{"gene":"CCNB2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2009,"finding":"HMGA1 and HMGA2 proteins directly bind to the promoter of the CCNB2 gene (demonstrated by EMSA and ChIP) and transcriptionally upregulate CCNB2 promoter activity (demonstrated by luciferase reporter assay), contributing to cyclin B2 overexpression in pituitary adenomas.","method":"Electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), luciferase promoter activity assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — three orthogonal methods (EMSA, ChIP, luciferase assay) in a single focused study with direct promoter binding and functional readout","pmids":["19223528"],"is_preprint":false},{"year":2016,"finding":"ISL1 transcription factor activates CCNB2 expression in gastric cancer cells by directly binding to conserved binding sites on the CCNB2 promoter/enhancer, promoting G2/M cell cycle progression.","method":"Chromatin immunoprecipitation, promoter binding assay, ISL1 knockdown/overexpression with gene expression readout, flow cytometry cell cycle analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing direct binding plus knockdown/overexpression functional validation, single lab","pmids":["27183908"],"is_preprint":false},{"year":2019,"finding":"PBK (PDZ-binding kinase) transcriptionally regulates CCNB2 expression in glioblastoma cells; PBK-dependent upregulation of CCNB2 is critical for GBM tumorigenesis and radio-resistance.","method":"PBK inhibition/knockdown in vitro and in vivo with CCNB2 expression measurement, functional cell proliferation and radiation sensitivity assays","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with defined cellular phenotype and mechanistic pathway link (PBK→CCNB2), single lab","pmids":["31874375"],"is_preprint":false},{"year":2017,"finding":"KPNA2 knockdown downregulates CCNB2 and CDK1, induces G2/M cell cycle arrest, and inhibits hepatocellular carcinoma cell proliferation, placing KPNA2 upstream of CCNB2/CDK1 in HCC cell cycle regulation.","method":"RNA interference knockdown of KPNA2, RT-qPCR for CCNB2/CDK1 expression, flow cytometry cell cycle analysis, proliferation assay","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNAi knockdown with gene expression readout and cell cycle phenotype, single lab, two methods","pmids":["29435009"],"is_preprint":false},{"year":2021,"finding":"YTHDC2 (an m6A binding protein) positively regulates CCNB2 expression; overexpression of YTHDC2 increases CCNB2 protein levels and rescues G2/M cell cycle arrest and reproductive toxicity caused by manganese exposure in spermatogonia.","method":"YTHDC2 overexpression in spermatogonia with CCNB2 protein measurement, flow cytometry cell cycle analysis, in vivo mouse testis histomorphology","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain-of-function with defined molecular and cellular phenotype, in vivo validation, single lab","pmids":["34822792"],"is_preprint":false},{"year":2020,"finding":"miR-335-5p directly targets the 3'-UTR of CCNB2 mRNA (validated by dual-luciferase reporter assay), reducing CCNB2 expression and thereby inhibiting LUAD cell proliferation, migration, and invasion; CCNB2 overexpression rescues these phenotypes.","method":"Dual-luciferase reporter assay, CCNB2 silencing, miR-335-5p overexpression, rescue experiments, MTT/colony formation/Transwell/flow cytometry assays","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter for direct targeting, rescue experiments confirming specificity, single lab","pmids":["32636645"],"is_preprint":false},{"year":2020,"finding":"miR-205 directly targets CCNB2 mRNA (validated by luciferase reporter assay), and its overexpression reduces CCNB2 protein levels and inhibits thyroid cancer cell proliferation and migration; CCNB2 overexpression reverses these inhibitory effects.","method":"Luciferase reporter assay, qRT-PCR, Western blot, CCK-8 proliferation assay, Transwell migration assay, rescue experiment","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus rescue experiments, single lab, two orthogonal methods","pmids":["32194761"],"is_preprint":false},{"year":2022,"finding":"Knockdown of CCNB2 in breast cancer cell lines reduces cell migration, inhibits proliferation, blocks G2/M cell cycle transition, increases apoptosis, and reduces adherence and transmigration across endothelial cell lines, demonstrating a role for CCNB2 in lymphovascular invasion.","method":"CCNB2 mRNA knockdown, cell migration/proliferation/apoptosis assays, flow cytometry cell cycle analysis, endothelial cell