_preprint":false},{"pmid":"20971734","id":"PMC_20971734","title":"Mutant (CCTG)n expansion causes abnormal expression of zinc finger protein 9 (ZNF9) in myotonic dystrophy type 2.","date":"2010","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20971734","citation_count":61,"is_preprint":false},{"pmid":"16816559","id":"PMC_16816559","title":"Cognitive-behavioral intervention to enhance adherence to antiretroviral therapy: a randomized controlled trial (CCTG 578).","date":"2006","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16816559","citation_count":60,"is_preprint":false},{"pmid":"16762366","id":"PMC_16762366","title":"Quantitative actin folding reactions using yeast CCT purified via an internal tag in the CCT3/gamma subunit.","date":"2006","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16762366","citation_count":58,"is_preprint":false},{"pmid":"27390551","id":"PMC_27390551","title":"Expression and diagnostic value of CCT3 and IQGAP3 in hepatocellular carcinoma.","date":"2016","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/27390551","citation_count":54,"is_preprint":false},{"pmid":"31501420","id":"PMC_31501420","title":"CCT3 acts upstream of YAP and TFCP2 as a potential target and tumour biomarker in liver cancer.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31501420","citation_count":53,"is_preprint":false},{"pmid":"31420468","id":"PMC_31420468","title":"A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229).","date":"2019","source":"The oncologist","url":"https://pubmed.ncbi.nlm.nih.gov/31420468","citation_count":53,"is_preprint":false},{"pmid":"35022268","id":"PMC_35022268","title":"CCT3-LINC00326 axis regulates hepatocarcinogenic lipid metabolism.","date":"2022","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/35022268","citation_count":51,"is_preprint":false},{"pmid":"15292165","id":"PMC_15292165","title":"Hairpin structure-forming propensity of the (CCTG.CAGG) tetranucleotide repeats contributes to the genetic instability associated with myotonic dystrophy type 2.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15292165","citation_count":50,"is_preprint":false},{"pmid":"15718211","id":"PMC_15718211","title":"Biomolecular identification of (CCTG)n mutation in myotonic dystrophy type 2 (DM2) by FISH on muscle biopsy.","date":"2004","source":"European journal of histochemistry : EJH","url":"https://pubmed.ncbi.nlm.nih.gov/15718211","citation_count":48,"is_preprint":false},{"pmid":"29748010","id":"PMC_29748010","title":"Canadian Cancer Trials Group (CCTG) IND211: A randomized trial of pelareorep (Reolysin) in patients with previously treated advanced or metastatic non-small cell lung cancer receiving standard salvage therapy.","date":"2018","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/29748010","citation_count":46,"is_preprint":false},{"pmid":"15231584","id":"PMC_15231584","title":"Homozygosity for CCTG mutation in myotonic dystrophy type 2.","date":"2004","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15231584","citation_count":45,"is_preprint":false},{"pmid":"16376058","id":"PMC_16376058","title":"Effect of the [CCTG]n repeat expansion on ZNF9 expression in myotonic dystrophy type II (DM2).","date":"2005","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/16376058","citation_count":41,"is_preprint":false},{"pmid":"34800700","id":"PMC_34800700","title":"CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.","date":"2021","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34800700","citation_count":36,"is_preprint":false},{"pmid":"15019706","id":"PMC_15019706","title":"New methods for molecular diagnosis and demonstration of the (CCTG)n mutation in myotonic dystrophy type 2 (DM2).","date":"2004","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/15019706","citation_count":35,"is_preprint":false},{"pmid":"19731031","id":"PMC_19731031","title":"Longest form of CCTG microsatellite repeat in the promoter of the CD2BP1/PSTPIP1 gene is associated with aseptic abscesses and with Crohn disease in French patients.","date":"2010","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19731031","citation_count":35,"is_preprint":false},{"pmid":"31707687","id":"PMC_31707687","title":"A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: a CCTG study.","date":"2019","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/31707687","citation_count":33,"is_preprint":false},{"pmid":"23112166","id":"PMC_23112166","title":"Interactions of subunit CCT3 in the yeast chaperonin CCT/TRiC with Q/N-rich proteins revealed by high-throughput microscopy analysis.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23112166","citation_count":32,"is_preprint":false},{"pmid":"33508424","id":"PMC_33508424","title":"CCT3 suppression prompts apoptotic machinery through oxidative stress and energy deprivation in breast and prostate cancers.","date":"2021","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33508424","citation_count":31,"is_preprint":false},{"pmid":"27449804","id":"PMC_27449804","title":"A Phase II Study of PF-03446962 in Patients with Advanced Malignant Pleural Mesothelioma. CCTG Trial IND.207.","date":"2016","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27449804","citation_count":31,"is_preprint":false},{"pmid":"15718840","id":"PMC_15718840","title":"A randomized, prospective study of phenotype susceptibility testing versus standard of care to manage antiretroviral therapy: CCTG 575.","date":"2005","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15718840","citation_count":30,"is_preprint":false},{"pmid":"37963313","id":"PMC_37963313","title":"Prediction of Adjuvant Gemcitabine Sensitivity in Resectable Pancreatic Adenocarcinoma Using the GemPred RNA Signature: An Ancillary Study of the PRODIGE-24/CCTG PA6 Clinical Trial.","date":"2023","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37963313","citation_count":29,"is_preprint":false},{"pmid":"32518527","id":"PMC_32518527","title":"Suppression of CCT3 inhibits the proliferation and migration in breast cancer cells.