{"gene":"CCNA2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2024,"finding":"CCNA2 binding to CDK2 phosphorylates the AXIN1 complex, which induces ubiquitination-dependent degradation of β-catenin and inhibits the WNT signaling pathway, thereby promoting AT2 cell differentiation into AT2-like cancer stem cells in lung adenocarcinoma.","method":"Co-immunoprecipitation, phosphorylation assay, western blot, single-cell sequencing analysis, CCNA2 inhibition experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab with multiple orthogonal methods (Co-IP, functional inhibition, single-cell analysis) but no full reconstitution or mutagenesis","pmids":["38704137"],"is_preprint":false},{"year":2019,"finding":"CCNA2 promotes trophoblast migration via the RhoA-ROCK signaling pathway, and promotes trophoblast proliferation while inhibiting apoptosis via the p53 pathway; CCNA2 knockdown impairs these functions in HTR8/SVneo cells.","method":"siRNA knockdown, overexpression, migration assay, proliferation assay, apoptosis assay, western blot in HTR8/SVneo cells and ex vivo villi explant culture","journal":"American journal of reproductive immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal functional assays with defined pathway readouts (RhoA-ROCK, p53)","pmids":["31087423"],"is_preprint":false},{"year":2018,"finding":"CCNA2 regulates cell cycle progression by promoting G1/S and G2/M transitions; knockdown of CCNA2 in colorectal cancer cells impairs cell cycle progression and induces apoptosis.","method":"siRNA knockdown, cell cycle analysis by flow cytometry, apoptosis assay, cell growth assay","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple assays (cell cycle, apoptosis, proliferation) with defined readouts","pmids":["30464611"],"is_preprint":false},{"year":2018,"finding":"CCNA2 functions in a non-canonical, non-cell-cycle role in mature hippocampal neurons: cyclin A2 colocalizes with dendritic rRNA, and its ablation results in decreased synaptic density and accumulation of rRNA granules in dendrite shafts, indicating a role in neuronal ribostasis.","method":"Conditional knockout mouse model, immunohistochemistry, electron microscopy, confocal colocalization with rRNA markers","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — well-defined KO model with multiple orthogonal histological and ultrastructural readouts establishing a non-cell-cycle function","pmids":["30579783"],"is_preprint":false},{"year":2019,"finding":"The p53/miRNAs/CCNA2 pathway regulates cellular senescence independently of the canonical p53/p21 pathway: p53-responsive miRNAs (miR-124, miR-29) target CCNA2, silencing of CCNA2 triggers senescence, and CCNA2 overexpression delays senescence and reverses miRNA-induced senescence even in p21-deficient cells.","method":"miRNA/mRNA microarray, luciferase reporter assay, senescence assays (SA-β-gal), overexpression and knockdown, p21-deficient cell experiments","journal":"Aging cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods across multiple cell contexts including genetic p21 deficiency, establishing epistatic independence from p53/p21","pmids":["30848072"],"is_preprint":false},{"year":2013,"finding":"MicroRNA-124 directly targets CCNA2, and decreased miR-124 leads to increased CCNA2 expression and increased S-phase fraction in Huntington's disease striatal cells; exogenous manipulation of either miR-124 or CCNA2 alters cell cycle distribution.","method":"qRT-PCR, cell cycle analysis (flow cytometry), miR-124 overexpression/inhibition, CCNA2 overexpression/knockdown, validated in HD mouse model (R6/2)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional experiments in cell and animal model, single lab","pmids":["23796713"],"is_preprint":false},{"year":2022,"finding":"E2F1 transcription factor directly binds the CCNA2 promoter at position +677 and transcriptionally activates CCNA2 expression; E2F1 knockdown reduces CCNA2 expression and decreases TNBC cell proliferation, invasion, and migration.","method":"Luciferase reporter assay, ChIP, rescue experiments, bioinformatics correlation analysis","journal":"Cancer biomarkers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter and rescue experiments in single lab establishing direct transcriptional regulation","pmids":["34366326"],"is_preprint":false},{"year":2021,"finding":"CREB1 directly binds the proximal promoter region of CCNA2 and transcriptionally activates it, promoting S-phase DNA synthesis and G2 cell division in bovine myoblasts.","method":"Dual luciferase reporter assay, promoter binding assay, CREB1 overexpression/knockdown, cell cycle analysis","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual luciferase and functional assays, single lab","pmids":["35777504"],"is_preprint":false},{"year":2021,"finding":"CDCA7 directly binds to the CCNA2 promoter and upregulates its expression in esophageal squamous cell carcinoma; knockdown of CCNA2 reverses the malignant proliferative phenotype induced by CDCA7 overexpression.","method":"ChIP assay, luciferase reporter assay, rescue experiment, western blot, cell proliferation and colony formation assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase establishing direct promoter binding, rescue experiments, single lab","pmids":["34737951"],"is_preprint":false},{"year":2021,"finding":"ROBO1 inhibits pancreatic cancer cell proliferation and S-phase progression via the CCNA2/CDK2 axis; YY1 directly binds the ROBO1 promoter to promote its transcription, establishing a YY1-ROBO1-CCNA2-CDK2 axis.","method":"Luciferase reporter assay, ChIP, EMSA, overexpression experiments in vitro and xenograft in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (luciferase, ChIP, EMSA, in vivo), single lab","pmids":["33714986"],"is_preprint":false},{"year":2021,"finding":"KDM4B histone demethylase is bound at the promoter regions of CCNA2 (and CDK6) and regulates their transcription to control cell cycle progression in rhabdomyosarcoma; sustained KDM4B knockdown leads to compensatory KDM4A recruitment to the same CCNA2 and CDK6 promoter regions.","method":"RNAi screening, ChIP showing KDM4B and KDM4A promoter occupancy at CCNA2, cell cycle analysis, rescue/recovery experiments","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based promoter occupancy with functional cell cycle readout, single lab","pmids":["33917420"],"is_preprint":false},{"year":2021,"finding":"PKMYT1 physically binds CCNA2 (shown by co-immunoprecipitation) and PKMYT1 knockdown reduces CCNA2 expression, inhibiting proliferation, migration, invasion, and EMT in oral squamous cell carcinoma cells.","method":"Co-immunoprecipitation, siRNA knockdown, western blot, proliferation/migration/invasion assays, wound healing assay","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus multiple functional assays in single lab","pmids":["35069872"],"is_preprint":false},{"year":2022,"finding":"6-Methoxyflavone induces S-phase arrest in HeLa cells via the CCNA2/CDK2/p21CIP1 signaling pathway; molecular docking showed that the combination of CDK2 and CCNA2 enhances compound binding affinity to CDK2.","method":"Cell cycle flow cytometry, western blot, qPCR, molecular docking, transcriptome sequencing","journal":"Bioengineered","confidence":"Low","confidence_rationale":"Tier 3 / Weak — molecular docking is computational; western blot of pathway proteins without mutagenesis, single lab","pmids":["35246013"],"is_preprint":false},{"year":2021,"finding":"Tanshinone IIA suppresses lung adenocarcinoma cell cycle progression by downregulating the CCNA2-CDK2 complex and AURKA/PLK1 pathway, inducing G1/S arrest and apoptosis.","method":"Western blot, flow cytometry (cell cycle and apoptosis), MTT/clonogenic assay, molecular docking","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — molecular docking plus western blot without reconstitution or mutagenesis; pathway placement inferred rather than proven by epistasis","pmids":["34880385"],"is_preprint":false},{"year":2018,"finding":"miR-381-3p directly targets the 3'UTR of CCNA2; inhibition of CCNA2 by miR-381-3p participates in proliferation regulation together with CDK6 and also modulates EMT progression via the ROCK/AKT/β-catenin/SNAIL pathway in bladder cancer.","method":"Dual-luciferase reporter assay, bioinformatics, siRNA knockdown, in vitro proliferation and migration assays, in vivo tumor models","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase validating direct 3'UTR targeting plus multiple functional assays and in vivo validation, single lab","pmids":["30138038"],"is_preprint":false},{"year":2016,"finding":"FXR-regulated miR-22 directly represses CCNA2 in hepatocellular carcinoma; WA induces miR-22 expression leading to CCNA2 