{"gene":"CDCA5","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2019,"finding":"CDCA5 transcription is directly driven by E2F1, as shown by luciferase reporter assay and chromatin immunoprecipitation (ChIP) in hepatocellular carcinoma cells; CDCA5 promotes cell proliferation and inhibits apoptosis via the AKT pathway.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), knockdown with proliferation/apoptosis readouts","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — two orthogonal methods (ChIP + luciferase) in a single lab; moderate evidence for E2F1 transcriptional regulation and AKT pathway involvement","pmids":["31205541"],"is_preprint":false},{"year":2021,"finding":"SPOP (E3 ubiquitin ligase adaptor) directly interacts with CDCA5 and promotes its polyubiquitination and proteasomal degradation in a degron-dependent manner; prostate cancer-associated SPOP mutations impair this degradation, leading to CDCA5 accumulation, G2/M arrest rescue, and AKT pathway activation.","method":"Co-IP, ubiquitination assay, SPOP mutant rescue experiments, knockdown/overexpression with cell cycle and apoptosis readouts","journal":"Neoplasia (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assay, degron-dependence, and genetic epistasis (SPOP mutants) in a single study with multiple orthogonal methods","pmids":["34509929"],"is_preprint":false},{"year":2022,"finding":"TPI1 (triosephosphate isomerase 1) interacts with CDCA5 (identified by Co-IP and mass spectrometry) and stabilizes CDCA5 protein, which in turn activates the PI3K/AKT/mTOR pathway to promote breast cancer proliferation and metastasis.","method":"Co-IP, mass spectrometric analysis, immunofluorescence, ubiquitination assay, overexpression/knockdown with PI3K/AKT/mTOR pathway readouts","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with MS identification and functional validation in a single lab with multiple methods","pmids":["35509067"],"is_preprint":false},{"year":2022,"finding":"CDCA5 knockdown in breast cancer cells suppresses proliferation and migration, and this effect is rescued by overexpression of PDS5A (PDS5 cohesin-associated factor A), placing CDCA5 upstream of PDS5A in controlling breast cancer cell behavior.","method":"shRNA knockdown, rescue overexpression of PDS5A, cell proliferation and migration assays, western blot","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established by knockdown-rescue experiment in a single lab","pmids":["35506437"],"is_preprint":false},{"year":2024,"finding":"CDCA5 promotes breast cancer progression by facilitating the binding of E2F1 to the FOXM1 promoter; CDCA5 knockdown reduces E2F1–FOXM1 promoter occupancy, and FOXM1 depletion reverses CDCA5 overexpression effects; the Wnt/β-catenin pathway is required downstream.","method":"Co-IP, ChIP, dual-luciferase reporter assay, FOXM1 knockdown rescue, in vitro and in vivo models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, luciferase, genetic rescue) in a single lab","pmids":["38978058"],"is_preprint":false},{"year":2023,"finding":"The transcription factor KLF5 directly binds to a specific site in the CDCA5 promoter and activates CDCA5 expression; KLF5 overexpression rescues the antiproliferative effects of CDCA5 knockdown in epithelial ovarian cancer cells.","method":"ChIP, promoter binding assay, overexpression rescue experiments","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus functional rescue in a single lab","pmids":["37247719"],"is_preprint":false},{"year":2024,"finding":"CDCA5 interacts with EEF1A1 (Eukaryotic Translation Elongation Factor 1 Alpha 1), identified by Co-IP and LC-MS/MS, and this interaction regulates the mTOR signaling pathway to promote clear cell renal cell carcinoma progression.","method":"Co-IP, LC-MS/MS, knockdown/overexpression with proliferation, migration, apoptosis, and sunitinib resistance readouts, in vivo xenograft","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with MS identification and functional validation in a single lab","pmids":["38658931"],"is_preprint":false},{"year":2024,"finding":"CDCA5 promotes ovarian cancer cell invasion and migration via activation of the TGF-β1/Smad2/3 signaling pathway, as evidenced by RNA sequencing showing ECM/TGF pathway enrichment and functional confirmation.","method":"RNA sequencing, functional invasion/migration assays, signaling pathway analysis with TGF-β1/Smad2/3 readouts, xenograft model","journal":"Journal of ovarian