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32518527","citation_count":29,"is_preprint":false},{"pmid":"37226534","id":"PMC_37226534","title":"Contact Days Associated With Cancer Treatments in the CCTG LY.12 Trial.","date":"2023","source":"The oncologist","url":"https://pubmed.ncbi.nlm.nih.gov/37226534","citation_count":29,"is_preprint":false},{"pmid":"37092305","id":"PMC_37092305","title":"m6A-modification regulated circ-CCT3 acts as the sponge of miR-378a-3p to promote hepatocellular carcinoma progression.","date":"2023","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/37092305","citation_count":26,"is_preprint":false},{"pmid":"29805652","id":"PMC_29805652","title":"Suppression of CCT3 inhibits malignant proliferation of human papillary thyroid carcinoma cell.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29805652","citation_count":26,"is_preprint":false},{"pmid":"19218442","id":"PMC_19218442","title":"A Z-DNA sequence reduces slipped-strand structure formation in the myotonic dystrophy type 2 (CCTG) x (CAGG) repeat.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19218442","citation_count":26,"is_preprint":false},{"pmid":"31200828","id":"PMC_31200828","title":"Selumetinib in patients receiving standard pemetrexed and platinum-based chemotherapy for advanced or metastatic KRAS wildtype or unknown non-squamous non-small cell lung cancer: A randomized, multicenter, phase II study. Canadian Cancer Trials Group (CCTG) IND.219.","date":"2019","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/31200828","citation_count":26,"is_preprint":false},{"pmid":"33072568","id":"PMC_33072568","title":"Upregulation of CCT-3 Induces Breast Cancer Cell Proliferation Through miR-223 Competition and Wnt/β-Catenin Signaling Pathway Activation.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33072568","citation_count":25,"is_preprint":false},{"pmid":"21478167","id":"PMC_21478167","title":"The origin of genetic instability in CCTG repeats.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21478167","citation_count":25,"is_preprint":false},{"pmid":"39210442","id":"PMC_39210442","title":"CCT3/ACTN4/TFRC axis protects hepatocellular carcinoma cells from ferroptosis by inhibiting iron endocytosis.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/39210442","citation_count":24,"is_preprint":false},{"pmid":"34651664","id":"PMC_34651664","title":"Upregulation of CCT3 promotes cervical cancer progression through FN1.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34651664","citation_count":24,"is_preprint":false},{"pmid":"27993811","id":"PMC_27993811","title":"Treatment outcomes for older patients with relapsed/refractory aggressive lymphoma receiving salvage chemotherapy and autologous stem cell transplantation are similar to younger patients: a subgroup analysis from the phase III CCTG LY.12 trial.","date":"2017","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27993811","citation_count":24,"is_preprint":false},{"pmid":"23561036","id":"PMC_23561036","title":"Uninterrupted CCTG tracts in the myotonic dystrophy type 2 associated locus.","date":"2013","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/23561036","citation_count":24,"is_preprint":false},{"pmid":"29554282","id":"PMC_29554282","title":"Effects of Celecoxib and Low-dose Aspirin on Outcomes in Adjuvant Aromatase Inhibitor-Treated Patients: CCTG MA.27.","date":"2018","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/29554282","citation_count":22,"is_preprint":false},{"pmid":"29128193","id":"PMC_29128193","title":"Vitamin D Levels, Vitamin D Receptor Polymorphisms, and Inflammatory Cytokines in Aromatase Inhibitor-Induced Arthralgias: An Analysis of CCTG MA.27.","date":"2017","source":"Clinical breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29128193","citation_count":22,"is_preprint":false},{"pmid":"22723857","id":"PMC_22723857","title":"The unstable CCTG repeat responsible for myotonic dystrophy type 2 originates from an AluSx element insertion into an early primate genome.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22723857","citation_count":20,"is_preprint":false},{"pmid":"34387610","id":"PMC_34387610","title":"Circular RNA circ-CCT3 promotes bortezomib resistance in multiple myeloma via modulating miR-223-3p/BRD4 axis.","date":"2022","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/34387610","citation_count":19,"is_preprint":false},{"pmid":"34612768","id":"PMC_34612768","title":"Chaperonin containing TCP1 subunit 3 (CCT3) promotes cisplatin resistance of lung adenocarcinoma cells through targeting the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34612768","citation_count":19,"is_preprint":false},{"pmid":"8573069","id":"PMC_8573069","title":"Cloning, structure and mRNA expression of human Cctg, which encodes the chaperonin subunit CCT gamma.","date":"1996","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8573069","citation_count":19,"is_preprint":false},{"pmid":"36185198","id":"PMC_36185198","title":"Current understanding on the role of CCT3 in cancer research.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36185198","citation_count":18,"is_preprint":false},{"pmid":"26384951","id":"PMC_26384951","title":"New insights into the genetic instability in CCTG repeats.","date":"2015","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/26384951","citation_count":17,"is_preprint":false},{"pmid":"29274617","id":"PMC_29274617","title":"Outcomes in women with invasive ductal or invasive lobular early stage breast cancer treated with anastrozole or exemestane in CCTG (NCIC CTG) MA.27.","date":"2017","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/29274617","citation_count":17,"is_preprint":false},{"pmid":"16753177","id":"PMC_16753177","title":"DM2 CCTG*CAGG repeats are crossover hotspots that are more prone to expansions than the DM1 CTG*CAG repeats in Escherichia coli.","date":"2006","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16753177","citation_count":16,"is_preprint":false},{"pmid":"19306311","id":"PMC_19306311","title":"Genetic instabilities of (CCTG).(CAGG) and (ATTCT).(AGAAT) disease-associated repeats reveal multiple pathways for repeat deletion.","date":"2009","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/19306311","citation_count":15,"is_preprint":false},{"pmid":"28634730","id":"PMC_28634730","title":"Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG).","date":"2017","source":"Surgery today","url":"https://pubmed.ncbi.nlm.nih.gov/28634730","citation_count":15,"is_preprint":false},{"pmid":"35409343","id":"PMC_35409343","title":"Suppression of CCT3 Inhibits Tumor Progression by Impairing ATP Production and Cytoplasmic Translation in Lung Adenocarcinoma.