repression and cell proliferation arrest; FXR knockdown or miR-22 silencing reverses CCNA2 repression and restores proliferation.","method":"FXR/miR-22/CCNA2 expression in clinical samples, miR-22 manipulation (overexpression/silencing), FXR knockdown, in vivo xenograft model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis established across three nodes (FXR-miR-22-CCNA2) with multiple methods including in vivo, single lab","pmids":["27738335"],"is_preprint":false},{"year":2025,"finding":"6PGD binds ALKBH5 and inhibits its m6A demethylase activity through a non-metabolic function, increasing m6A modification and stability of MDM2 mRNA, decreasing p53 protein stability, which subsequently activates CCNA2 expression and promotes colorectal cancer tumor growth and metastasis.","method":"Co-immunoprecipitation, m6A modification assay, mRNA stability assay, western blot, siRNA knockdown, in vitro and in vivo tumor models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods establishing upstream regulatory mechanism controlling CCNA2, single lab","pmids":["40611205"],"is_preprint":false},{"year":2025,"finding":"CDCA5 physically interacts with CCNA2 (shown by co-immunoprecipitation) and regulates its expression in NSCLC cells; berberine treatment reduces both CDCA5 and CCNA2 levels, and overexpression of either attenuates berberine's inhibitory effects on NSCLC.","method":"Co-immunoprecipitation, qRT-PCR, western blot, overexpression rescue assay, in vivo xenograft model","journal":"Journal of natural medicines","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP establishing CDCA5-CCNA2 interaction, single lab","pmids":["40155519"],"is_preprint":false},{"year":2026,"finding":"H3K18 lactylation at the CCNA2 locus drives its transcription in bladder cancer; circBARD1 promotes ENO1 ubiquitination and FBXW7-mediated degradation, which reduces intracellular lactate and H3K18 lactylation, thereby suppressing CCNA2 transcription.","method":"CUT&Tag, ChIP assay, RNA immunoprecipitation (RIP), Co-immunoprecipitation, ubiquitination assay, gain-of-function experiments","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag and ChIP directly measuring histone lactylation at CCNA2 locus combined with mechanistic upstream pathway dissection, single lab","pmids":["41854933"],"is_preprint":false},{"year":2022,"finding":"ADM overexpression inhibits miR-152, which normally directly targets and suppresses CCNA2; the ADM/miR-152/CCNA2 axis promotes cell cycle progression (increased G2/M phase) and reduces p53, p21WAF1, and p16INK4A in human dental pulp stem cells, conferring antisenescence effects.","method":"Luciferase reporter assay, transfection with miR-152 mimic/antagomir, western blot, flow cytometry (cell cycle), transcriptome analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase validating direct miR-152/CCNA2 targeting, rescue experiments, multiple functional assays, single lab","pmids":["36310381"],"is_preprint":false},{"year":2019,"finding":"miR-219a-5p upregulation in neuronal injury models inhibits CCNA2 and CACUL1 expression, activating akt/Foxo3a and p53/Bcl-2 signaling pathways and increasing cleaved caspase-3, thereby inducing neuronal apoptosis.","method":"TaqMan Low Density Array, RT-qPCR validation, neuronal cell injury model, western blot for signaling pathway proteins","journal":"Journal of neurochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — target validation by expression correlation in injury model without direct luciferase confirmation of CCNA2 3'UTR targeting reported in abstract, single lab","pmids":["31077370"],"is_preprint":false},{"year":2018,"finding":"Sevoflurane exposure upregulates miR-19-3p, which post-transcriptionally inhibits CCNA2 protein translation in neurons; intracranial injection of anti-miR-19-3p AAV reversed SEVO-induced impairment of neuron proliferation and learning/memory in neonatal rats.","method":"Luciferase reporter assay, western blot, AAV-mediated in vivo anti-miRNA injection, behavioral testing (Morris water maze, Plus-Maze)","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase validating post-transcriptional CCNA2 regulation plus in vivo rescue, single lab","pmids":["30540563"],"is_preprint":false},{"year":2025,"finding":"MEIOC downregulates CCNA2 protein expression during the mitosis-to-meiosis transition in mouse oogenesis, contributing to repression of the mitotic G1/S cyclin program prior to meiotic entry.","method":"Cell cycle transcriptomics, cell cycle-associated protein expression analysis, proliferation assays, MEIOC loss-of-function mouse model","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model with protein expression analysis and functional cell cycle readouts, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"GSK6853 (BRPF1 inhibitor) suppresses CCNA2 expression via inhibition of the JAK2/STAT3 signaling pathway, inducing G0/G1 cell cycle arrest and apoptosis in NSCLC cells.","method":"RNA sequencing, western blot validating JAK2/STAT3/CCNA2 protein levels, flow cytometry (cell cycle and apoptosis), CCK-8 and colony formation assays","journal":"Investigational new drugs","confidence":"Low","confidence_rationale":"Tier 3 / Weak — western blot showing pathway protein changes without epistatic rescue or mutagenesis, single lab","pmids":["41160097"],"is_preprint":false},{"year":2026,"finding":"MYC directly transcriptionally activates CCNA2 (and KPNA2) in melanoma; kojic acid does not alter MYC expression but impairs MYC promoter binding and transcriptional activation of CCNA2, reducing melanoma proliferation.","method":"Transcriptomic profiling, ChIP showing reduced MYC binding at CCNA2 promoter after kojic acid treatment, xenograft in vivo model, single-cell analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct MYC-CCNA2 promoter interaction plus in vivo functional validation, single lab","pmids":["41690656"],"is_preprint":false},{"year":2026,"finding":"CCNA2 expression in macrophages is upregulated by dimethyl phosphate and promotes a pro-inflammatory M1-like macrophage phenotype; CCNA2-expressing macrophage conditioned medium induces lipid accumulation in hepatocytes via paracrine signaling, and CCNA2 silencing attenuates both macrophage polarization and hepatocyte lipid accumulation.","method":"siRNA knockdown and re-expression in macrophages, conditioned medium transfer to hepatocytes, lipid accumulation assay, cytokine secretion assay, in vivo mouse model","journal":"Environmental pollution","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue/re-expression experiments establishing CCNA2 necessity in macrophage-hepatocyte crosstalk, multiple orthogonal readouts, single lab","pmids":["42235667"],"is_preprint":false}],"current_model":"CCNA2 (Cyclin A2) is a cell cycle regulator that activates CDK2 to drive G1/S and G2/M transitions; beyond canonical cell cycle control, CCNA2–CDK2 complexes phosphorylate substrates such as the AXIN1 complex to degrade β-catenin and inhibit WNT signaling, CCNA2 maintains neuronal ribostasis in post-mitotic hippocampal neurons by colocalizing with dendritic rRNA (its ablation causes rRNA granule accumulation and synaptic loss), and CCNA2 expression is transcriptionally regulated by E2F1, CREB1, CDCA7, MYC, and KDM4B/KDM4A at its promoter, while post-transcriptionally repressed by multiple miRNAs (miR-124, miR-29, miR-219-5p, miR-381-3p, miR-152, miR-19-3p) via 3'UTR targeting; CCNA2 also mediates cell migration through RhoA-ROCK signaling and modulates apoptosis through the p53 pathway."