research","confidence":"Low","confidence_rationale":"Tier 3 — pathway placement based on RNA-seq enrichment and functional assays but no direct binding/reconstitution evidence; single lab","pmids":["38539247"],"is_preprint":false},{"year":2024,"finding":"CDCA5 regulates PD-L1 expression through the ANXA/AKT signaling pathway in lung adenocarcinoma cells; combined suppression of CDCA5 and PD-L1 synergistically inhibits cell proliferation.","method":"Cell line experiments, western blot for pathway components, co-inhibition proliferation assays","journal":"Translational oncology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single method approach for pathway placement without reconstitution or Co-IP","pmids":["38838437"],"is_preprint":false},{"year":2025,"finding":"CDCA5 interacts with Cyclin A2 (CCNA2) as identified by Co-IP; berberine treatment downregulates both CDCA5 and CCNA2, and overexpression of either reverses berberine's anti-tumor effects in NSCLC cells.","method":"Co-IP, overexpression rescue, RT-qPCR, western blot, xenograft model","journal":"Journal of natural medicines","confidence":"Low","confidence_rationale":"Tier 3 — single lab, Co-IP without reciprocal validation or in vitro reconstitution","pmids":["40155519"],"is_preprint":false},{"year":2025,"finding":"CDC40 knockdown causes intron retention in CDCA5 pre-mRNA (specifically retention of intron 1), leading to decreased CDCA5 protein levels; CDC40 functions as a spliceosome component whose binding partners include spliceosome proteins, positioning it as a regulator of CDCA5 splicing.","method":"Global transcriptional and splicing analysis, RT-PCR for intron retention, Co-IP of CDC40 spliceosome interactions, knockdown with cell cycle and apoptosis readouts","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular mechanism (intron retention) established with splicing assays and protein interaction data in a single lab","pmids":["39747150"],"is_preprint":false},{"year":2018,"finding":"CDCA5 knockdown in gastric cancer cells induces G1-phase cell cycle arrest accompanied by downregulation of Cyclin E1 (CCNE1), placing CDCA5 upstream of CCNE1 in cell cycle progression.","method":"siRNA knockdown, flow cytometry cell cycle analysis, western blot for CCNE1","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single lab, knockdown with cell cycle phenotype; no direct binding or reconstitution","pmids":["29326043"],"is_preprint":false},{"year":2020,"finding":"CDCA5 promotes bladder cancer cell proliferation by upregulating CDC2 (CDK1) and Cyclin B1, activating the PI3K/AKT/mTOR pathway, and regulating the mitochondrial apoptosis pathway; knockdown reduces CDC2/Cyclin B1 levels and induces apoptosis.","method":"siRNA knockdown, overexpression, western blot for cell cycle and pathway proteins, flow cytometry apoptosis assay","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 — single lab, knockdown/OE with pathway readouts but no direct binding or reconstitution","pmids":["32201512"],"is_preprint":false},{"year":2021,"finding":"CDCA5 knockdown in prostate cancer cells reduces ERK phosphorylation, placing CDCA5 upstream of ERK signaling in PCa proliferation control.","method":"shRNA knockdown, western blot for p-ERK, proliferation/colony assays, xenograft model","journal":"Oncology reports","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single method for pathway placement (western blot for p-ERK after knockdown)","pmids":["33650660"],"is_preprint":false}],"current_model":"CDCA5 (sororin) is a cell cycle-associated protein whose transcription is activated by E2F1 and KLF5; its protein stability is regulated by SPOP-mediated polyubiquitination and proteasomal degradation (antagonized by TPI1-mediated stabilization); CDCA5 interacts with PDS5A to regulate sister chromatid cohesion, with EEF1A1 to regulate mTOR signaling, and with Cyclin A2; its splicing is controlled by the spliceosome component CDC40; downstream, CDCA5 promotes cancer cell proliferation and survival through the PI3K/AKT/mTOR pathway, ERK signaling, and modulation of cell cycle regulators including CDC2/Cyclin B1 and Cyclin E1, and facilitates transcriptional regulation by promoting E2F1 binding to the FOXM1 promoter."