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35409343","citation_count":13,"is_preprint":false},{"pmid":"29291944","id":"PMC_29291944","title":"Expanded [CCTG]n repetitions are not associated with abnormal methylation at the CNBP locus in myotonic dystrophy type 2 (DM2) patients.","date":"2017","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/29291944","citation_count":13,"is_preprint":false},{"pmid":"34485814","id":"PMC_34485814","title":"Cancer Antigen 15-3/Mucin 1 Levels in CCTG MA.32: A Breast Cancer Randomized Trial of Metformin vs Placebo.","date":"2021","source":"JNCI cancer spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/34485814","citation_count":13,"is_preprint":false},{"pmid":"33760147","id":"PMC_33760147","title":"Circular RNA circ‑CCT3 promotes hepatocellular carcinoma progression by regulating the miR‑1287‑5p/TEAD1/PTCH1/LOX axis.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/33760147","citation_count":12,"is_preprint":false},{"pmid":"30539716","id":"PMC_30539716","title":"Miles to go (mtgo) encodes FNDC3 proteins that interact with the chaperonin subunit CCT3 and are required for NMJ branching and growth in Drosophila.","date":"2018","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/30539716","citation_count":12,"is_preprint":false},{"pmid":"27827316","id":"PMC_27827316","title":"BRM Promoter Polymorphisms and Survival of Advanced Non-Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/27827316","citation_count":11,"is_preprint":false},{"pmid":"27879482","id":"PMC_27879482","title":"Unusual structures of CCTG repeats and their participation in repeat expansion.","date":"2016","source":"Biomolecular concepts","url":"https://pubmed.ncbi.nlm.nih.gov/27879482","citation_count":10,"is_preprint":false},{"pmid":"29263904","id":"PMC_29263904","title":"The competing mini-dumbbell mechanism: new insights into CCTG repeat expansion.","date":"2016","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29263904","citation_count":10,"is_preprint":false},{"pmid":"30317534","id":"PMC_30317534","title":"Canadian Cancer Trials Group (CCTG) IND215: A phase Ib study of Selumetinib in patients with untreated advanced or metastatic NSCLC who are receiving standard chemotherapy regimens.","date":"2018","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/30317534","citation_count":10,"is_preprint":false},{"pmid":"25443993","id":"PMC_25443993","title":"Eosinophilic myositis as first manifestation in a patient with type 2 myotonic dystrophy CCTG expansion mutation and rheumatoid arthritis.","date":"2014","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/25443993","citation_count":10,"is_preprint":false},{"pmid":"35399722","id":"PMC_35399722","title":"Suppression of CCT3 inhibits melanoma cell proliferation by downregulating CDK1 expression.","date":"2022","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35399722","citation_count":9,"is_preprint":false},{"pmid":"38992898","id":"PMC_38992898","title":"Repurposing cyclovirobuxine D as a novel inhibitor of colorectal cancer progression via modulating the CCT3/YAP axis.","date":"2024","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38992898","citation_count":9,"is_preprint":false},{"pmid":"18804219","id":"PMC_18804219","title":"Colocalization of ribonuclear inclusions with muscle blind like-proteins in a family with myotonic dystrophy type 2 associated with a short CCTG expansion.","date":"2008","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18804219","citation_count":9,"is_preprint":false},{"pmid":"37833621","id":"PMC_37833621","title":"Circular RNA CCT3 is a unique molecular marker in bladder cancer.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37833621","citation_count":8,"is_preprint":false},{"pmid":"40221386","id":"PMC_40221386","title":"Exosomal CCT3 as a biomarker for diagnosis and immune therapy response in patients diagnosed with hepatocellular carcinoma.","date":"2025","source":"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/40221386","citation_count":7,"is_preprint":false},{"pmid":"8001976","id":"PMC_8001976","title":"Assignment of the human homologue of the mTRiC-P5 gene (TRIC5) to band 1q23 by fluorescence in situ hybridization.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8001976","citation_count":7,"is_preprint":false},{"pmid":"39394034","id":"PMC_39394034","title":"A Phase II Study of Neoadjuvant Opnurasib KRAS G12C Inhibitor in Patients With Surgically Resectable Non-Small Cell Lung Cancer (CCTG IND.242A): A Substudy of the IND.242 Platform Master Protocol.","date":"2024","source":"Clinical lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39394034","citation_count":7,"is_preprint":false},{"pmid":"37157006","id":"PMC_37157006","title":"Metformin, placebo, and endocrine therapy discontinuation among participants in a randomized double-blind trial of metformin vs placebo in hormone receptor-positive early-stage breast cancer (CCTG MA32).","date":"2023","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/37157006","citation_count":7,"is_preprint":false},{"pmid":"36313331","id":"PMC_36313331","title":"Insights into the roles and driving forces of CCT3 in human tumors.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36313331","citation_count":6,"is_preprint":false},{"pmid":"38360074","id":"PMC_38360074","title":"Dysfunction of CCT3-associated network signals for the critical state during progression of hepatocellular carcinoma.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38360074","citation_count":5,"is_preprint":false},{"pmid":"36918801","id":"PMC_36918801","title":"Integrated analyzes identify CCT3 as a modulator to shape immunosuppressive tumor microenvironment in lung adenocarcinoma.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36918801","citation_count":4,"is_preprint":false},{"pmid":"26586700","id":"PMC_26586700","title":"Optimization PCR for Detection CTG/CCTG-Repeat Expansions in the Diagnosis of Myotonic Dystrophies.","date":"2015","source":"Annals of clinical and laboratory science","url":"https://pubmed.ncbi.nlm.nih.gov/26586700","citation_count":4,"is_preprint":false},{"pmid":"33802634","id":"PMC_33802634","title":"Evaluating the Indirect Costs of Care Associated with Salvage Chemotherapy for Relapsed and Refractory Aggressive-Histology Lymphoma: A Subset Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Clinical Trial.","date":"2021","source":"Current oncology (Toronto, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/33802634","citation_count":4,"is_preprint":false},{"pmid":"39478031","id":"PMC_39478031","title":"Silencing CCT3 induces ferroptosis through the NOD1-NF-κB signaling pathway in bladder cancer.