adherence and transmigration assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal functional readouts, single lab","pmids":["35261781"],"is_preprint":false},{"year":2021,"finding":"CCNB2 knockdown inhibits gastric cancer and rhabdomyosarcoma cell growth, invasion, migration, and induces cell cycle arrest and apoptosis; CCNB2 overexpression promotes these phenotypes and activates the PI3K/AKT signaling pathway, with RHBDL2 overexpression able to counteract CCNB2-mediated EMT and PI3K/AKT activation.","method":"CCNB2 knockdown/overexpression, RNA sequencing pathway analysis, proliferation/invasion/migration assays, flow cytometry, Western blot for PI3K/AKT pathway components, rescue experiments with RHBDL2","journal":"Scientific reports / Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss- and gain-of-function with pathway identification by RNA-seq and rescue experiment, single labs","pmids":["39962178","34838000"],"is_preprint":false},{"year":2021,"finding":"CCNB2 induces a senescence-associated secretory phenotype (SASP) in glioma cells, driving malignant progression (invasion and excessive proliferation) through secretion of SASP cytokines including Cathepsin B and PGE2.","method":"Gene expression profiling, CCNB2 functional assays in glioma cells with SASP cytokine measurement","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, phenotypic assay with cytokine measurement but limited mechanistic detail in abstract","pmids":["34512164"],"is_preprint":false},{"year":2025,"finding":"In porcine embryogenesis, CCNB2 is regulated by the sperm-derived circRNA-1572/bta-miR-2478-L-2 axis; knockdown of circRNA-1572 or overexpression of bta-miR-2478-L-2 reduces CCNB2 mRNA and protein levels, causing aberrant chromosomal organization and impaired zygotic genome activation, which is rescued by CCNB2 mRNA supplementation.","method":"circRNA knockdown, miRNA overexpression, CCNB2 mRNA supplementation rescue, whole-transcriptome sequencing, SMART-seq, Western blot, immunofluorescence for F-actin and chromosomes","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment with CCNB2 mRNA supplementation and multiple orthogonal readouts, single lab, porcine model","pmids":["40091686"],"is_preprint":false}],"current_model":"CCNB2 (Cyclin B2) is a cell cycle regulator whose expression is transcriptionally controlled by upstream factors including HMGA1/2 (via direct promoter binding), ISL1, and PBK; its mRNA is post-transcriptionally repressed by miR-335-5p and miR-205 targeting its 3'-UTR; YTHDC2-mediated m6A reading positively regulates CCNB2 levels; loss of CCNB2 consistently blocks G2/M cell cycle transition, reduces proliferation and migration, and induces apoptosis across multiple cancer cell types; in gastric cancer CCNB2 activates the PI3K/AKT signaling pathway and promotes EMT; in glioma it induces a SASP driving malignant progression through Cathepsin B and PGE2 secretion; and in early mammalian embryogenesis CCNB2 is required for proper chromosomal organization and zygotic genome activation downstream of sperm-derived circRNA signaling."},"narrative":{"mechanistic_narrative":"CCNB2 (Cyclin B2) is a cell cycle regulator required for the G2/M transition, whose loss across diverse cancer cell types blocks G2/M progression, suppresses proliferation and migration, and induces apoptosis [PMID:35261781, PMID:39962178, PMID:34838000]. Its expression is set by multiple upstream inputs: direct transcriptional activation through promoter binding by HMGA1/HMGA2 [PMID:19223528] and ISL1 [PMID:27183908], regulation by the kinase PBK [PMID:31874375] and the importin KPNA2 acting upstream of a CCNB2/CDK1 module [PMID:29435009], positive control by the m6A reader YTHDC2 at the protein level [PMID:34822792], and post-transcriptional repression via direct 3'-UTR targeting by miR-335-5p [PMID:32636645] and miR-205 [PMID:32194761]. Beyond canonical cell cycle control, CCNB2 promotes malignant behavior in gastric cancer by activating PI3K/AKT signaling and driving EMT, an axis counteracted by RHBDL2 [PMID:39962178, PMID:34838000]. In early mammalian embryogenesis CCNB2 is required for proper chromosomal organization and zygotic genome activation, acting downstream of a sperm-derived circRNA-1572/miRNA axis [PMID:40091686]. The biochemical activity of the Cyclin B2 protein itself, including its partner kinase and substrate engagement, is not characterized in the available corpus.","teleology":[{"year":2009,"claim":"Established a direct transcriptional mechanism for CCNB2 overexpression by showing