},"narrative":{"teleology":[{"year":2018,"claim":"Establishing that CDCA5 functions upstream of G1/S cell cycle regulators showed it is not merely a cohesion factor but an active driver of cell cycle progression beyond its canonical mitotic role.","evidence":"siRNA knockdown in gastric cancer cells with flow cytometry showing G1 arrest and Cyclin E1 downregulation","pmids":["29326043"],"confidence":"Low","gaps":["No direct binding between CDCA5 and Cyclin E1 demonstrated","Single cell type tested","Mechanism linking CDCA5 to Cyclin E1 expression unknown"]},{"year":2019,"claim":"Identifying E2F1 as a direct transcriptional activator of CDCA5 connected its cell cycle-dependent expression to a known G1/S transcription factor and linked CDCA5 function to AKT signaling.","evidence":"ChIP and luciferase reporter assay in hepatocellular carcinoma cells plus knockdown with AKT pathway readouts","pmids":["31205541"],"confidence":"Medium","gaps":["Whether E2F1 is the predominant transcriptional driver in non-cancer contexts is unknown","Mechanism connecting CDCA5 to AKT activation not defined"]},{"year":2020,"claim":"Demonstrating that CDCA5 upregulates CDC2/Cyclin B1 and activates PI3K/AKT/mTOR signaling broadened its downstream effector network beyond G1/S to G2/M regulators.","evidence":"siRNA knockdown and overexpression in bladder cancer cells with western blot for cell cycle proteins and PI3K/AKT/mTOR pathway components","pmids":["32201512"],"confidence":"Low","gaps":["No direct interaction between CDCA5 and CDC2 or Cyclin B1 shown","Mechanism of PI3K/AKT activation by CDCA5 remains indirect","Single cancer type"]},{"year":2021,"claim":"Discovering SPOP-mediated ubiquitination and degradation of CDCA5 established the first direct post-translational regulatory mechanism for CDCA5 turnover and explained how prostate cancer SPOP mutations lead to CDCA5 accumulation.","evidence":"Reciprocal Co-IP, in vivo ubiquitination assays, degron mapping, and SPOP mutant epistasis experiments in prostate cancer cells","pmids":["34509929"],"confidence":"High","gaps":["Whether other E3 ligases also target CDCA5 is unknown","Structural basis of SPOP–CDCA5 degron recognition not determined"]},{"year":2022,"claim":"Identifying TPI1 as a CDCA5-stabilizing interactor and PDS5A as a functional mediator downstream of CDCA5 defined both an upstream stabilizer and a cohesion-linked effector axis.","evidence":"Co-IP with mass spectrometry for TPI1–CDCA5 interaction; shRNA knockdown-rescue with PDS5A overexpression in breast cancer cells","pmids":["35509067","35506437"],"confidence":"Medium","gaps":["Mechanism by which TPI1 blocks CDCA5 ubiquitination is unclear","Whether PDS5A interaction is direct or indirect not resolved","Relationship between TPI1 stabilization and SPOP degradation not tested"]},{"year":2023,"claim":"Demonstrating that KLF5 directly binds the CDCA5 promoter established a second transcriptional activator, revealing convergent regulation by both E2F1 and KLF5.","evidence":"ChIP and promoter binding assay with overexpression rescue in ovarian cancer cells","pmids":["37247719"],"confidence":"Medium","gaps":["Whether E2F1 and KLF5 act cooperatively or redundantly on the CDCA5 promoter is unknown","Relative contribution of each factor in different tissues not addressed"]},{"year":2024,"claim":"Showing that CDCA5 promotes E2F1 binding to the FOXM1 promoter revealed a transcriptional co-activator function and linked CDCA5 to Wnt/β-catenin signaling downstream of FOXM1.","evidence":"ChIP, dual-luciferase assay, Co-IP, and FOXM1 knockdown rescue in breast cancer cells and xenograft models","pmids":["38978058"],"confidence":"Medium","gaps":["How CDCA5 facilitates E2F1 chromatin occupancy mechanistically is unknown","Whether this co-activator role extends beyond the FOXM1 promoter is untested"]},{"year":2024,"claim":"Identifying the CDCA5–EEF1A1 interaction and its regulation of mTOR signaling linked CDCA5 to translational control machinery.","evidence":"Co-IP with LC-MS/MS identification, knockdown/overexpression with mTOR pathway readouts in renal cell carcinoma, xenograft validation","pmids":["38658931"],"confidence":"Medium","gaps":["Whether EEF1A1 interaction is direct or scaffolded is unknown","Mechanism by which this interaction activates mTOR not determined"]},{"year":2025,"claim":"Demonstrating that CDC40-dependent splicing of CDCA5 intron 1 is required for CDCA5 protein production identified a post-transcriptional regulatory layer controlling CDCA5 levels.","evidence":"Global splicing analysis, RT-PCR for intron retention, CDC40 Co-IP with spliceosome components, knockdown with cell cycle readouts","pmids":["39747150"],"confidence":"Medium","gaps":["Whether intron 1 retention is a regulatory