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39478031","citation_count":3,"is_preprint":false},{"pmid":"40400346","id":"PMC_40400346","title":"Inhibition of tau aggregation by the CCT3 and CCT7 apical domains.","date":"2025","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/40400346","citation_count":3,"is_preprint":false},{"pmid":"37950892","id":"PMC_37950892","title":"Massive contractions of myotonic dystrophy type 2-associated CCTG tetranucleotide repeats occur via double-strand break repair with distinct requirements for DNA helicases.","date":"2024","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/37950892","citation_count":3,"is_preprint":false},{"pmid":"32715442","id":"PMC_32715442","title":"Variation in the UGT2B17 genotype, exemestane metabolism and menopause-related toxicities in the CCTG MAP.3 trial.","date":"2020","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/32715442","citation_count":3,"is_preprint":false},{"pmid":"8666276","id":"PMC_8666276","title":"Drosophila melanogaster P1 genomic clone DS05563 contains the chaperonin-encoding gene Cctg.","date":"1996","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8666276","citation_count":3,"is_preprint":false},{"pmid":"39631846","id":"PMC_39631846","title":"Plasma arginine as a predictive biomarker for outcomes with immune checkpoint inhibition in metastatic colorectal cancer: a correlative analysis of the CCTG CO.26 trial.","date":"2024","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39631846","citation_count":3,"is_preprint":false},{"pmid":"35664779","id":"PMC_35664779","title":"Corrigendum: Upregulation of CCT-3 Induces Breast Cancer Cell Proliferation Through miR-223 Competition and Wnt/b-Catenin Signaling Pathway Activation.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35664779","citation_count":3,"is_preprint":false},{"pmid":"39119544","id":"PMC_39119544","title":"Co-occurrence of CAPN3 homozygous mutation and CCTG expansion in the CNBP gene in a patient with muscular dystrophy.","date":"2024","source":"Postepy psychiatrii neurologii","url":"https://pubmed.ncbi.nlm.nih.gov/39119544","citation_count":2,"is_preprint":false},{"pmid":"8950171","id":"PMC_8950171","title":"Molecular characterisation of the Xenopus laevis chaperonin gene Cctg.","date":"1996","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8950171","citation_count":2,"is_preprint":false},{"pmid":"39928781","id":"PMC_39928781","title":"Advances in the study of CCT3 in malignant tumors: A review.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39928781","citation_count":1,"is_preprint":false},{"pmid":"40133672","id":"PMC_40133672","title":"Modulating CCTG repeat expansion toxicity in DM2 Drosophila model through TDP1 inhibition.","date":"2025","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40133672","citation_count":1,"is_preprint":false},{"pmid":"40184324","id":"PMC_40184324","title":"Effects of cannabinoids on immune checkpoint inhibitor response: CCTG pooled analysis of individual patient data.","date":"2025","source":"Immunotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/40184324","citation_count":1,"is_preprint":false},{"pmid":"30984523","id":"PMC_30984523","title":"Myotonic Dystrophy-2: Unusual Phenotype Due to a Small CCTG-expansion.","date":"2018","source":"Balkan journal of medical genetics : BJMG","url":"https://pubmed.ncbi.nlm.nih.gov/30984523","citation_count":1,"is_preprint":false},{"pmid":"41505338","id":"PMC_41505338","title":"CCT3 Facilitates the Malignant Progression of NSCLC and SCLC via PI3 K/AKT-EMT Axis and Emerges as a Novel Serum Diagnostic Biomarker.","date":"2026","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/41505338","citation_count":0,"is_preprint":false},{"pmid":"41123599","id":"PMC_41123599","title":"Continuous versus Standard Palbociclib Treatment and Molecular Profiling of Solid Tissues and Liquid Biopsies in the CCTG MA.38 Trial in Advanced Breast Cancer.","date":"2025","source":"Cancer research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41123599","citation_count":0,"is_preprint":false},{"pmid":"38922834","id":"PMC_38922834","title":"Effects of interrupting residues on DNA dumbbell structures formed by CCTG tetranucleotide repeats associated with myotonic dystrophy type 2.","date":"2024","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/38922834","citation_count":0,"is_preprint":false},{"pmid":"41732260","id":"PMC_41732260","title":"CCT3-mediated regulation of XPO1/RB1 axis stability promotes cellular senescence and tumor progression in clear cell renal carcinoma.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41732260","citation_count":0,"is_preprint":false},{"pmid":"41153715","id":"PMC_41153715","title":"A Retrospective Study in Colorectal Adenocarcinoma Uncovers the Potential of Circ-CCT3 as a Predictor of Tumor Recurrence.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/41153715","citation_count":0,"is_preprint":false},{"pmid":"37461657","id":"PMC_37461657","title":"Massive contractions of Myotonic Dystrophy Type 2-associated CCTG tetranucleotide repeats occur via double strand break repair with distinct requirements for helicases.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37461657","citation_count":0,"is_preprint":false},{"pmid":"41205108","id":"PMC_41205108","title":"Dihydroartemisinin: A Targeting Agent of CCT3-Mediated Oxidative Stress to Enhance the Antitumor Activity of Doxorubicin in Hepatocellular Carcinoma.","date":"2025","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41205108","citation_count":0,"is_preprint":false},{"pmid":"42225005","id":"PMC_42225005","title":"CRI-CCTG-0003/IND.240 an immunotherapy platform study in platinum-resistant high grade serous ovarian cancer (IPROC): Sub-studies A and B: Durvalumab (D) + mecbotamab vedotin (BA3011) or ozuriftamab vedotin (BA3021).","date":"2026","source":"Cancer treatment and research communications","url":"https://pubmed.ncbi.nlm.nih.gov/42225005","citation_count":0,"is_preprint":false},{"pmid":"41680121","id":"PMC_41680121","title":"The chaperonin TRiC component Cct3 is required for axonal transport, myelination, and neuromuscular junction refinement.