},"narrative":{"mechanistic_narrative":"CCNA2 (Cyclin A2) is a cell cycle regulator that activates CDK2 to drive G1/S and G2/M progression, and its loss in cancer cells impairs cell cycle transit and induces apoptosis [PMID:30464611]. The CCNA2–CDK2 complex executes both canonical proliferative functions and non-canonical signaling: it phosphorylates the AXIN1 complex to promote ubiquitination-dependent β-catenin degradation and WNT pathway inhibition during AT2 cell differentiation in lung adenocarcinoma [PMID:38704137], and the CCNA2/CDK2 axis is a downstream effector of ROBO1-mediated control of S-phase progression in pancreatic cancer [PMID:33714986]. Beyond proliferation, CCNA2 sets cellular lifespan: p53-responsive miRNAs (miR-124, miR-29) repress CCNA2, its silencing triggers senescence, and CCNA2 overexpression delays senescence even in p21-deficient cells, defining a p53/miRNA/CCNA2 axis that operates independently of canonical p53/p21 control [PMID:30848072]. CCNA2 also carries a non-cell-cycle role in mature hippocampal neurons, where it colocalizes with dendritic rRNA and is required for neuronal ribostasis—its ablation causes rRNA granule accumulation and synaptic loss [PMID:30579783]. CCNA2 transcription is directly activated by E2F1 [PMID:34366326], CREB1 [PMID:35777504], CDCA7 [PMID:34737951], and MYC [PMID:41690656] binding at its promoter, controlled by KDM4B/KDM4A histone demethylase occupancy [PMID:33917420] and H3K18 lactylation at its locus [PMID:41854933], and is post-transcriptionally repressed by multiple 3'UTR-targeting miRNAs including miR-381-3p, miR-22, and miR-152 [PMID:30138038, PMID:27738335, PMID:36310381]. CCNA2 additionally mediates trophoblast migration via RhoA-ROCK signaling [PMID:31087423] and drives pro-inflammatory M1 macrophage polarization that promotes hepatocyte lipid accumulation through paracrine signaling [PMID:42235667].","teleology":[{"year":2013,"claim":"Established that CCNA2 is a direct miRNA target whose derepression drives aberrant S-phase entry, linking its dosage to inappropriate cell cycle re-entry in neurons.","evidence":"miR-124 manipulation and cell cycle flow cytometry in Huntington's disease striatal cells and R6/2 mouse model","pmids":["23796713"],"confidence":"Medium","gaps":["Direct 3'UTR luciferase confirmation of miR-124 targeting not detailed","Mechanism connecting S-phase entry to neuronal pathology unresolved"]},{"year":2018,"claim":"Defined CCNA2 as a driver of both G1/S and G2/M transitions whose loss couples cell cycle arrest to apoptosis, framing it as a proliferative dependency in cancer.","evidence":"siRNA knockdown with cell cycle and apoptosis flow cytometry in colorectal cancer cells","pmids":["30464611"],"confidence":"Medium","gaps":["CDK partner not directly demonstrated in this context","Apoptotic effector pathway not mapped"]},{"year":2018,"claim":"Revealed a non-canonical CCNA2 function in post-mitotic neurons, showing it is required for dendritic ribostasis rather than cell division.","evidence":"Conditional knockout mouse, immunohistochemistry, electron microscopy, and rRNA colocalization","pmids":["30579783"],"confidence":"High","gaps":["Molecular mechanism linking CCNA2 to rRNA granule clearance unknown","No identified CCNA2 partner in neuronal dendrites"]},{"year":2019,"claim":"Placed CCNA2 as the effector node of a senescence-controlling pathway operating independently of p21, redefining its role from pure proliferation to lifespan regulation.","evidence":"miRNA/mRNA microarray, luciferase reporter, SA-β-gal assays, and p21-deficient cell experiments","pmids":["30848072"],"confidence":"High","gaps":["Downstream substrates of CCNA2 mediating senescence delay not identified","Relationship to canonical CDK2 activity in this context unresolved"]},{"year":2019,"claim":"Extended CCNA2 function to cell motility, implicating it in trophoblast migration via RhoA-ROCK alongside p53-pathway control of proliferation and apoptosis.","evidence":"siRNA knockdown, overexpression, migration/proliferation/apoptosis assays in HTR8/SVneo cells and villi explants","pmids":["31087423"],"confidence":"Medium","gaps":["Direct link between CCNA2 and RhoA-ROCK activation not biochemically established","Whether migration role requires CDK2 unknown"]},{"year":2022,"claim":"Mapped the upstream transcriptional control of CCNA2, identifying multiple direct activators converging on its promoter to set proliferative output.","evidence":"Luciferase reporter, ChIP, and rescue experiments for E2F1, CREB1, CDCA7, and MYC across cancer and myoblast models","pmids":["34366326","35777504","34737951","41690656"],"confidence":"Medium","gaps":["Combinatorial logic among activators at the promoter not resolved","Cell-type specificity of each factor's contribution unclear"]},{"year":2021,"claim":"Established epigenetic control of CCNA2 transcription through histone demethylase occupancy with built-in paralog compensation.","evidence":"RNAi screen and ChIP showing KDM4B and compensatory KDM4A occupancy at the CCNA2 promoter in rhabdomyosarcoma","pmids":["33917420"],"confidence":"Medium","gaps":["Histone mark altered at the CCNA2 promoter not directly measured","Mechanism of KDM4A compensatory recruitment unknown"]},{"year":2024,"claim":"Identified a non-cell-cycle signaling output of the CCNA2-CDK2 complex, phosphorylating the AXIN1 complex to degrade β-catenin and gate WNT-dependent cancer stem cell differentiation.","evidence":"Co-IP, phosphorylation assay, single-cell sequencing, and CCNA2 inhibition in lung adenocarcinoma","pmids":["38704137"],"confidence":"Medium","gaps":["Direct AXIN1 phosphosite not mapped by mutagenesis","Reconstitution of the kinase reaction not performed"]},{"year":2026,"claim":"Showed that metabolite-driven epigenetic signaling controls CCNA2 transcription, with H3K18 lactylation at its locus serving as a regulatory input.","evidence":"CUT&Tag, ChIP, RIP, and ubiquitination assays linking circBARD1-ENO1-lactate to CCNA2 lactylation in bladder cancer","pmids":["41854933"],"confidence":"Medium","gaps":["Reader of H3K18 lactylation at the CCNA2 locus not identified","Quantitative contribution of lactylation versus transcription factors unresolved"]},{"year":2026,"claim":"Expanded CCNA2 function to immune-metabolic crosstalk, showing it drives pro-inflammatory macrophage polarization that promotes hepatocyte lipid accumulation by paracrine signaling.","evidence":"siRNA knockdown/re-expression, conditioned medium transfer, lipid and cytokine assays, and in vivo mouse model","pmids":["42235667"],"confidence":"Medium","gaps":["Paracrine mediator induced by CCNA2 not identified","Mechanism linking CCNA2 to M1 polarization unknown"]},{"year":null,"claim":"How CCNA2's distinct cell-cycle and non-canonical functions (WNT signaling, neuronal ribostasis, macrophage polarization) are partitioned and whether they all depend on CDK2 catalytic activity remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified substrate map distinguishing canonical from non-canonical functions","CDK2-dependence of non-cell-cycle roles untested","No structural model of context-specific CCNA2 complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,10]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,7,8,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]}],"complexes":["CCNA2-CDK2 complex"],"partners":["CDK2","AXIN1","PKMYT1","CDCA5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P20248","full_name":"Cyclin-A2","aliases":["Cyclin A"],"length_aa":432,"mass_kda":48.6,"function":"Cyclin which controls both the G1/S and the G2/M transition phases of the cell cycle. Functions through the formation of specific serine/threonine protein kinase holoenzyme complexes with the cyclin-dependent protein kinases CDK1 or CDK2. The cyclin subunit confers the substrate specificity of these complexes and differentially interacts with and activates CDK1 and CDK2 throughout the cell cycle","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P20248/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNA2","classification":"Common Essential","n_dependent_lines":1194,"n_total_lines":1208,"dependency_fraction":0.9884105960264901},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDK2","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/CCNA2","total_profiled":1310},"omim":[{"mim_id":"620226","title":"UBIQUITIN-SPECIFIC PEPTIDASE 37; USP37","url":"https://www.omim.org/entry/620226"},{"mim_id":"617374","title":"INHIBITOR OF CDK, CYCLIN A1-INTERACTING PROTEIN 1; INCA1","url":"https://www.omim.org/entry/617374"},{"mim_id":"616934","title":"MEIOSIS-SPECIFIC PROTEIN WITH COILED-COIL DOMAIN; MEIOC","url":"https://www.omim.org/entry/616934"},{"mim_id":"614333","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 29; MRT29","url":"https://www.omim.org/entry/614333"},{"mim_id":"613713","title":"PCI DOMAIN-CONTAINING PROTEIN 2; PCID2","url":"https://www.omim.org/entry/613713"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":36.4},{"tissue":"lymphoid tissue","ntpm":43.6},{"tissue":"retina","ntpm":29.4}],"url":"https://www.proteinatlas.org/search/CCNA2"},"hgnc":{"alias_symbol":[],"prev_symbol":["CCNA","CCN1"]},"alphafold":{"accession":"P20248","domains":[{"cath_id":"1.10.472.10","chopping":"196-303","consensus_level":"high","plddt":97.4017,"start":196,"end":303},{"cath_id":"1.10.472.10","chopping":"312-424","consensus_level":"high","plddt":97.4915,"start":312,"end":424}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20248","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20248-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20248-F1-predicted_aligned_error_v6.png","plddt_mean":73.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCNA2","jax_strain_url":"https://www.jax.org/strain/search?query=CCNA2"},"sequence":{"accession":"P20248","fasta_url":"https://rest.uniprot.org/uniprotkb/P20248.