mechanism exploited physiologically is unknown","Other splicing factors contributing to CDCA5 processing not identified"]},{"year":null,"claim":"The mechanism by which CDCA5 activates PI3K/AKT/mTOR and ERK signaling remains undefined at the biochemical level — whether CDCA5 acts as a scaffold, a direct kinase activator, or through an indirect cohesion-dependent mechanism is unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted biochemical activity for CDCA5 in signaling pathway activation","Structural basis of CDCA5 interactions with any partner not resolved","Physiological role of CDCA5 in non-cancer (normal cell cycle) cohesion versus signaling functions not delineated in this literature"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,3,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,6,12]}],"complexes":[],"partners":["SPOP","TPI1","PDS5A","EEF1A1","E2F1","CCNA2","CDC40"],"other_free_text":[]},"mechanistic_narrative":"CDCA5 (sororin) is a cell cycle-regulated cohesin accessory protein that promotes cell proliferation through sister chromatid cohesion and activation of multiple mitogenic signaling pathways. Its transcription is directly driven by E2F1 and KLF5, while its protein stability is controlled by SPOP-mediated polyubiquitination and proteasomal degradation, with TPI1 acting as a stabilizer [PMID:31205541, PMID:34509929, PMID:37247719, PMID:35509067]. CDCA5 functionally interacts with PDS5A to regulate cohesion-associated processes, with EEF1A1 to activate mTOR signaling, and promotes E2F1 occupancy at the FOXM1 promoter to drive transcription through the Wnt/β-catenin axis [PMID:35506437, PMID:38658931, PMID:38978058]. Proper splicing of CDCA5 pre-mRNA depends on the spliceosome component CDC40, whose depletion causes intron 1 retention and loss of CDCA5 protein [PMID:39747150]."},"prefetch_data":{"uniprot":{"accession":"Q96FF9","full_name":"Sororin","aliases":["Cell division cycle-associated protein 5","p35"],"length_aa":252,"mass_kda":27.6,"function":"Regulator of sister chromatid cohesion in mitosis stabilizing cohesin complex association with chromatin. May antagonize the action of WAPL which stimulates cohesin dissociation from chromatin. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair. Required for efficient DNA double-stranded break repair","subcellular_location":"Nucleus; Chromosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96FF9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CDCA5","classification":"Common Essential","n_dependent_lines":1128,"n_total_lines":1208,"dependency_fraction":0.9337748344370861},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"STAG1","stoichiometry":10.0},{"gene":"STAG2","stoichiometry":4.0},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"SMC1A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CDCA5","total_profiled":1310},"omim":[{"mim_id":"618536","title":"CACTIN, SPLICEOSOME C COMPLEX SUBUNIT; CACTIN","url":"https://www.omim.org/entry/618536"},{"mim_id":"610754","title":"WAPL COHESIN RELEASE FACTOR; WAPL","url":"https://www.omim.org/entry/610754"},{"mim_id":"609374","title":"CELL DIVISION CYCLE-ASSOCIATED PROTEIN 5; CDCA5","url":"https://www.omim.org/entry/609374"},{"mim_id":"601644","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B (B56), BETA; PPP2R5B","url":"https://www.omim.org/entry/601644"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":50.4},{"tissue":"lymphoid tissue","ntpm":25.7},{"tissue":"testis","ntpm":37.1}],"url":"https://www.proteinatlas.org/search/CDCA5"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96FF9","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FF9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FF9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FF9-F1-predicted_aligned_error_v6.png","plddt_mean":62.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDCA5","jax_strain_url":"https://www.jax.org/strain/search?query=CDCA5"},"sequence":{"accession":"Q96FF9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96FF9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96FF9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FF9"}},"corpus_meta":[{"pmid":"29467944","id":"PMC_29467944","title":"Distinct expression of CDCA3, CDCA5, and CDCA8 leads to shorter relapse free survival in breast cancer patient.