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41680121","citation_count":0,"is_preprint":false},{"pmid":"42063220","id":"PMC_42063220","title":"Exploration of BMI and circulating metabolic factors as predictors of metformin benefit in CCTG MA.32.","date":"2026","source":"JNCI cancer spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/42063220","citation_count":0,"is_preprint":false},{"pmid":"41175109","id":"PMC_41175109","title":"Effects of serotonergic drugs on immune checkpoint inhibitor response: a pooled analysis of individual patient data from four Canadian Cancer Trials Group (CCTG) trials.","date":"2025","source":"Immunotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/41175109","citation_count":0,"is_preprint":false},{"pmid":"34825307","id":"PMC_34825307","title":"Predicting the clinical outcomes and benefit from letrozole after 5 years of treatment with aromatase inhibitors for early breast cancer: analysis from CCTG MA.17R.","date":"2021","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/34825307","citation_count":0,"is_preprint":false},{"pmid":"42255257","id":"PMC_42255257","title":"A phase 1 study of R-GDP-venetoclax before autologous transplant in relapsed/refractory large B-cell lymphoma (CCTG LY.18).","date":"2026","source":"Blood neoplasia","url":"https://pubmed.ncbi.nlm.nih.gov/42255257","citation_count":0,"is_preprint":false},{"pmid":"40078191","id":"PMC_40078191","title":"Retraction: Upregulation of CCT-3 induces breast cancer cell proliferation through miR-223 competition and Wnt/β-catenin signaling pathway activation.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40078191","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53599,"output_tokens":4848,"usd":0.116759,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13137,"output_tokens":4289,"usd":0.086455,"stage2_stop_reason":"end_turn"},"total_usd":0.203214,"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\": 1996,\n      \"finding\": \"Human CCT3 (Cctg) encodes the gamma subunit of the CCT/TRiC chaperonin complex, a ~60 kDa protein of 544 amino acids that shares conserved domains with other TF55/TCP-1 family chaperonins including GroEL and Hsp60. The gene is expressed ubiquitously across human and mouse tissues, with higher expression in testis.\",\n      \"method\": \"cDNA cloning, sequence analysis, Southern blot, mRNA expression analysis\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular characterization with multiple methods (cloning, sequencing, expression analysis) in a single study\",\n      \"pmids\": [\"8573069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The human CCT3 gene (TRIC5) maps to chromosome 1q23, demonstrating it is not syntenic with TCP1/CCT1 (which maps to chromosome 6 in humans), despite both encoding subunits of the same TRiC complex.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH), cDNA cloning\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct FISH localization experiment, single lab\",\n      \"pmids\": [\"8001976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The CCT3 subunit of yeast CCT/TRiC was used to develop an affinity-tagged purification via an internal calmodulin-binding peptide tag in the apical domain loop. Purified CCT/TRiC catalyzes actin folding in a quantitative in vitro assay following approximately first-order kinetics (rate constant ~0.03 min⁻¹). The reaction is consistent with a model where CCT and actin folding intermediate (Ac(I)) are in a binding pre-equilibrium with a rate-limiting binding step followed by ATP-driven processing to native actin.\",\n      \"method\": \"Affinity purification via CCT3 internal tag, quantitative in vitro actin folding assay, mutagenesis of actin (D244S, G150P)\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution assay with purified components, kinetic analysis, and mutagenesis validation in a single rigorous study\",\n      \"pmids\": [\"16762366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The Drosophila Cctg gene is an ortholog of human CCT3, encoding a ~60 kDa protein of 545 amino acids sharing 70% sequence identity with human CCT gamma. The gene comprises four exons interrupted by three introns.\",\n      \"method\": \"Genomic clone sequence analysis, structural gene characterization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single gene characterization by sequence analysis only, no functional assay\",\n      \"pmids\": [\"8666276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Xenopus laevis CCT3 (XlCctg) encodes a 547-amino acid gamma subunit of the CCT chaperonin complex (~60 kDa), expressed ubiquitously in all tissues examined, with significantly higher mRNA levels in the ovary.\",\n      \"method\": \"Library screening, PCR, cDNA sequencing, mRNA expression analysis\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — characterization by sequence analysis and expression; no functional mechanistic assay\",\n      \"pmids\": [\"8950171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A point mutation in the ATP-binding site of the CCT3 subunit (Glu to Asp) induced cytoplasmic P-body formation in yeast cells. CCT3 interacts specifically with Gln/Asn-rich segments enriched in P-body proteins. An in vitro gel-shift assay showed that this mutation in CCT3 interferes with the ability of the CCT complex to bind a Gln/Asn-rich protein aggregate, establishing that CCT3 has a distinct substrate-binding specificity for Q/N-rich sequences.\",\n      \"method\": \"High-throughput microscopy of yeast cells, ATP-binding site mutagenesis, in vitro gel-shift assay, structural modeling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay plus mutagenesis plus cell-based imaging, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23112166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCT3 depletion in hepatocellular carcinoma (HCC) cells suppresses cell proliferation by inducing mitotic arrest at prometaphase and apoptosis. CCT3 is required for spindle integrity and proper kinetochore-microtubule attachment during mitosis.\",\n      \"method\": \"siRNA/shRNA knockdown, cell proliferation assay, immunofluorescence of spindle/kinetochore markers, flow cytometry\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotype (mitotic arrest, kinetochore-MT defects), single lab with multiple readouts\",\n      \"pmids\": [\"26739059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCT3 co-interacts with YAP and TFCP2 (identified by mass spectrometry and confirmed by Co-IP). CCT3 prolongs the half-life of YAP and TFCP2 by blocking their ubiquitination mediated by PCBP2 in a βTrCP-independent manner. PCBP2 directly interacts with YAP via a WB motif–WW domain interaction, and CCT3 disrupts PCBP2-YAP interactions, thereby preventing YAP and TFCP2 from PCBP2-induced ubiquitination and degradation.