HMGA1/HMGA2 bind its promoter and drive its activity, linking architectural transcription factors to cyclin B2 dysregulation.","evidence":"EMSA, ChIP, and luciferase promoter assays in pituitary adenoma context","pmids":["19223528"],"confidence":"High","gaps":["Does not address whether CCNB2 protein activity or stability is altered downstream","Promoter regulation shown in one tumor type only"]},{"year":2016,"claim":"Identified ISL1 as a second direct transcriptional activator of CCNB2, connecting its expression to G2/M progression in gastric cancer.","evidence":"ChIP and promoter binding with ISL1 knockdown/overexpression and flow cytometry cell cycle analysis","pmids":["27183908"],"confidence":"Medium","gaps":["Single lab","Does not establish whether ISL1 and HMGA inputs converge or act independently"]},{"year":2017,"claim":"Placed KPNA2 upstream of a CCNB2/CDK1 module in hepatocellular carcinoma, broadening the set of regulators controlling CCNB2-driven G2/M transit.","evidence":"KPNA2 RNAi knockdown with RT-qPCR and flow cytometry cell cycle analysis","pmids":["29435009"],"confidence":"Medium","gaps":["Mechanism by which KPNA2 controls CCNB2 transcript levels unresolved","Correlative expression rather than direct binding"]},{"year":2019,"claim":"Linked the kinase PBK to CCNB2 expression in glioblastoma, tying CCNB2 levels to tumorigenesis and radio-resistance.","evidence":"PBK knockdown/inhibition in vitro and in vivo with CCNB2 measurement and radiation sensitivity assays","pmids":["31874375"],"confidence":"Medium","gaps":["Whether regulation is direct or indirect not defined","No structural or biochemical link between PBK and the CCNB2 promoter"]},{"year":2020,"claim":"Demonstrated post-transcriptional repression of CCNB2 by direct 3'-UTR targeting from miR-335-5p and miR-205, with rescue confirming CCNB2 as the functional effector controlling proliferation and migration.","evidence":"Dual-luciferase reporter assays plus miRNA overexpression and CCNB2 rescue in lung adenocarcinoma and thyroid cancer cells","pmids":["32636645","32194761"],"confidence":"Medium","gaps":["Single lab per study","Relative contribution of each miRNA in vivo not established"]},{"year":2021,"claim":"Added an m6A-dependent layer of positive regulation, showing the reader YTHDC2 raises CCNB2 protein to relieve G2/M arrest and reproductive toxicity in spermatogonia.","evidence":"YTHDC2 overexpression with CCNB2 protein measurement, flow cytometry, and mouse testis histology","pmids":["34822792"],"confidence":"Medium","gaps":["Direct m6A modification of CCNB2 transcript not mapped","Single lab"]},{"year":2021,"claim":"Defined CCNB2 as a driver of malignant phenotypes beyond cell cycle control, activating PI3K/AKT signaling and EMT in gastric cancer and rhabdomyosarcoma, with RHBDL2 acting as an antagonist.","evidence":"CCNB2 knockdown/overexpression with RNA-seq pathway analysis, functional assays, and RHBDL2 rescue","pmids":["39962178","34838000"],"confidence":"Medium","gaps":["Mechanism linking cyclin B2 to PI3K/AKT activation undefined","Single labs"]},{"year":2022,"claim":"Consolidated the core CCNB2 loss-of-function phenotype across cancer, showing knockdown blocks G2/M, reduces proliferation/migration, increases apoptosis, and impairs endothelial transmigration relevant to lymphovascular invasion.","evidence":"CCNB2 knockdown with proliferation, apoptosis, cell cycle, and endothelial adherence/transmigration assays in breast cancer cells","pmids":["35261781"],"confidence":"Medium","gaps":["Molecular basis of the transmigration phenotype not resolved","Single lab"]},{"year":2021,"claim":"Proposed a non-canonical CCNB2 role in inducing a senescence-associated secretory phenotype that drives glioma progression via Cathepsin B and PGE2.","evidence":"Gene expression profiling and CCNB2 functional assays with SASP cytokine measurement in glioma cells","pmids":["34512164"],"confidence":"Low","gaps":["Limited mechanistic detail; how CCNB2 triggers SASP is unestablished","Single lab, not independently confirmed"]},{"year":2025,"claim":"Extended CCNB2 function to early embryogenesis, showing it acts downstream of a sperm-derived circRNA/miRNA axis and is required for chromosomal organization and zygotic genome activation, with mRNA supplementation rescuing the defects.","evidence":"circRNA knockdown, miRNA overexpression, CCNB2 mRNA rescue, transcriptome sequencing, and immunofluorescence in porcine embryos","pmids":["40091686"],"confidence":"Medium","gaps":["Mechanism by which CCNB2 controls chromosomal