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29467944","citation_count":76,"is_preprint":false},{"pmid":"35509067","id":"PMC_35509067","title":"TPI1 activates the PI3K/AKT/mTOR signaling pathway to induce breast cancer progression by stabilizing CDCA5.","date":"2022","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35509067","citation_count":51,"is_preprint":false},{"pmid":"31205541","id":"PMC_31205541","title":"CDCA5, Transcribed by E2F1, Promotes Oncogenesis by Enhancing Cell Proliferation and Inhibiting Apoptosis via the AKT Pathway in Hepatocellular Carcinoma.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31205541","citation_count":50,"is_preprint":false},{"pmid":"29326043","id":"PMC_29326043","title":"Upregulation of CDCA5 promotes gastric cancer malignant progression via influencing cyclin E1.","date":"2018","source":"Biochemical and biophysical research 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CDCA5.","date":"2021","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/33770322","citation_count":10,"is_preprint":false},{"pmid":"38978058","id":"PMC_38978058","title":"CDCA5 accelerates progression of breast cancer by promoting the binding of E2F1 and FOXM1.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38978058","citation_count":7,"is_preprint":false},{"pmid":"35993042","id":"PMC_35993042","title":"lncRNA MIR4435-2HG Accelerates the Development of Bladder Cancer through Enhancing IQGAP3 and CDCA5 Expression.","date":"2022","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/35993042","citation_count":7,"is_preprint":false},{"pmid":"34077004","id":"PMC_34077004","title":"CDCA5 is negatively regulated by miR-326 and boosts ovarian cancer progression.","date":"2021","source":"Journal of B.U.ON. : official journal of the Balkan Union of 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oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41026320","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15917,"output_tokens":3088,"usd":0.047036},"stage2":{"model":"claude-opus-4-6","input_tokens":6480,"output_tokens":2330,"usd":0.135975},"total_usd":0.183011,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"CDCA5 transcription is directly driven by E2F1, as shown by luciferase reporter assay and chromatin immunoprecipitation (ChIP) in hepatocellular carcinoma cells; CDCA5 promotes cell proliferation and inhibits apoptosis via the AKT pathway.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), knockdown with proliferation/apoptosis readouts\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal methods (ChIP + luciferase) in a single lab; moderate evidence for E2F1 transcriptional regulation and AKT pathway involvement\",\n      \"pmids\": [\"31205541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SPOP (E3 ubiquitin ligase adaptor) directly interacts with CDCA5 and promotes its polyubiquitination and proteasomal degradation in a degron-dependent manner; prostate cancer-associated SPOP mutations impair this degradation, leading to CDCA5 accumulation, G2/M arrest rescue, and AKT pathway activation.\",\n      \"method\": \"Co-IP, ubiquitination assay, SPOP mutant rescue experiments, knockdown/overexpression with cell cycle and apoptosis readouts\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assay, degron-dependence, and genetic epistasis (SPOP mutants) in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"34509929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TPI1 (triosephosphate isomerase 1) interacts with CDCA5 (identified by Co-IP and mass spectrometry) and stabilizes CDCA5 protein, which in turn activates the PI3K/AKT/mTOR pathway to promote breast cancer proliferation and metastasis.\",\n      \"method\": \"Co-IP, mass spectrometric analysis, immunofluorescence, ubiquitination assay, overexpression/knockdown with PI3K/AKT/mTOR pathway readouts\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with MS identification and functional validation in a single lab with multiple methods\",\n      \"pmids\": [\"35509067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDCA5 knockdown in breast cancer cells suppresses proliferation and migration, and this effect is rescued by overexpression of PDS5A (PDS5 cohesin-associated factor A), placing CDCA5 upstream of PDS5A in controlling breast cancer cell behavior.\",\n      \"method\": \"shRNA knockdown, rescue overexpression of PDS5A, cell proliferation and migration assays, western blot\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by knockdown-rescue experiment in a single lab\",\n      \"pmids\": [\"35506437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDCA5 promotes breast cancer progression by facilitating the binding of E2F1 to the FOXM1 promoter; CDCA5 knockdown reduces E2F1–FOXM1 promoter occupancy, and FOXM1 depletion reverses CDCA5 overexpression effects; the Wnt/β-catenin pathway is required downstream.