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20248/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20248"}},"corpus_meta":[{"pmid":"30464611","id":"PMC_30464611","title":"CCNA2 acts as a novel biomarker in regulating the growth and apoptosis of colorectal cancer.","date":"2018","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/30464611","citation_count":81,"is_preprint":false},{"pmid":"30848072","id":"PMC_30848072","title":"The p53/miRNAs/Ccna2 pathway serves as a novel regulator of cellular senescence: Complement of the canonical p53/p21 pathway.","date":"2019","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/30848072","citation_count":64,"is_preprint":false},{"pmid":"30138038","id":"PMC_30138038","title":"Dual regulatory role of CCNA2 in modulating CDK6 and MET-mediated cell-cycle pathway and EMT progression is blocked by miR-381-3p in bladder cancer.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30138038","citation_count":57,"is_preprint":false},{"pmid":"35401923","id":"PMC_35401923","title":"CCNA2 as an Immunological Biomarker Encompassing Tumor Microenvironment and Therapeutic Response in Multiple Cancer Types.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/35401923","citation_count":45,"is_preprint":false},{"pmid":"31966683","id":"PMC_31966683","title":"CCNA2 facilitates epithelial-to-mesenchymal transition via the integrin αvβ3 signaling in NSCLC.","date":"2017","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31966683","citation_count":42,"is_preprint":false},{"pmid":"27738335","id":"PMC_27738335","title":"Waltonitone inhibits proliferation of hepatoma cells and tumorigenesis via FXR-miR-22-CCNA2 signaling pathway.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27738335","citation_count":41,"is_preprint":false},{"pmid":"30766610","id":"PMC_30766610","title":"MiR-219-5p suppresses cell proliferation and cell cycle progression in esophageal squamous cell carcinoma by targeting CCNA2.","date":"2019","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30766610","citation_count":39,"is_preprint":false},{"pmid":"31087423","id":"PMC_31087423","title":"Downregulation of CCNA2 disturbs trophoblast migration, proliferation, and apoptosis during the pathogenesis of recurrent miscarriage.","date":"2019","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/31087423","citation_count":38,"is_preprint":false},{"pmid":"34880385","id":"PMC_34880385","title":"Tanshinone IIA suppresses the progression of lung adenocarcinoma through regulating CCNA2-CDK2 complex and AURKA/PLK1 pathway.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34880385","citation_count":38,"is_preprint":false},{"pmid":"23796713","id":"PMC_23796713","title":"MicroRNA-124 targets CCNA2 and regulates cell cycle in STHdh(Q111)/Hdh(Q111) cells.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23796713","citation_count":34,"is_preprint":false},{"pmid":"34366326","id":"PMC_34366326","title":"E2F1 transcriptionally regulates CCNA2 expression to promote triple negative breast cancer tumorigenicity.","date":"2022","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/34366326","citation_count":28,"is_preprint":false},{"pmid":"32154226","id":"PMC_32154226","title":"MiR-29c-3p Suppresses the Migration, Invasion and Cell Cycle in Esophageal Carcinoma via CCNA2/p53 Axis.","date":"2020","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32154226","citation_count":27,"is_preprint":false},{"pmid":"32377701","id":"PMC_32377701","title":"miR‑508‑3p suppresses the development of ovarian carcinoma by targeting CCNA2 and MMP7.","date":"2020","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32377701","citation_count":27,"is_preprint":false},{"pmid":"31077370","id":"PMC_31077370","title":"Screening the expression of several miRNAs from TaqMan Low Density Array in traumatic brain injury: miR-219a-5p regulates neuronal apoptosis by modulating CCNA2 and CACUL1.","date":"2019","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31077370","citation_count":26,"is_preprint":false},{"pmid":"32981678","id":"PMC_32981678","title":"Long noncoding RNA DNAH17-AS1 promotes tumorigenesis and metastasis of non-small cell lung cancer via regulating miR-877-5p/CCNA2 pathway.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32981678","citation_count":23,"is_preprint":false},{"pmid":"33714986","id":"PMC_33714986","title":"Roundabout homolog 1 inhibits proliferation via the YY1-ROBO1-CCNA2-CDK2 axis in human pancreatic cancer.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33714986","citation_count":22,"is_preprint":false},{"pmid":"38704137","id":"PMC_38704137","title":"Smoking-induced CCNA2 expression promotes lung adenocarcinoma tumorigenesis by boosting AT2/AT2-like cell differentiation.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38704137","citation_count":19,"is_preprint":false},{"pmid":"35777504","id":"PMC_35777504","title":"CREB1 promotes proliferation and differentiation by mediating the transcription of CCNA2 and MYOG in bovine myoblasts.","date":"2022","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35777504","citation_count":19,"is_preprint":false},{"pmid":"34737951","id":"PMC_34737951","title":"CDCA7 Facilitates Tumor Progression by Directly Regulating CCNA2 Expression in Esophageal Squamous Cell Carcinoma.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34737951","citation_count":19,"is_preprint":false},{"pmid":"32486290","id":"PMC_32486290","title":"Pharmacogenomic Analysis Reveals CCNA2 as a Predictive Biomarker of Sensitivity to Polo-Like Kinase I Inhibitor in Gastric Cancer.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32486290","citation_count":19,"is_preprint":false},{"pmid":"33859479","id":"PMC_33859479","title":"Integrated Profiling Identifies CCNA2 as a Potential Biomarker of Immunotherapy in Breast Cancer.","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33859479","citation_count":17,"is_preprint":false},{"pmid":"30540563","id":"PMC_30540563","title":"Sevoflurane impairs learning and memory of the developing brain through post-transcriptional inhibition of CCNA2 via microRNA-19-3p.","date":"2018","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/30540563","citation_count":17,"is_preprint":false},{"pmid":"32537647","id":"PMC_32537647","title":"Hsa_circ_0003732 promotes osteosarcoma cells proliferation via miR-545/CCNA2 axis.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32537647","citation_count":16,"is_preprint":false},{"pmid":"27020049","id":"PMC_27020049","title":"Mmu-miR-125b overexpression suppresses NO production in activated macrophages by targeting eEF2K and CCNA2.","date":"2016","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27020049","citation_count":16,"is_preprint":false},{"pmid":"38516683","id":"PMC_38516683","title":"CCNA2 and NEK2 regulate glioblastoma progression by targeting the cell cycle.","date":"2024","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/38516683","citation_count":13,"is_preprint":false},{"pmid":"35069872","id":"PMC_35069872","title":"PKMYT1 regulates the proliferation and epithelial-mesenchymal transition of oral squamous cell carcinoma cells by targeting CCNA2.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/35069872","citation_count":13,"is_preprint":false},{"pmid":"38640322","id":"PMC_38640322","title":"CDK1 and CCNA2 play important roles in oral squamous cell carcinoma.","date":"2024","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38640322","citation_count":12,"is_preprint":false},{"pmid":"35192605","id":"PMC_35192605","title":"The noncoding RNA CcnA modulates the master cell cycle regulators CtrA and GcrA in Caulobacter crescentus.","date":"2022","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/35192605","citation_count":11,"is_preprint":false},{"pmid":"34703311","id":"PMC_34703311","title":"Silencing of LncRNA AFAP1-AS1 Inhibits Cell Proliferation in Oral Squamous Cancer by Suppressing CCNA2.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/34703311","citation_count":11,"is_preprint":false},{"pmid":"35246013","id":"PMC_35246013","title":"6-Methoxyflavone induces S-phase arrest through the CCNA2/CDK2/p21CIP1 signaling pathway in HeLa cells.