organization not defined","Single lab, porcine model"]},{"year":null,"claim":"The intrinsic biochemical activity of the Cyclin B2 protein—its kinase partner, substrate engagement, and how its abundance is translated into G2/M control—remains uncharacterized in this corpus.","evidence":"No discovery directly assays cyclin B2 enzymatic partnership or substrate phosphorylation","pmids":[],"confidence":"Low","gaps":["No structural model","No direct CDK partner or substrate assay","Mechanistic basis of G2/M control inferred from expression phenotypes only"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,3,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,5,6,8]}],"complexes":[],"partners":["CDK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95067","full_name":"G2/mitotic-specific cyclin-B2","aliases":[],"length_aa":398,"mass_kda":45.3,"function":"Essential for the control of the cell cycle at the G2/M (mitosis) transition","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O95067/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNB2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCNB2","total_profiled":1310},"omim":[{"mim_id":"602755","title":"CYCLIN B2; CCNB2","url":"https://www.omim.org/entry/602755"},{"mim_id":"601728","title":"PHOSPHATASE AND TENSIN HOMOLOG; PTEN","url":"https://www.omim.org/entry/601728"},{"mim_id":"601648","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 4; PSMD4","url":"https://www.omim.org/entry/601648"},{"mim_id":"123836","title":"CYCLIN B1; CCNB1","url":"https://www.omim.org/entry/123836"},{"mim_id":"123835","title":"CYCLIN A2; CCNA2","url":"https://www.omim.org/entry/123835"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":70.4},{"tissue":"lymphoid tissue","ntpm":68.1},{"tissue":"testis","ntpm":64.9}],"url":"https://www.proteinatlas.org/search/CCNB2"},"hgnc":{"alias_symbol":["HsT17299"],"prev_symbol":[]},"alphafold":{"accession":"O95067","domains":[{"cath_id":"1.10.472.10","chopping":"164-258","consensus_level":"high","plddt":97.8088,"start":164,"end":258},{"cath_id":"1.10.472.10","chopping":"267-393","consensus_level":"high","plddt":96.7523,"start":267,"end":393}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95067","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95067-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95067-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCNB2","jax_strain_url":"https://www.jax.org/strain/search?query=CCNB2"},"sequence":{"accession":"O95067","fasta_url":"https://rest.uniprot.org/uniprotkb/O95067.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95067/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95067"}},"corpus_meta":[{"pmid":"19223528","id":"PMC_19223528","title":"HMGA 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docking","date":"2025-09-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.22.677916","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19057,"output_tokens":2764,"usd":0.049315,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10034,"output_tokens":3133,"usd":0.064247,"stage2_stop_reason":"end_turn"},"total_usd":0.113562,"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\": 2009,\n      \"finding\": \"HMGA1 and HMGA2 proteins directly bind to the promoter of the CCNB2 gene (demonstrated by EMSA and ChIP) and transcriptionally upregulate CCNB2 promoter activity (demonstrated by luciferase reporter assay), contributing to cyclin B2 overexpression in pituitary adenomas.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), luciferase promoter activity assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — three orthogonal methods (EMSA, ChIP, luciferase assay) in a single focused study with direct promoter binding and functional readout\",\n      \"pmids\": [\"19223528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ISL1 transcription factor activates CCNB2 expression in gastric cancer cells by directly binding to conserved binding sites on the CCNB2 promoter/enhancer, promoting G2/M cell cycle progression.\",\n      \"method\": \"Chromatin immunoprecipitation, promoter binding assay, ISL1 knockdown/overexpression with gene expression readout, flow cytometry cell cycle analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing direct binding plus knockdown/overexpression functional validation, single lab\",\n      \"pmids\": [\"27183908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PBK (PDZ-binding kinase) transcriptionally regulates CCNB2 expression in glioblastoma cells; PBK-dependent upregulation of CCNB2 is critical for GBM tumorigenesis and radio-resistance.