\",\n      \"method\": \"Mass spectrometry, Co-IP, ubiquitination assay, protein half-life assay, epistasis by overexpression/knockdown\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and mass spectrometry identification with functional ubiquitination assay, single lab\",\n      \"pmids\": [\"31501420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCT3 regulates LINC00326 in a chaperonin-independent manner (as a non-canonical RNA-binding protein). Perturbation of the CCT3-LINC00326 regulatory network leads to decreased lipid accumulation, increased lipid degradation in cells, and diminished tumor growth in vivo.\",\n      \"method\": \"RBP knockdown, RNA sequencing, CRISPRa overexpression, lipid accumulation assays, in vivo tumor models\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (sequencing, cell assays, in vivo), single lab\",\n      \"pmids\": [\"35022268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Drosophila CCT3 physically and genetically interacts with MTGO (the FNDC3 ortholog). Heterozygous mutation in CCT3 reducing binding between CCT3 and MTGO causes abnormal NMJ development (reduced branching, fewer synaptic boutons) similar to mtgo null mutants, establishing that CCT3 and MTGO form a macromolecular complex required for NMJ development.\",\n      \"method\": \"Co-IP (physical interaction), genetic epistasis in Drosophila, confocal microscopy of NMJ morphology\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical interaction confirmed by Co-IP and genetic interaction confirmed by epistasis, single lab\",\n      \"pmids\": [\"30539716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCT3 knockdown in breast cancer cells reduces proliferation and migration. A rescue experiment showed that overexpression of NF-κB p65 rescued cell proliferation and migration impaired by CCT3 knockdown, placing CCT3 upstream of the NF-κB pathway in breast cancer cell growth.\",\n      \"method\": \"Lentiviral shRNA knockdown, proliferation assay, Transwell migration, flow cytometry, western blot, rescue overexpression\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pathway rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"32518527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCT3 knockdown in cisplatin-resistant lung adenocarcinoma cells re-sensitizes them to cisplatin by inhibiting the JAK2/STAT3 signaling pathway, establishing that CCT3 acts upstream of JAK2/STAT3 to promote cisplatin resistance.\",\n      \"method\": \"shRNA knockdown, cell viability/proliferation/invasion assays, in vivo xenograft, western blot of JAK2/STAT3 pathway\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with in vitro and in vivo validation, pathway identified by western blot, single lab\",\n      \"pmids\": [\"34612768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCT3 suppression inhibits glycolytic function and reduces total intracellular ATP levels by at least 25% in lung adenocarcinoma cells. CCT3 was found to interact with eukaryotic translation initiation factor 3 subunit G (EIF3G) by Co-IP, and EIF3G knockdown phenocopies CCT3 knockdown in impairing protein synthesis and cell growth.\",\n      \"method\": \"siRNA knockdown, Co-IP, ATP measurement, protein translation assay, in vivo tumor growth\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding partner identified, functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"35409343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCT3 suppression in breast and prostate cancer cells via miRNA mimics (miR-24-3p, miR-128-3p, miR-149-5p) causes G0/G1 cell cycle arrest, impaired mitochondrial membrane potential, increased intracellular ROS, and apoptosis, with shifts in intracellular free amino acid profiles (glutamine, beta-alanine, glycine, serine, asparagine, sarcosine), suggesting CCT3 maintains energy metabolism homeostasis.\",\n      \"method\": \"miRNA mimic-mediated knockdown, acridine orange/ethidium bromide staining, Annexin V/PI flow cytometry, ROS measurement, mitochondria membrane potential analysis, free amino acid profiling\",\n      \"journal\": \"Free Radical Biology & Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal cellular readouts, single lab\",\n      \"pmids\": [\"33508424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT3 interacts with ACTN4 to hinder the recycling of transferrin receptor protein 1 (TFRC) to the cell membrane, thus obstructing iron endocytosis and inhibiting ferroptosis. CCT3-mediated ferroptosis inhibition depends on deubiquitination of K6-linked non-degradative ubiquitination at lysine 21 (K21), which occurs upon Sorafenib treatment.\",\n      \"method\": \"Co-IP, CRISPR/Cas9 knockout screening, PTM omics, xenograft model, western blot\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed interaction, PTM omics identified K21 ubiquitination, in vivo validation, single lab\",\n      \"pmids\": [\"39210442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT3 promotes nuclear export of tumor suppressors RB1 and p21 by enhancing the stability of XPO1 through correct folding, confirmed by Co-IP and GST pull-down. This suppresses cellular senescence in clear cell renal carcinoma, causing G1 phase arrest upon CCT3 depletion.\",\n      \"method\": \"Co-IP, GST pull-down, SA-β-gal activity assay, cell cycle analysis, xenograft tumor model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding confirmed by reciprocal Co-IP and GST pull-down, functional consequence validated in vitro and in vivo, single lab\",\n      \"pmids\": [\"41732260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The isolated apical domain of CCT3 (human) strongly inhibits tau aggregation in vitro. Kinetic analysis and negative-stain electron microscopy indicate that in the presence of the CCT3 apical domain, tau aggregation fits a saturating elongation and fragmentation mechanism, mechanistically distinct from CCT7's apical domain (which follows a fragmentation model alone). Coarse-grained molecular dynamics simulations show tau interacts with different regions of CCT3 versus CCT7 apical domains.