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35246013","citation_count":9,"is_preprint":false},{"pmid":"36310381","id":"PMC_36310381","title":"Overexpression of adrenomedullin (ADM) alleviates the senescence of human dental pulp stem cells by regulating the miR-152/CCNA2 pathway.","date":"2022","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/36310381","citation_count":9,"is_preprint":false},{"pmid":"35835355","id":"PMC_35835355","title":"Coevolution of HTLV-1-HBZ, Tax, and proviral load with host IRF-1 and CCNA-2 in HAM/TSP patients.","date":"2022","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/35835355","citation_count":8,"is_preprint":false},{"pmid":"26868647","id":"PMC_26868647","title":"A prospective study of two isothermal amplification assays compared with real-time PCR, CCNA and toxigenic culture for the diagnosis of Clostridium difficile infection.","date":"2016","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26868647","citation_count":8,"is_preprint":false},{"pmid":"33917420","id":"PMC_33917420","title":"Role for the Histone Demethylase KDM4B in Rhabdomyosarcoma via CDK6 and CCNA2: Compensation by KDM4A and Apoptotic Response of Targeting Both KDM4B and KDM4A.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33917420","citation_count":7,"is_preprint":false},{"pmid":"37853361","id":"PMC_37853361","title":"BUB1, BUB1B, CCNA2, and CDCA8, along with miR-524-5p, as clinically relevant biomarkers for the diagnosis and treatment of endometrial carcinoma.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37853361","citation_count":5,"is_preprint":false},{"pmid":"36454788","id":"PMC_36454788","title":"ECPPF (E2F1, CCNA2, POLE, PPP2R1A, FBXW7) stratification: Profiling high-risk subtypes of histomorphologically low-risk and treatment-insensitive endometrioid endometrial cancer.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36454788","citation_count":5,"is_preprint":false},{"pmid":"22095474","id":"PMC_22095474","title":"Identification of single nucleotide polymorphisms in the CCNA2 gene and its association with wool density in Rex rabbits.","date":"2011","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/22095474","citation_count":5,"is_preprint":false},{"pmid":"34486391","id":"PMC_34486391","title":"Muse Cells Have Higher Stress Tolerance than Adipose Stem Cells due to the Overexpression of the CCNA2 Gene.","date":"2021","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/34486391","citation_count":5,"is_preprint":false},{"pmid":"40155519","id":"PMC_40155519","title":"Berberine diminishes the malignant progression of non-small cell lung cancer cells by targeting CDCA5 and CCNA2.","date":"2025","source":"Journal of natural medicines","url":"https://pubmed.ncbi.nlm.nih.gov/40155519","citation_count":4,"is_preprint":false},{"pmid":"30579783","id":"PMC_30579783","title":"CCNA2 Ablation in Aged Mice Results in Abnormal rRNA Granule Accumulation in Hippocampus.","date":"2018","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30579783","citation_count":4,"is_preprint":false},{"pmid":"38288951","id":"PMC_38288951","title":"Antihyperlipidemic drug rosuvastatin suppressed tumor progression and potentiated chemosensitivity by downregulating CCNA2 in lung adenocarcinoma.","date":"2024","source":"Journal of chemotherapy (Florence, Italy)","url":"https://pubmed.ncbi.nlm.nih.gov/38288951","citation_count":3,"is_preprint":false},{"pmid":"37276868","id":"PMC_37276868","title":"Hsa_Circ_0104206 is An Oncogenic circRNA in Colon Cancer by Targeting Mir-188-3p/CCNA2 Axis.","date":"2023","source":"Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme","url":"https://pubmed.ncbi.nlm.nih.gov/37276868","citation_count":2,"is_preprint":false},{"pmid":"40611205","id":"PMC_40611205","title":"The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/40611205","citation_count":1,"is_preprint":false},{"pmid":"40345591","id":"PMC_40345591","title":"Exploring the regulatory mechanism of CCNA2 in colorectal cancer: Insights from multiomics and experimental analysis.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40345591","citation_count":1,"is_preprint":false},{"pmid":"40183277","id":"PMC_40183277","title":"Metformin Inhibits the Development of Lung Adenocarcinoma by Regulating the Expression of CCNA2 via E2F1.","date":"2026","source":"Combinatorial chemistry & high throughput screening","url":"https://pubmed.ncbi.nlm.nih.gov/40183277","citation_count":1,"is_preprint":false},{"pmid":"40411825","id":"PMC_40411825","title":"CCNA2 and CCND2 Are Differentially Involved in β-Cell Proliferation in Perinatal Japanese Autopsied Individuals.","date":"2025","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40411825","citation_count":0,"is_preprint":false},{"pmid":"40598454","id":"PMC_40598454","title":"Investigating the molecular mechanisms, drug prediction, and validation of CCNA2 and MAD2L1 in esophageal squamous cell carcinoma based on bioinformatics.","date":"2025","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40598454","citation_count":0,"is_preprint":false},{"pmid":"40915462","id":"PMC_40915462","title":"Bioinformatics, machine learning, and functional validation reveal CCNA2 as a key target of Ammopiptanthus nanus against rheumatoid arthritis.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40915462","citation_count":0,"is_preprint":false},{"pmid":"41160097","id":"PMC_41160097","title":"BRPF1 inhibitor GSK6853 inhibits NSCLC cell proliferation via the JAK2/STAT3/CCNA2 axis to induce cell cycle arrest.","date":"2025","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/41160097","citation_count":0,"is_preprint":false},{"pmid":"41153330","id":"PMC_41153330","title":"CCNA2 and CCNB3 as Early Potential Molecular Candidates of Oocyte Maturation in Cumulus-Oophorous Complex Cells from Follicular Fluid.","date":"2025","source":"Diagnostics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41153330","citation_count":0,"is_preprint":false},{"pmid":"42210102","id":"PMC_42210102","title":"CCNA2, MAD2L1, AURKA, and PTTG1 promote proliferation and migration in hepatocellular carcinoma.","date":"2026","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/42210102","citation_count":0,"is_preprint":false},{"pmid":"40037461","id":"PMC_40037461","title":"The role of cyclin dependent kinase molecules in the pathogenesis and immune cell infiltration of TNBC in silicosis: Based on core stem cell related genes TPX2 and CCNA2.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40037461","citation_count":0,"is_preprint":false},{"pmid":"41690656","id":"PMC_41690656","title":"Kojic acid inhibits melanoma progression by targeting the MYC-CCNA2/KPNA2 axis.","date":"2026","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/41690656","citation_count":0,"is_preprint":false},{"pmid":"42235667","id":"PMC_42235667","title":"Integrative epidemiological and experimental evidence implicates CCNA2-associated macrophage-hepatocyte crosstalk in dimethyl phosphate exposure-associated NAFLD.","date":"2026","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/42235667","citation_count":0,"is_preprint":false},{"pmid":"41854933","id":"PMC_41854933","title":"CircBARD1 suppresses tumor progression driven by H3K18 lactylation-CCNA2 axis in human bladder cancer.","date":"2026","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/41854933","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.14.682410","title":"Resting-state functional MRI derivatives: A dataset derived from the The Comprehensive Assessment of Neurodegeneration and Dementia Study","date":"2025-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.14.682410","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.22.677916","title":"Elucidating the potential carcinogenic molecular mechanisms of parabens in head and neck squamous cell carcinoma through network toxicology and molecular docking","date":"2025-09-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.22.677916","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.25.672065","title":"Cisplatin-induced oxidative stress regulates YAP to modulate epigenome promoting survival of osteosarcoma cells","date":"2025-08-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.25.672065","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.12.659330","title":"MEIOC prevents continued mitotic cycling and promotes meiotic entry during mouse oogenesis","date":"2025-06-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.12.659330","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.09.632243","title":"CpgD is a phosphoglycerate cytidylyltransferase required for ceramide diphosphoglycerate synthesis","date":"2025-01-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.09.632243","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.02.640945","title":"Novel transcription factor BTNL9 enhances tumor suppression and drug sensitivity in non-small cell lung cancer through cell cycle regulation","date":"2025-03-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.02.640945","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.10.617319","title":"Identification of Hub Genes and CDK1-Targeting Therapeutics in Hepatocellular Carcinoma: Bioinformatics and Simulation