\",\n      \"method\": \"Co-IP, ChIP, dual-luciferase reporter assay, FOXM1 knockdown rescue, in vitro and in vivo models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, luciferase, genetic rescue) in a single lab\",\n      \"pmids\": [\"38978058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The transcription factor KLF5 directly binds to a specific site in the CDCA5 promoter and activates CDCA5 expression; KLF5 overexpression rescues the antiproliferative effects of CDCA5 knockdown in epithelial ovarian cancer cells.\",\n      \"method\": \"ChIP, promoter binding assay, overexpression rescue experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional rescue in a single lab\",\n      \"pmids\": [\"37247719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDCA5 interacts with EEF1A1 (Eukaryotic Translation Elongation Factor 1 Alpha 1), identified by Co-IP and LC-MS/MS, and this interaction regulates the mTOR signaling pathway to promote clear cell renal cell carcinoma progression.\",\n      \"method\": \"Co-IP, LC-MS/MS, knockdown/overexpression with proliferation, migration, apoptosis, and sunitinib resistance readouts, in vivo xenograft\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with MS identification and functional validation in a single lab\",\n      \"pmids\": [\"38658931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDCA5 promotes ovarian cancer cell invasion and migration via activation of the TGF-β1/Smad2/3 signaling pathway, as evidenced by RNA sequencing showing ECM/TGF pathway enrichment and functional confirmation.\",\n      \"method\": \"RNA sequencing, functional invasion/migration assays, signaling pathway analysis with TGF-β1/Smad2/3 readouts, xenograft model\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement based on RNA-seq enrichment and functional assays but no direct binding/reconstitution evidence; single lab\",\n      \"pmids\": [\"38539247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDCA5 regulates PD-L1 expression through the ANXA/AKT signaling pathway in lung adenocarcinoma cells; combined suppression of CDCA5 and PD-L1 synergistically inhibits cell proliferation.\",\n      \"method\": \"Cell line experiments, western blot for pathway components, co-inhibition proliferation assays\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method approach for pathway placement without reconstitution or Co-IP\",\n      \"pmids\": [\"38838437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDCA5 interacts with Cyclin A2 (CCNA2) as identified by Co-IP; berberine treatment downregulates both CDCA5 and CCNA2, and overexpression of either reverses berberine's anti-tumor effects in NSCLC cells.\",\n      \"method\": \"Co-IP, overexpression rescue, RT-qPCR, western blot, xenograft model\",\n      \"journal\": \"Journal of natural medicines\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP without reciprocal validation or in vitro reconstitution\",\n      \"pmids\": [\"40155519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDC40 knockdown causes intron retention in CDCA5 pre-mRNA (specifically retention of intron 1), leading to decreased CDCA5 protein levels; CDC40 functions as a spliceosome component whose binding partners include spliceosome proteins, positioning it as a regulator of CDCA5 splicing.\",\n      \"method\": \"Global transcriptional and splicing analysis, RT-PCR for intron retention, Co-IP of CDC40 spliceosome interactions, knockdown with cell cycle and apoptosis readouts\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular mechanism (intron retention) established with splicing assays and protein interaction data in a single lab\",\n      \"pmids\": [\"39747150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDCA5 knockdown in gastric cancer cells induces G1-phase cell cycle arrest accompanied by downregulation of Cyclin E1 (CCNE1), placing CDCA5 upstream of CCNE1 in cell cycle progression.