\",\n      \"method\": \"In vitro tau aggregation kinetics, negative-stain electron microscopy, coarse-grained molecular dynamics simulations\",\n      \"journal\": \"Protein Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with structural analysis and simulation, single study, single lab\",\n      \"pmids\": [\"40400346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss of cct3 function in zebrafish causes failure to form normal myelin sheaths due to early apoptotic death of Schwann cells, abnormal NMJ refinement, cytoskeletal alterations (tubulin/microtubules), and severely disturbed microtubule-dependent axonal transport of organelles in peripheral motor axons, establishing Cct3/TRiC as essential for myelination, Schwann cell survival, NMJ development, and axonal transport.\",\n      \"method\": \"CRISPR/Cas9 loss-of-function in zebrafish, confocal microscopy, electron microscopy, immunostaining, comparison with human patient-derived tissue\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo methods (CRISPR KO, confocal, EM, transgenic lines), multiple phenotypic readouts, validated against human patient tissue\",\n      \"pmids\": [\"41680121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCT3 knockdown in melanoma cells inhibits proliferation and cell cycle progression and induces apoptosis. Rescue experiments showed that CDK1 overexpression rescues decreased proliferation caused by CCT3 silencing, placing CCT3 upstream of CDK1 in melanoma cell cycle regulation.\",\n      \"method\": \"shRNA knockdown, gene array analysis, proliferation/apoptosis assays, CDK1 overexpression rescue, in vivo xenograft\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue experiment, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"35399722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCT3 knockdown in cervical cancer cells suppresses proliferation, migration, invasion, and promotes apoptosis and cell cycle arrest. Rescue assays demonstrated that CCT3 promotes CESC proliferation and migration via fibronectin 1 (FN1), as FN1 protein expression is suppressed after CCT3 knockdown and restoration of FN1 rescues the phenotype.\",\n      \"method\": \"siRNA knockdown, Transwell assay, flow cytometry, western blot, rescue overexpression of FN1\",\n      \"journal\": \"Molecular Medicine Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue placing CCT3 upstream of FN1, single lab with multiple assays\",\n      \"pmids\": [\"34651664\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCT3 is the gamma subunit of the ATP-dependent CCT/TRiC chaperonin complex that folds cytoskeletal proteins (actin, tubulin) and other substrates; its apical domain has subunit-specific binding affinity for Gln/Asn-rich sequences and can inhibit tau aggregation, while in cells CCT3 supports mitotic spindle integrity, kinetochore-microtubule attachment, axonal transport, myelination, and NMJ refinement, and acts as a non-canonical chaperone that stabilizes client proteins (YAP, TFCP2, XPO1) by blocking their ubiquitin-mediated degradation, placing it upstream of multiple oncogenic pathways including NF-κB, JAK2/STAT3, YAP/TFCP2, and CDK1-dependent cell cycle regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCT3 is the gamma subunit of the ATP-dependent CCT/TRiC chaperonin, a complex that catalyzes the folding of cytoskeletal substrates such as actin through a binding pre-equilibrium followed by ATP-driven processing to the native state [#0, #2]. The CCT3 subunit contributes subunit-specific substrate recognition: its apical domain binds Gln/Asn-rich sequences, a specificity disrupted by an ATP-site point mutation [#5], and the isolated CCT3 apical domain inhibits tau aggregation through a saturating elongation-and-fragmentation mechanism distinct from that of CCT7 [#16]. Consistent with its folding role, CCT3 is required in cells for mitotic spindle integrity and proper kinetochore-microtubule attachment [#6], and its loss in vivo causes cytoskeletal/microtubule alterations, defective microtubule-dependent axonal transport, Schwann cell death with myelination failure, and abnormal neuromuscular junction development [#17], the last of which it supports through a physical and genetic interaction with the FNDC3 ortholog MTGO [#9]. Beyond canonical folding, CCT3 acts as a non-canonical chaperone and RNA-binding protein that stabilizes client proteins by opposing their ubiquitin-mediated turnover: it prolongs the half-life of YAP and TFCP2 by disrupting PCBP2-mediated ubiquitination [#7], stabilizes XPO1 to drive nuclear export of RB1 and p21 and suppress senescence [#15], regulates the lncRNA LINC00326 to control lipid metabolism and tumor growth [#8], and restrains ferroptosis by interacting with ACTN4 to block transferrin receptor recycling [#14]. Through these activities CCT3 functions upstream of multiple growth and survival pathways in cancer, including NF-\\u03baB [#10], JAK2/STAT3 [#11], CDK1-dependent cell-cycle progression [#18], and FN1-dependent proliferation and migration [#19], and supports tumor cell energy metabolism and protein synthesis in part via interaction with EIF3G [#12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the molecular identity of CCT3 as the gamma subunit of the CCT/TRiC chaperonin was the foundational step, defining it as a TF55/TCP-1 family chaperonin expressed ubiquitously.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and tissue expression profiling of human CCT3, with FISH mapping to chromosome 1q23\",\n      \"pmids\": [\"8573069\", \"8001976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional folding assay in these studies\", \"Substrate range and complex assembly not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Reconstitution with CCT3-tagged purified chaperonin demonstrated the complex catalyzes actin folding with defined kinetics, establishing the canonical chaperonin activity quantitatively.\",\n      \"evidence\": \"Affinity purification via a CCT3 internal tag and a quantitative in vitro actin folding assay with actin mutagenesis\",\n      \"pmids\": [\"16762366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CCT3-specific contribution to substrate recognition not isolated here\", \"Folding of non-actin substrates not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mutagenesis of the CCT3 ATP-binding site revealed that this subunit confers a distinct substrate-binding specificity for Gln/Asn-rich sequences, explaining subunit-level division of labor within the complex.