Study","date":"2024-10-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.10.617319","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.27.613548","title":"Inhibition of FOXM1 synergizes with BCL2 inhibitor Venetoclax in killing non-t(11;14) multiple myeloma cells via repressing MYC pathway","date":"2024-09-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.27.613548","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.25.24314374","title":"Patient-centered Transcriptomic and Multimodal Neuroimaging Determinants of Clinical Progression, Physical Activity and Treatment Needs in Parkinson’s Disease","date":"2024-09-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.25.24314374","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.21.609070","title":"Identification and Functional Characterization of Up-Regulated Hub Genes in Adenocarcinoma Across Multiple Organ Sites","date":"2024-08-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.21.609070","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.29.24314328","title":"Distribution of White Matter Hyperintensities across Arterial Territories in Neurodegenerative Diseases","date":"2024-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.29.24314328","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38160,"output_tokens":5923,"usd":0.101663,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14567,"output_tokens":3556,"usd":0.080867,"stage2_stop_reason":"end_turn"},"total_usd":0.18253,"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\": 2024,\n      \"finding\": \"CCNA2 binding to CDK2 phosphorylates the AXIN1 complex, which induces ubiquitination-dependent degradation of β-catenin and inhibits the WNT signaling pathway, thereby promoting AT2 cell differentiation into AT2-like cancer stem cells in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, western blot, single-cell sequencing analysis, CCNA2 inhibition experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab with multiple orthogonal methods (Co-IP, functional inhibition, single-cell analysis) but no full reconstitution or mutagenesis\",\n      \"pmids\": [\"38704137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCNA2 promotes trophoblast migration via the RhoA-ROCK signaling pathway, and promotes trophoblast proliferation while inhibiting apoptosis via the p53 pathway; CCNA2 knockdown impairs these functions in HTR8/SVneo cells.\",\n      \"method\": \"siRNA knockdown, overexpression, migration assay, proliferation assay, apoptosis assay, western blot in HTR8/SVneo cells and ex vivo villi explant culture\",\n      \"journal\": \"American journal of reproductive immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal functional assays with defined pathway readouts (RhoA-ROCK, p53)\",\n      \"pmids\": [\"31087423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCNA2 regulates cell cycle progression by promoting G1/S and G2/M transitions; knockdown of CCNA2 in colorectal cancer cells impairs cell cycle progression and induces apoptosis.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis by flow cytometry, apoptosis assay, cell growth assay\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple assays (cell cycle, apoptosis, proliferation) with defined readouts\",\n      \"pmids\": [\"30464611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCNA2 functions in a non-canonical, non-cell-cycle role in mature hippocampal neurons: cyclin A2 colocalizes with dendritic rRNA, and its ablation results in decreased synaptic density and accumulation of rRNA granules in dendrite shafts, indicating a role in neuronal ribostasis.\",\n      \"method\": \"Conditional knockout mouse model, immunohistochemistry, electron microscopy, confocal colocalization with rRNA markers\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — well-defined KO model with multiple orthogonal histological and ultrastructural readouts establishing a non-cell-cycle function\",\n      \"pmids\": [\"30579783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The p53/miRNAs/CCNA2 pathway regulates cellular senescence independently of the canonical p53/p21 pathway: p53-responsive miRNAs (miR-124, miR-29) target CCNA2, silencing of CCNA2 triggers senescence, and CCNA2 overexpression delays senescence and reverses miRNA-induced senescence even in p21-deficient cells.\",\n      \"method\": \"miRNA/mRNA microarray, luciferase reporter assay, senescence assays (SA-β-gal), overexpression and knockdown, p21-deficient cell experiments\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods across multiple cell contexts including genetic p21 deficiency, establishing epistatic independence from p53/p21\",\n      \"pmids\": [\"30848072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MicroRNA-124 directly targets CCNA2, and decreased miR-124 leads to increased CCNA2 expression and increased S-phase fraction in Huntington's disease striatal cells; exogenous manipulation of either miR-124 or CCNA2 alters cell cycle distribution.\",\n      \"method\": \"qRT-PCR, cell cycle analysis (flow cytometry), miR-124 overexpression/inhibition, CCNA2 overexpression/knockdown, validated in HD mouse model (R6/2)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional experiments in cell and animal model, single lab\",\n      \"pmids\": [\"23796713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"E2F1 transcription factor directly binds the CCNA2 promoter at position +677 and transcriptionally activates CCNA2 expression; E2F1 knockdown reduces CCNA2 expression and decreases TNBC cell proliferation, invasion, and migration.\",\n      \"method\": \"Luciferase reporter assay, ChIP, rescue experiments, bioinformatics correlation analysis\",\n      \"journal\": \"Cancer biomarkers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter and rescue experiments in single lab establishing direct transcriptional regulation\",\n      \"pmids\": [\"34366326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREB1 directly binds the proximal promoter region of CCNA2 and transcriptionally activates it, promoting S-phase DNA synthesis and G2 cell division in bovine myoblasts.\",\n      \"method\": \"Dual luciferase reporter assay, promoter binding assay, CREB1 overexpression/knockdown, cell cycle analysis\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual luciferase and functional assays, single lab\",\n      \"pmids\": [\"35777504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDCA7 directly binds to the CCNA2 promoter and upregulates its expression in esophageal squamous cell carcinoma; knockdown of CCNA2 reverses the malignant proliferative phenotype induced by CDCA7 overexpression.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, rescue experiment, western blot, cell proliferation and colony formation assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase establishing direct promoter binding, rescue experiments, single lab\",\n      \"pmids\": [\"34737951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ROBO1 inhibits pancreatic cancer cell proliferation and S-phase progression via the CCNA2/CDK2 axis; YY1 directly binds the ROBO1 promoter to promote its transcription, establishing a YY1-ROBO1-CCNA2-CDK2 axis.\",\n      \"method\": \"Luciferase reporter assay, ChIP, EMSA, overexpression experiments in vitro and xenograft in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (luciferase, ChIP, EMSA, in vivo), single lab\",\n      \"pmids\": [\"33714986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4B histone demethylase is bound at the promoter regions of CCNA2 (and CDK6) and regulates their transcription to control cell cycle progression in rhabdomyosarcoma; sustained KDM4B knockdown leads to compensatory KDM4A recruitment to the same CCNA2 and CDK6 promoter regions.\",\n      \"method\": \"RNAi screening, ChIP showing KDM4B and KDM4A promoter occupancy at CCNA2, cell cycle analysis, rescue/recovery experiments\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based promoter occupancy with functional cell cycle readout, single lab\",\n      \"pmids\": [\"33917420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKMYT1 physically binds CCNA2 (shown by co-immunoprecipitation) and PKMYT1 knockdown reduces CCNA2 expression, inhibiting proliferation, migration, invasion, and EMT in oral squamous cell carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, western blot, proliferation/migration/invasion assays, wound healing assay\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus multiple functional assays in single lab\",\n      \"pmids\": [\"35069872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"6-Methoxyflavone induces S-phase arrest in HeLa cells via the CCNA2/CDK2/p21CIP1 signaling pathway; molecular docking showed that the combination of CDK2 and CCNA2 enhances compound binding affinity to CDK2.