\",\n      \"method\": \"PBK inhibition/knockdown in vitro and in vivo with CCNB2 expression measurement, functional cell proliferation and radiation sensitivity assays\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with defined cellular phenotype and mechanistic pathway link (PBK→CCNB2), single lab\",\n      \"pmids\": [\"31874375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KPNA2 knockdown downregulates CCNB2 and CDK1, induces G2/M cell cycle arrest, and inhibits hepatocellular carcinoma cell proliferation, placing KPNA2 upstream of CCNB2/CDK1 in HCC cell cycle regulation.\",\n      \"method\": \"RNA interference knockdown of KPNA2, RT-qPCR for CCNB2/CDK1 expression, flow cytometry cell cycle analysis, proliferation assay\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNAi knockdown with gene expression readout and cell cycle phenotype, single lab, two methods\",\n      \"pmids\": [\"29435009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC2 (an m6A binding protein) positively regulates CCNB2 expression; overexpression of YTHDC2 increases CCNB2 protein levels and rescues G2/M cell cycle arrest and reproductive toxicity caused by manganese exposure in spermatogonia.\",\n      \"method\": \"YTHDC2 overexpression in spermatogonia with CCNB2 protein measurement, flow cytometry cell cycle analysis, in vivo mouse testis histomorphology\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain-of-function with defined molecular and cellular phenotype, in vivo validation, single lab\",\n      \"pmids\": [\"34822792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-335-5p directly targets the 3'-UTR of CCNB2 mRNA (validated by dual-luciferase reporter assay), reducing CCNB2 expression and thereby inhibiting LUAD cell proliferation, migration, and invasion; CCNB2 overexpression rescues these phenotypes.\",\n      \"method\": \"Dual-luciferase reporter assay, CCNB2 silencing, miR-335-5p overexpression, rescue experiments, MTT/colony formation/Transwell/flow cytometry assays\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter for direct targeting, rescue experiments confirming specificity, single lab\",\n      \"pmids\": [\"32636645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-205 directly targets CCNB2 mRNA (validated by luciferase reporter assay), and its overexpression reduces CCNB2 protein levels and inhibits thyroid cancer cell proliferation and migration; CCNB2 overexpression reverses these inhibitory effects.\",\n      \"method\": \"Luciferase reporter assay, qRT-PCR, Western blot, CCK-8 proliferation assay, Transwell migration assay, rescue experiment\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus rescue experiments, single lab, two orthogonal methods\",\n      \"pmids\": [\"32194761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of CCNB2 in breast cancer cell lines reduces cell migration, inhibits proliferation, blocks G2/M cell cycle transition, increases apoptosis, and reduces adherence and transmigration across endothelial cell lines, demonstrating a role for CCNB2 in lymphovascular invasion.\",\n      \"method\": \"CCNB2 mRNA knockdown, cell migration/proliferation/apoptosis assays, flow cytometry cell cycle analysis, endothelial cell adherence and transmigration assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal functional readouts, single lab\",\n      \"pmids\": [\"35261781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCNB2 knockdown inhibits gastric cancer and rhabdomyosarcoma cell growth, invasion, migration, and induces cell cycle arrest and apoptosis; CCNB2 overexpression promotes these phenotypes and activates the PI3K/AKT signaling pathway, with RHBDL2 overexpression able to counteract CCNB2-mediated EMT and PI3K/AKT activation.\",\n      \"method\": \"CCNB2 knockdown/overexpression, RNA sequencing pathway analysis, proliferation/invasion/migration assays, flow cytometry, Western blot for PI3K/AKT pathway components, rescue experiments with RHBDL2\",\n      \"journal\": \"Scientific reports / Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss- and gain-of-function with pathway identification by RNA-seq and rescue experiment, single labs\",\n      \"pmids\": [\"39962178\", \"34838000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCNB2 induces a senescence-associated secretory phenotype (SASP) in glioma cells, driving malignant progression (invasion and excessive proliferation) through secretion of SASP cytokines including Cathepsin B and PGE2.