\",\n      \"evidence\": \"Yeast ATP-site mutagenesis with P-body imaging, in vitro gel-shift binding to Q/N-rich aggregates, and structural modeling\",\n      \"pmids\": [\"23112166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian Q/N substrate repertoire not enumerated\", \"Link to disease aggregation not addressed in this study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The isolated CCT3 apical domain was shown to inhibit tau aggregation by a mechanism distinct from CCT7, mechanistically linking CCT3 substrate-binding to control of amyloidogenic proteins.\",\n      \"evidence\": \"In vitro tau aggregation kinetics, negative-stain EM, and coarse-grained molecular dynamics simulations\",\n      \"pmids\": [\"40400346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect within the intact CCT/TRiC complex not tested\", \"No cellular or in vivo validation of tau protection\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Loss-of-function in cancer cells connected CCT3 to mitotic fidelity, showing it is required for spindle integrity and kinetochore-microtubule attachment.\",\n      \"evidence\": \"siRNA/shRNA knockdown with spindle/kinetochore immunofluorescence and flow cytometry in HCC cells\",\n      \"pmids\": [\"26739059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the phenotype reflects tubulin folding versus a non-canonical role not distinguished\", \"Direct mitotic substrates not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"In vivo zebrafish loss-of-function established CCT3/TRiC as essential for cytoskeletal integrity, axonal transport, Schwann cell survival, myelination, and NMJ development, extending its role to the nervous system.\",\n      \"evidence\": \"CRISPR/Cas9 knockout with confocal/electron microscopy and immunostaining, compared against human patient-derived tissue\",\n      \"pmids\": [\"41680121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causative human mutation/genetics not fully defined here\", \"Molecular link between folding defect and Schwann cell apoptosis unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A physical and genetic interaction between CCT3 and MTGO (FNDC3 ortholog) in Drosophila defined a specific developmental complex required for NMJ morphogenesis.\",\n      \"evidence\": \"Co-IP and genetic epistasis with confocal NMJ morphology analysis in Drosophila\",\n      \"pmids\": [\"30539716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MTGO is a folding client or a partner unresolved\", \"Conservation of the interaction in mammals not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of YAP and TFCP2 as CCT3-stabilized clients revealed a non-canonical chaperone function in which CCT3 blocks PCBP2-mediated, \\u03b2TrCP-independent ubiquitination.\",\n      \"evidence\": \"Mass spectrometry, reciprocal Co-IP, ubiquitination and half-life assays with epistasis\",\n      \"pmids\": [\"31501420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stabilization requires the full chaperonin or folding activity not resolved\", \"Structural basis of PCBP2 displacement unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CCT3 was shown to stabilize XPO1 by promoting its correct folding, driving nuclear export of RB1 and p21 and suppressing senescence, linking the chaperone activity to tumor suppressor inactivation.\",\n      \"evidence\": \"Co-IP, GST pull-down, SA-\\u03b2-gal and cell-cycle assays, and xenograft models in clear cell renal carcinoma\",\n      \"pmids\": [\"41732260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of XPO1 misfolding upon CCT3 loss limited\", \"Generality across cell types not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CCT3 was found to act as a non-canonical RNA-binding protein regulating LINC00326 to control lipid metabolism and tumor growth, broadening its function beyond protein folding.\",\n      \"evidence\": \"RBP knockdown, RNA-seq, CRISPRa overexpression, lipid assays, and in vivo tumor models\",\n      \"pmids\": [\"35022268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding mode and sequence specificity not defined\", \"Relation to chaperonin complex unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CCT3 was shown to restrain ferroptosis by interacting with ACTN4 to block transferrin receptor recycling, a mechanism dependent on K6-linked K21 ubiquitination, defining a role in iron handling and drug response.\",\n      \"evidence\": \"Co-IP, CRISPR/Cas9 screening, PTM omics, and xenograft models under Sorafenib treatment\",\n      \"pmids\": [\"39210442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme controlling K21 ubiquitination not identified\", \"Whether ACTN4 is a folding client unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple cancer studies placed CCT3 upstream of growth and survival pathways and metabolism, defining its oncogenic significance across tumor types.\",\n      \"evidence\": \"Knockdown with pathway-rescue epistasis (NF-\\u03baB p65, JAK2/STAT3, CDK1, FN1), EIF3G Co-IP, ATP/translation and metabolic profiling, in vitro and in vivo\",\n      \"pmids\": [\"32518527\", \"34612768\", \"35409343\", \"33508424\", \"35399722\", \"34651664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these pathway effects are direct chaperone clients or downstream consequences not resolved\", \"Common upstream mechanism across tumor types not unified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCT3's canonical folding activity, its subunit-specific Q/N substrate recognition, and its chaperonin-independent roles (RNA binding, client stabilization, ubiquitination control) are mechanistically integrated remains unresolved.\",\n      \"evidence\": \"No single study reconciles the folding-dependent and folding-independent functions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of CCT3 engaging non-canonical clients\", \"Boundary between free CCT3 and complex-assembled CCT3 functions undefined\", \"No human Mendelian disease mechanism established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 2, 5, 15, 16]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14, 17]}\n    ],\n    \"complexes\": [\"CCT/TRiC chaperonin\"],\n    \"partners\": [\"YAP1\", \"TFCP2\", \"PCBP2\", \"XPO1\", \"ACTN4\", \"EIF3G\", \"MTGO\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}