\",\n      \"method\": \"Cell cycle flow cytometry, western blot, qPCR, molecular docking, transcriptome sequencing\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — molecular docking is computational; western blot of pathway proteins without mutagenesis, single lab\",\n      \"pmids\": [\"35246013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tanshinone IIA suppresses lung adenocarcinoma cell cycle progression by downregulating the CCNA2-CDK2 complex and AURKA/PLK1 pathway, inducing G1/S arrest and apoptosis.\",\n      \"method\": \"Western blot, flow cytometry (cell cycle and apoptosis), MTT/clonogenic assay, molecular docking\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — molecular docking plus western blot without reconstitution or mutagenesis; pathway placement inferred rather than proven by epistasis\",\n      \"pmids\": [\"34880385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-381-3p directly targets the 3'UTR of CCNA2; inhibition of CCNA2 by miR-381-3p participates in proliferation regulation together with CDK6 and also modulates EMT progression via the ROCK/AKT/β-catenin/SNAIL pathway in bladder cancer.\",\n      \"method\": \"Dual-luciferase reporter assay, bioinformatics, siRNA knockdown, in vitro proliferation and migration assays, in vivo tumor models\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase validating direct 3'UTR targeting plus multiple functional assays and in vivo validation, single lab\",\n      \"pmids\": [\"30138038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FXR-regulated miR-22 directly represses CCNA2 in hepatocellular carcinoma; WA induces miR-22 expression leading to CCNA2 repression and cell proliferation arrest; FXR knockdown or miR-22 silencing reverses CCNA2 repression and restores proliferation.\",\n      \"method\": \"FXR/miR-22/CCNA2 expression in clinical samples, miR-22 manipulation (overexpression/silencing), FXR knockdown, in vivo xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis established across three nodes (FXR-miR-22-CCNA2) with multiple methods including in vivo, single lab\",\n      \"pmids\": [\"27738335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"6PGD binds ALKBH5 and inhibits its m6A demethylase activity through a non-metabolic function, increasing m6A modification and stability of MDM2 mRNA, decreasing p53 protein stability, which subsequently activates CCNA2 expression and promotes colorectal cancer tumor growth and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, m6A modification assay, mRNA stability assay, western blot, siRNA knockdown, in vitro and in vivo tumor models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods establishing upstream regulatory mechanism controlling CCNA2, single lab\",\n      \"pmids\": [\"40611205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDCA5 physically interacts with CCNA2 (shown by co-immunoprecipitation) and regulates its expression in NSCLC cells; berberine treatment reduces both CDCA5 and CCNA2 levels, and overexpression of either attenuates berberine's inhibitory effects on NSCLC.\",\n      \"method\": \"Co-immunoprecipitation, qRT-PCR, western blot, overexpression rescue assay, in vivo xenograft model\",\n      \"journal\": \"Journal of natural medicines\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP establishing CDCA5-CCNA2 interaction, single lab\",\n      \"pmids\": [\"40155519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"H3K18 lactylation at the CCNA2 locus drives its transcription in bladder cancer; circBARD1 promotes ENO1 ubiquitination and FBXW7-mediated degradation, which reduces intracellular lactate and H3K18 lactylation, thereby suppressing CCNA2 transcription.\",\n      \"method\": \"CUT&Tag, ChIP assay, RNA immunoprecipitation (RIP), Co-immunoprecipitation, ubiquitination assay, gain-of-function experiments\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag and ChIP directly measuring histone lactylation at CCNA2 locus combined with mechanistic upstream pathway dissection, single lab\",\n      \"pmids\": [\"41854933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADM overexpression inhibits miR-152, which normally directly targets and suppresses CCNA2; the ADM/miR-152/CCNA2 axis promotes cell cycle progression (increased G2/M phase) and reduces p53, p21WAF1, and p16INK4A in human dental pulp stem cells, conferring antisenescence effects.\",\n      \"method\": \"Luciferase reporter assay, transfection with miR-152 mimic/antagomir, western blot, flow cytometry (cell cycle), transcriptome analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase validating direct miR-152/CCNA2 targeting, rescue experiments, multiple functional assays, single lab\",\n      \"pmids\": [\"36310381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-219a-5p upregulation in neuronal injury models inhibits CCNA2 and CACUL1 expression, activating akt/Foxo3a and p53/Bcl-2 signaling pathways and increasing cleaved caspase-3, thereby inducing neuronal apoptosis.\",\n      \"method\": \"TaqMan Low Density Array, RT-qPCR validation, neuronal cell injury model, western blot for signaling pathway proteins\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — target validation by expression correlation in injury model without direct luciferase confirmation of CCNA2 3'UTR targeting reported in abstract, single lab\",\n      \"pmids\": [\"31077370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sevoflurane exposure upregulates miR-19-3p, which post-transcriptionally inhibits CCNA2 protein translation in neurons; intracranial injection of anti-miR-19-3p AAV reversed SEVO-induced impairment of neuron proliferation and learning/memory in neonatal rats.\",\n      \"method\": \"Luciferase reporter assay, western blot, AAV-mediated in vivo anti-miRNA injection, behavioral testing (Morris water maze, Plus-Maze)\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase validating post-transcriptional CCNA2 regulation plus in vivo rescue, single lab\",\n      \"pmids\": [\"30540563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MEIOC downregulates CCNA2 protein expression during the mitosis-to-meiosis transition in mouse oogenesis, contributing to repression of the mitotic G1/S cyclin program prior to meiotic entry.\",\n      \"method\": \"Cell cycle transcriptomics, cell cycle-associated protein expression analysis, proliferation assays, MEIOC loss-of-function mouse model\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model with protein expression analysis and functional cell cycle readouts, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GSK6853 (BRPF1 inhibitor) suppresses CCNA2 expression via inhibition of the JAK2/STAT3 signaling pathway, inducing G0/G1 cell cycle arrest and apoptosis in NSCLC cells.\",\n      \"method\": \"RNA sequencing, western blot validating JAK2/STAT3/CCNA2 protein levels, flow cytometry (cell cycle and apoptosis), CCK-8 and colony formation assays\",\n      \"journal\": \"Investigational new drugs\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — western blot showing pathway protein changes without epistatic rescue or mutagenesis, single lab\",\n      \"pmids\": [\"41160097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MYC directly transcriptionally activates CCNA2 (and KPNA2) in melanoma; kojic acid does not alter MYC expression but impairs MYC promoter binding and transcriptional activation of CCNA2, reducing melanoma proliferation.\",\n      \"method\": \"Transcriptomic profiling, ChIP showing reduced MYC binding at CCNA2 promoter after kojic acid treatment, xenograft in vivo model, single-cell analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct MYC-CCNA2 promoter interaction plus in vivo functional validation, single lab\",\n      \"pmids\": [\"41690656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCNA2 expression in macrophages is upregulated by dimethyl phosphate and promotes a pro-inflammatory M1-like macrophage phenotype; CCNA2-expressing macrophage conditioned medium induces lipid accumulation in hepatocytes via paracrine signaling, and CCNA2 silencing attenuates both macrophage polarization and hepatocyte lipid accumulation.