\",\n      \"method\": \"Gene expression profiling, CCNB2 functional assays in glioma cells with SASP cytokine measurement\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, phenotypic assay with cytokine measurement but limited mechanistic detail in abstract\",\n      \"pmids\": [\"34512164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In porcine embryogenesis, CCNB2 is regulated by the sperm-derived circRNA-1572/bta-miR-2478-L-2 axis; knockdown of circRNA-1572 or overexpression of bta-miR-2478-L-2 reduces CCNB2 mRNA and protein levels, causing aberrant chromosomal organization and impaired zygotic genome activation, which is rescued by CCNB2 mRNA supplementation.\",\n      \"method\": \"circRNA knockdown, miRNA overexpression, CCNB2 mRNA supplementation rescue, whole-transcriptome sequencing, SMART-seq, Western blot, immunofluorescence for F-actin and chromosomes\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment with CCNB2 mRNA supplementation and multiple orthogonal readouts, single lab, porcine model\",\n      \"pmids\": [\"40091686\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCNB2 (Cyclin B2) is a cell cycle regulator whose expression is transcriptionally controlled by upstream factors including HMGA1/2 (via direct promoter binding), ISL1, and PBK; its mRNA is post-transcriptionally repressed by miR-335-5p and miR-205 targeting its 3'-UTR; YTHDC2-mediated m6A reading positively regulates CCNB2 levels; loss of CCNB2 consistently blocks G2/M cell cycle transition, reduces proliferation and migration, and induces apoptosis across multiple cancer cell types; in gastric cancer CCNB2 activates the PI3K/AKT signaling pathway and promotes EMT; in glioma it induces a SASP driving malignant progression through Cathepsin B and PGE2 secretion; and in early mammalian embryogenesis CCNB2 is required for proper chromosomal organization and zygotic genome activation downstream of sperm-derived circRNA signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCNB2 (Cyclin B2) is a cell cycle regulator required for the G2/M transition, whose loss across diverse cancer cell types blocks G2/M progression, suppresses proliferation and migration, and induces apoptosis [#7, #8]. Its expression is set by multiple upstream inputs: direct transcriptional activation through promoter binding by HMGA1/HMGA2 [#0] and ISL1 [#1], regulation by the kinase PBK [#2] and the importin KPNA2 acting upstream of a CCNB2/CDK1 module [#3], positive control by the m6A reader YTHDC2 at the protein level [#4], and post-transcriptional repression via direct 3'-UTR targeting by miR-335-5p [#5] and miR-205 [#6]. Beyond canonical cell cycle control, CCNB2 promotes malignant behavior in gastric cancer by activating PI3K/AKT signaling and driving EMT, an axis counteracted by RHBDL2 [#8]. In early mammalian embryogenesis CCNB2 is required for proper chromosomal organization and zygotic genome activation, acting downstream of a sperm-derived circRNA-1572/miRNA axis [#10]. The biochemical activity of the Cyclin B2 protein itself, including its partner kinase and substrate engagement, is not characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established a direct transcriptional mechanism for CCNB2 overexpression by showing HMGA1/HMGA2 bind its promoter and drive its activity, linking architectural transcription factors to cyclin B2 dysregulation.\",\n      \"evidence\": \"EMSA, ChIP, and luciferase promoter assays in pituitary adenoma context\",\n      \"pmids\": [\"19223528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address whether CCNB2 protein activity or stability is altered downstream\", \"Promoter regulation shown in one tumor type only\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified ISL1 as a second direct transcriptional activator of CCNB2, connecting its expression to G2/M progression in gastric cancer.\",\n      \"evidence\": \"ChIP and promoter binding with ISL1 knockdown/overexpression and flow cytometry cell cycle analysis\",\n      \"pmids\": [\"27183908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Does not establish whether ISL1 and HMGA inputs converge or act independently\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed KPNA2 upstream of a CCNB2/CDK1 module in hepatocellular carcinoma, broadening the set of regulators controlling CCNB2-driven G2/M transit.