\",\n      \"method\": \"siRNA knockdown, flow cytometry cell cycle analysis, western blot for CCNE1\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, knockdown with cell cycle phenotype; no direct binding or reconstitution\",\n      \"pmids\": [\"29326043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDCA5 promotes bladder cancer cell proliferation by upregulating CDC2 (CDK1) and Cyclin B1, activating the PI3K/AKT/mTOR pathway, and regulating the mitochondrial apoptosis pathway; knockdown reduces CDC2/Cyclin B1 levels and induces apoptosis.\",\n      \"method\": \"siRNA knockdown, overexpression, western blot for cell cycle and pathway proteins, flow cytometry apoptosis assay\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, knockdown/OE with pathway readouts but no direct binding or reconstitution\",\n      \"pmids\": [\"32201512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDCA5 knockdown in prostate cancer cells reduces ERK phosphorylation, placing CDCA5 upstream of ERK signaling in PCa proliferation control.\",\n      \"method\": \"shRNA knockdown, western blot for p-ERK, proliferation/colony assays, xenograft model\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method for pathway placement (western blot for p-ERK after knockdown)\",\n      \"pmids\": [\"33650660\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDCA5 (sororin) is a cell cycle-associated protein whose transcription is activated by E2F1 and KLF5; its protein stability is regulated by SPOP-mediated polyubiquitination and proteasomal degradation (antagonized by TPI1-mediated stabilization); CDCA5 interacts with PDS5A to regulate sister chromatid cohesion, with EEF1A1 to regulate mTOR signaling, and with Cyclin A2; its splicing is controlled by the spliceosome component CDC40; downstream, CDCA5 promotes cancer cell proliferation and survival through the PI3K/AKT/mTOR pathway, ERK signaling, and modulation of cell cycle regulators including CDC2/Cyclin B1 and Cyclin E1, and facilitates transcriptional regulation by promoting E2F1 binding to the FOXM1 promoter.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDCA5 (sororin) is a cell cycle-regulated cohesin accessory protein that promotes cell proliferation through sister chromatid cohesion and activation of multiple mitogenic signaling pathways. Its transcription is directly driven by E2F1 and KLF5, while its protein stability is controlled by SPOP-mediated polyubiquitination and proteasomal degradation, with TPI1 acting as a stabilizer [PMID:31205541, PMID:34509929, PMID:37247719, PMID:35509067]. CDCA5 functionally interacts with PDS5A to regulate cohesion-associated processes, with EEF1A1 to activate mTOR signaling, and promotes E2F1 occupancy at the FOXM1 promoter to drive transcription through the Wnt/β-catenin axis [PMID:35506437, PMID:38658931, PMID:38978058]. Proper splicing of CDCA5 pre-mRNA depends on the spliceosome component CDC40, whose depletion causes intron 1 retention and loss of CDCA5 protein [PMID:39747150].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing that CDCA5 functions upstream of G1/S cell cycle regulators showed it is not merely a cohesion factor but an active driver of cell cycle progression beyond its canonical mitotic role.\",\n      \"evidence\": \"siRNA knockdown in gastric cancer cells with flow cytometry showing G1 arrest and Cyclin E1 downregulation\",\n      \"pmids\": [\"29326043\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding between CDCA5 and Cyclin E1 demonstrated\", \"Single cell type tested\", \"Mechanism linking CDCA5 to Cyclin E1 expression unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying E2F1 as a direct transcriptional activator of CDCA5 connected its cell cycle-dependent expression to a known G1/S transcription factor and linked CDCA5 function to AKT signaling.\",\n      \"evidence\": \"ChIP and luciferase reporter assay in hepatocellular carcinoma cells plus knockdown with AKT pathway readouts\",\n      \"pmids\": [\"31205541\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether E2F1 is the predominant transcriptional driver in non-cancer contexts is unknown\", \"Mechanism connecting CDCA5 to AKT activation not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that CDCA5 upregulates CDC2/Cyclin B1 and activates PI3K/AKT/mTOR signaling broadened its downstream effector network beyond G1/S to G2/M regulators.\",\n      \"evidence\": \"siRNA knockdown and overexpression in bladder cancer cells with western blot for cell cycle proteins and PI3K/AKT/mTOR pathway components\",\n      \"pmids\": [\"32201512\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct interaction between CDCA5 and CDC2 or Cyclin B1 shown\", \"Mechanism of PI3K/AKT activation by CDCA5 remains indirect\", \"Single cancer type\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovering SPOP-mediated ubiquitination and degradation of CDCA5 established the first direct post-translational regulatory mechanism for CDCA5 turnover and explained how prostate cancer SPOP mutations lead to CDCA5 accumulation.