\",\n      \"method\": \"siRNA knockdown and re-expression in macrophages, conditioned medium transfer to hepatocytes, lipid accumulation assay, cytokine secretion assay, in vivo mouse model\",\n      \"journal\": \"Environmental pollution\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue/re-expression experiments establishing CCNA2 necessity in macrophage-hepatocyte crosstalk, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"42235667\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCNA2 (Cyclin A2) is a cell cycle regulator that activates CDK2 to drive G1/S and G2/M transitions; beyond canonical cell cycle control, CCNA2–CDK2 complexes phosphorylate substrates such as the AXIN1 complex to degrade β-catenin and inhibit WNT signaling, CCNA2 maintains neuronal ribostasis in post-mitotic hippocampal neurons by colocalizing with dendritic rRNA (its ablation causes rRNA granule accumulation and synaptic loss), and CCNA2 expression is transcriptionally regulated by E2F1, CREB1, CDCA7, MYC, and KDM4B/KDM4A at its promoter, while post-transcriptionally repressed by multiple miRNAs (miR-124, miR-29, miR-219-5p, miR-381-3p, miR-152, miR-19-3p) via 3'UTR targeting; CCNA2 also mediates cell migration through RhoA-ROCK signaling and modulates apoptosis through the p53 pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCNA2 (Cyclin A2) is a cell cycle regulator that activates CDK2 to drive G1/S and G2/M progression, and its loss in cancer cells impairs cell cycle transit and induces apoptosis [#2]. The CCNA2–CDK2 complex executes both canonical proliferative functions and non-canonical signaling: it phosphorylates the AXIN1 complex to promote ubiquitination-dependent β-catenin degradation and WNT pathway inhibition during AT2 cell differentiation in lung adenocarcinoma [#0], and the CCNA2/CDK2 axis is a downstream effector of ROBO1-mediated control of S-phase progression in pancreatic cancer [#9]. Beyond proliferation, CCNA2 sets cellular lifespan: p53-responsive miRNAs (miR-124, miR-29) repress CCNA2, its silencing triggers senescence, and CCNA2 overexpression delays senescence even in p21-deficient cells, defining a p53/miRNA/CCNA2 axis that operates independently of canonical p53/p21 control [#4]. CCNA2 also carries a non-cell-cycle role in mature hippocampal neurons, where it colocalizes with dendritic rRNA and is required for neuronal ribostasis—its ablation causes rRNA granule accumulation and synaptic loss [#3]. CCNA2 transcription is directly activated by E2F1 [#6], CREB1 [#7], CDCA7 [#8], and MYC [#24] binding at its promoter, controlled by KDM4B/KDM4A histone demethylase occupancy [#10] and H3K18 lactylation at its locus [#18], and is post-transcriptionally repressed by multiple 3'UTR-targeting miRNAs including miR-381-3p, miR-22, and miR-152 [#14, #15, #19]. CCNA2 additionally mediates trophoblast migration via RhoA-ROCK signaling [#1] and drives pro-inflammatory M1 macrophage polarization that promotes hepatocyte lipid accumulation through paracrine signaling [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that CCNA2 is a direct miRNA target whose derepression drives aberrant S-phase entry, linking its dosage to inappropriate cell cycle re-entry in neurons.\",\n      \"evidence\": \"miR-124 manipulation and cell cycle flow cytometry in Huntington's disease striatal cells and R6/2 mouse model\",\n      \"pmids\": [\"23796713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct 3'UTR luciferase confirmation of miR-124 targeting not detailed\", \"Mechanism connecting S-phase entry to neuronal pathology unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined CCNA2 as a driver of both G1/S and G2/M transitions whose loss couples cell cycle arrest to apoptosis, framing it as a proliferative dependency in cancer.\",\n      \"evidence\": \"siRNA knockdown with cell cycle and apoptosis flow cytometry in colorectal cancer cells\",\n      \"pmids\": [\"30464611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CDK partner not directly demonstrated in this context\", \"Apoptotic effector pathway not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a non-canonical CCNA2 function in post-mitotic neurons, showing it is required for dendritic ribostasis rather than cell division.\",\n      \"evidence\": \"Conditional knockout mouse, immunohistochemistry, electron microscopy, and rRNA colocalization\",\n      \"pmids\": [\"30579783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking CCNA2 to rRNA granule clearance unknown\", \"No identified CCNA2 partner in neuronal dendrites\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed CCNA2 as the effector node of a senescence-controlling pathway operating independently of p21, redefining its role from pure proliferation to lifespan regulation.\",\n      \"evidence\": \"miRNA/mRNA microarray, luciferase reporter, SA-β-gal assays, and p21-deficient cell experiments\",\n      \"pmids\": [\"30848072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream substrates of CCNA2 mediating senescence delay not identified\", \"Relationship to canonical CDK2 activity in this context unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended CCNA2 function to cell motility, implicating it in trophoblast migration via RhoA-ROCK alongside p53-pathway control of proliferation and apoptosis.\",\n      \"evidence\": \"siRNA knockdown, overexpression, migration/proliferation/apoptosis assays in HTR8/SVneo cells and villi explants\",\n      \"pmids\": [\"31087423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between CCNA2 and RhoA-ROCK activation not biochemically established\", \"Whether migration role requires CDK2 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the upstream transcriptional control of CCNA2, identifying multiple direct activators converging on its promoter to set proliferative output.\",\n      \"evidence\": \"Luciferase reporter, ChIP, and rescue experiments for E2F1, CREB1, CDCA7, and MYC across cancer and myoblast models\",\n      \"pmids\": [\"34366326\", \"35777504\", \"34737951\", \"41690656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Combinatorial logic among activators at the promoter not resolved\", \"Cell-type specificity of each factor's contribution unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established epigenetic control of CCNA2 transcription through histone demethylase occupancy with built-in paralog compensation.\",\n      \"evidence\": \"RNAi screen and ChIP showing KDM4B and compensatory KDM4A occupancy at the CCNA2 promoter in rhabdomyosarcoma\",\n      \"pmids\": [\"33917420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Histone mark altered at the CCNA2 promoter not directly measured\", \"Mechanism of KDM4A compensatory recruitment unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a non-cell-cycle signaling output of the CCNA2-CDK2 complex, phosphorylating the AXIN1 complex to degrade β-catenin and gate WNT-dependent cancer stem cell differentiation.\",\n      \"evidence\": \"Co-IP, phosphorylation assay, single-cell sequencing, and CCNA2 inhibition in lung adenocarcinoma\",\n      \"pmids\": [\"38704137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AXIN1 phosphosite not mapped by mutagenesis\", \"Reconstitution of the kinase reaction not performed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed that metabolite-driven epigenetic signaling controls CCNA2 transcription, with H3K18 lactylation at its locus serving as a regulatory input.\",\n      \"evidence\": \"CUT&Tag, ChIP, RIP, and ubiquitination assays linking circBARD1-ENO1-lactate to CCNA2 lactylation in bladder cancer\",\n      \"pmids\": [\"41854933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reader of H3K18 lactylation at the CCNA2 locus not identified\", \"Quantitative contribution of lactylation versus transcription factors unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Expanded CCNA2 function to immune-metabolic crosstalk, showing it drives pro-inflammatory macrophage polarization that promotes hepatocyte lipid accumulation by paracrine signaling.\",\n      \"evidence\": \"siRNA knockdown/re-expression, conditioned medium transfer, lipid and cytokine assays, and in vivo mouse model\",\n      \"pmids\": [\"42235667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Paracrine mediator induced by CCNA2 not identified\", \"Mechanism linking CCNA2 to M1 polarization unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCNA2's distinct cell-cycle and non-canonical functions (WNT signaling, neuronal ribostasis, macrophage polarization) are partitioned and whether they all depend on CDK2 catalytic activity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified substrate map distinguishing canonical from non-canonical functions\", \"CDK2-dependence of non-cell-cycle roles untested\", \"No structural model of context-specific CCNA2 complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 7, 8, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"CCNA2-CDK2 complex\"],\n    \"partners\": [\"CDK2\", \"AXIN1\", \"PKMYT1\", \"CDCA5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}