\",\n      \"evidence\": \"KPNA2 RNAi knockdown with RT-qPCR and flow cytometry cell cycle analysis\",\n      \"pmids\": [\"29435009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which KPNA2 controls CCNB2 transcript levels unresolved\", \"Correlative expression rather than direct binding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked the kinase PBK to CCNB2 expression in glioblastoma, tying CCNB2 levels to tumorigenesis and radio-resistance.\",\n      \"evidence\": \"PBK knockdown/inhibition in vitro and in vivo with CCNB2 measurement and radiation sensitivity assays\",\n      \"pmids\": [\"31874375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether regulation is direct or indirect not defined\", \"No structural or biochemical link between PBK and the CCNB2 promoter\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated post-transcriptional repression of CCNB2 by direct 3'-UTR targeting from miR-335-5p and miR-205, with rescue confirming CCNB2 as the functional effector controlling proliferation and migration.\",\n      \"evidence\": \"Dual-luciferase reporter assays plus miRNA overexpression and CCNB2 rescue in lung adenocarcinoma and thyroid cancer cells\",\n      \"pmids\": [\"32636645\", \"32194761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab per study\", \"Relative contribution of each miRNA in vivo not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Added an m6A-dependent layer of positive regulation, showing the reader YTHDC2 raises CCNB2 protein to relieve G2/M arrest and reproductive toxicity in spermatogonia.\",\n      \"evidence\": \"YTHDC2 overexpression with CCNB2 protein measurement, flow cytometry, and mouse testis histology\",\n      \"pmids\": [\"34822792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct m6A modification of CCNB2 transcript not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined CCNB2 as a driver of malignant phenotypes beyond cell cycle control, activating PI3K/AKT signaling and EMT in gastric cancer and rhabdomyosarcoma, with RHBDL2 acting as an antagonist.\",\n      \"evidence\": \"CCNB2 knockdown/overexpression with RNA-seq pathway analysis, functional assays, and RHBDL2 rescue\",\n      \"pmids\": [\"39962178\", \"34838000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking cyclin B2 to PI3K/AKT activation undefined\", \"Single labs\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Consolidated the core CCNB2 loss-of-function phenotype across cancer, showing knockdown blocks G2/M, reduces proliferation/migration, increases apoptosis, and impairs endothelial transmigration relevant to lymphovascular invasion.\",\n      \"evidence\": \"CCNB2 knockdown with proliferation, apoptosis, cell cycle, and endothelial adherence/transmigration assays in breast cancer cells\",\n      \"pmids\": [\"35261781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the transmigration phenotype not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Proposed a non-canonical CCNB2 role in inducing a senescence-associated secretory phenotype that drives glioma progression via Cathepsin B and PGE2.\",\n      \"evidence\": \"Gene expression profiling and CCNB2 functional assays with SASP cytokine measurement in glioma cells\",\n      \"pmids\": [\"34512164\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic detail; how CCNB2 triggers SASP is unestablished\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended CCNB2 function to early embryogenesis, showing it acts downstream of a sperm-derived circRNA/miRNA axis and is required for chromosomal organization and zygotic genome activation, with mRNA supplementation rescuing the defects.\",\n      \"evidence\": \"circRNA knockdown, miRNA overexpression, CCNB2 mRNA rescue, transcriptome sequencing, and immunofluorescence in porcine embryos\",\n      \"pmids\": [\"40091686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CCNB2 controls chromosomal organization not defined\", \"Single lab, porcine model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic biochemical activity of the Cyclin B2 protein—its kinase partner, substrate engagement, and how its abundance is translated into G2/M control—remains uncharacterized in this corpus.\",\n      \"evidence\": \"No discovery directly assays cyclin B2 enzymatic partnership or substrate phosphorylation\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model\", \"No direct CDK partner or substrate assay\", \"Mechanistic basis of G2/M control inferred from expression phenotypes only\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 3, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 5, 6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CDK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}