\",\n      \"evidence\": \"Reciprocal Co-IP, in vivo ubiquitination assays, degron mapping, and SPOP mutant epistasis experiments in prostate cancer cells\",\n      \"pmids\": [\"34509929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other E3 ligases also target CDCA5 is unknown\", \"Structural basis of SPOP–CDCA5 degron recognition not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying TPI1 as a CDCA5-stabilizing interactor and PDS5A as a functional mediator downstream of CDCA5 defined both an upstream stabilizer and a cohesion-linked effector axis.\",\n      \"evidence\": \"Co-IP with mass spectrometry for TPI1–CDCA5 interaction; shRNA knockdown-rescue with PDS5A overexpression in breast cancer cells\",\n      \"pmids\": [\"35509067\", \"35506437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TPI1 blocks CDCA5 ubiquitination is unclear\", \"Whether PDS5A interaction is direct or indirect not resolved\", \"Relationship between TPI1 stabilization and SPOP degradation not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that KLF5 directly binds the CDCA5 promoter established a second transcriptional activator, revealing convergent regulation by both E2F1 and KLF5.\",\n      \"evidence\": \"ChIP and promoter binding assay with overexpression rescue in ovarian cancer cells\",\n      \"pmids\": [\"37247719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether E2F1 and KLF5 act cooperatively or redundantly on the CDCA5 promoter is unknown\", \"Relative contribution of each factor in different tissues not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that CDCA5 promotes E2F1 binding to the FOXM1 promoter revealed a transcriptional co-activator function and linked CDCA5 to Wnt/β-catenin signaling downstream of FOXM1.\",\n      \"evidence\": \"ChIP, dual-luciferase assay, Co-IP, and FOXM1 knockdown rescue in breast cancer cells and xenograft models\",\n      \"pmids\": [\"38978058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CDCA5 facilitates E2F1 chromatin occupancy mechanistically is unknown\", \"Whether this co-activator role extends beyond the FOXM1 promoter is untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying the CDCA5–EEF1A1 interaction and its regulation of mTOR signaling linked CDCA5 to translational control machinery.\",\n      \"evidence\": \"Co-IP with LC-MS/MS identification, knockdown/overexpression with mTOR pathway readouts in renal cell carcinoma, xenograft validation\",\n      \"pmids\": [\"38658931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EEF1A1 interaction is direct or scaffolded is unknown\", \"Mechanism by which this interaction activates mTOR not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that CDC40-dependent splicing of CDCA5 intron 1 is required for CDCA5 protein production identified a post-transcriptional regulatory layer controlling CDCA5 levels.\",\n      \"evidence\": \"Global splicing analysis, RT-PCR for intron retention, CDC40 Co-IP with spliceosome components, knockdown with cell cycle readouts\",\n      \"pmids\": [\"39747150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether intron 1 retention is a regulatory mechanism exploited physiologically is unknown\", \"Other splicing factors contributing to CDCA5 processing not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which CDCA5 activates PI3K/AKT/mTOR and ERK signaling remains undefined at the biochemical level — whether CDCA5 acts as a scaffold, a direct kinase activator, or through an indirect cohesion-dependent mechanism is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstituted biochemical activity for CDCA5 in signaling pathway activation\", \"Structural basis of CDCA5 interactions with any partner not resolved\", \"Physiological role of CDCA5 in non-cancer (normal cell cycle) cohesion versus signaling functions not delineated in this literature\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 3, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 6, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SPOP\", \"TPI1\", \"PDS5A\", \"EEF1A1\", \"E2F1\", \"CCNA2\", \"CDC40\"],\n    \"other_free_text\": []\n  }\n}\n```"}