{"gene":"CCNB1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2019,"finding":"CDK1-CCNB1 localizes to unattached kinetochores (lost upon microtubule attachment) and is recruited there in an MPS1-dependent fashion through direct interaction with the first 100 amino acids of MAD1. This pool of CDK1-CCNB1 creates a positive feedback loop for timely MPS1 kinetochore recruitment and sustained spindle checkpoint arrest, making CDK1-CCNB1 an integral component of the spindle checkpoint.","method":"Complementary proteomics, reciprocal Co-IP, cell biological imaging, and genetic rescue experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, proteomic identification, live-cell imaging, and genetic rescue in a single focused study; replicated in companion paper (PMID:30674582)","pmids":["30674583"],"is_preprint":false},{"year":2019,"finding":"CDK1-CCNB1 phosphorylates MPS1 at S281 to enable its kinetochore binding during mitotic entry; a counteracting phosphatase PP2A-B55 (itself negatively regulated by CDK1-CCNB1) dephosphorylates S281 to promote mitotic exit. This creates a spindle checkpoint-permissive state that persists until CCNB1 concentration falls below a threshold that fully activates PP2A-B55.","method":"Phospho-specific mutant analysis (MPS1-S281A/D), tethering bypass experiments (MPS1-Mis12 fusion), quantitative live-cell imaging, and genetic epistasis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in-cell phospho-mutant rescue, direct tethering bypass, and quantitative imaging; companion to PMID:30674583 providing orthogonal mechanistic validation","pmids":["30674582"],"is_preprint":false},{"year":2015,"finding":"USP22 is a deubiquitinase of CCNB1: it directly interacts with CCNB1, stabilizes it by antagonizing proteasome-mediated degradation in a cell-cycle-specific manner, and its deubiquitinating activity toward CCNB1 is enhanced by CDK1-mediated phosphorylation of USP22. APC/C-CDC20 targets USP22 for degradation during mitotic exit, thereby permitting CCNB1 degradation.","method":"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor rescue, cell-cycle fractionation, USP22 knockdown with CCNB1 protein-level readout","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct biochemical deubiquitinase assay, Co-IP, CDK1 phosphorylation validation, and APC/C epistasis in a single focused study with multiple orthogonal methods","pmids":["27030811"],"is_preprint":false},{"year":2021,"finding":"WDR4 (m7G methyltransferase) promotes CCNB1 mRNA stability and translation by enhancing binding of EIF2A to CCNB1 mRNA. CCNB1 in turn promotes PI3K/AKT phosphorylation and reduces p53 protein expression by promoting p53 ubiquitination.","method":"RNA stability assays, translation reporter assays, RIP (RNA immunoprecipitation) for EIF2A-CCNB1 mRNA interaction, Co-IP, WDR4 knockdown/overexpression with protein-level readouts","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP confirmed EIF2A-CCNB1 mRNA binding, multiple functional assays, but single lab","pmids":["34244479"],"is_preprint":false},{"year":2017,"finding":"The timing of Ccnb1 mRNA translation in mouse oocytes is determined by the presence of transcripts with distinct 3' UTRs generated by alternative polyadenylation: inclusion or exclusion of specific cis-acting elements directs early vs. late translational activation during meiotic maturation.","method":"In vivo translation reporter assays with 3'UTR variants, cytoplasmic polyadenylation element (CPE) mutation analysis, oocyte microinjection","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo functional dissection of cis-regulatory elements with mutagenesis and reporter assays in mouse oocytes; extended by in vivo gene-editing study (PMID:38048302)","pmids":["28808066"],"is_preprint":false},{"year":2024,"finding":"Alternative cleavage and polyadenylation (APA) generates Ccnb1 mRNA variants with short or long 3' UTRs; in vivo mutation of proximal (short) polyadenylation elements showed that short-3'UTR mRNA translation specifies the Cyclin B1 levels that set the timing of meiotic re-entry, whereas long-3'UTR mRNA translation drives Cyclin B1 accumulation during the MI/MII transition.","method":"CRISPR/gene editing to mutate polyadenylation signals in mice, in vivo loss-of-function experiments, mRNA variant quantification","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo gene editing with loss-of-function and phenotypic cell-cycle readout; single lab but rigorous genetic approach","pmids":["38048302"],"is_preprint":false},{"year":2020,"finding":"ERK1/2 (MAPK) activation is required for translational activation of Ccnb1 long-3'UTR transcripts during meiotic resumption in mouse oocytes. CDK1 activity also contributes to Ccnb1 mRNA translational activation. ERK1/2-driven degradation (not just phosphorylation) of CPEB1 is the principal mechanism, whereas CDK1 only phosphorylates CPEB1 without triggering its degradation.","method":"MAPK inhibition/activation in GV-stage oocytes, CDK1 inhibitor/activator treatments, CPEB1 phosphorylation and degradation assays, Ccnb1-3'UTR translation reporters","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic manipulation with multiple readouts, single lab","pmids":["33282880"],"is_preprint":false},{"year":2018,"finding":"FOXM1 directly binds the CCNB1 promoter and transcriptionally activates CCNB1 expression; CCNB1 is required for FOXM1-driven cell proliferation in hepatocellular carcinoma cells.","method":"ChIP (chromatin immunoprecipitation) demonstrating FOXM1 binding to CCNB1 promoter, FOXM1 knockdown with mRNA/protein-level readouts, CCNB1 rescue experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus loss-of-function/rescue functional assays, single lab","pmids":["29705704"],"is_preprint":false},{"year":2016,"finding":"ISL1 transcription factor directly binds conserved sites in the CCNB1 (and CCNB2, c-MYC) promoters/enhancers to activate their expression, promoting G2/M cell cycle transition in gastric cancer cells.","method":"ChIP demonstrating ISL1 binding to CCNB1 promoter/enhancer, ISL1 overexpression and knockdown with CCNB1 mRNA/protein-level readouts, cell cycle analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional rescue experiments, single lab","pmids":["27183908"],"is_preprint":false},{"year":2012,"finding":"STOX1A transcription factor directly binds the CCNB1 promoter (shown by ChIP) and upregulates cyclin B1 expression, promoting mitotic entry.","method":"ChIP, STOX1A overexpression and knockdown with CCNB1 expression readout, cell cycle analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP and functional experiments, but single lab and single paper","pmids":["22253775"],"is_preprint":false},{"year":2019,"finding":"CCNB1 degradation by APC11 is mediated through UBA52-driven ubiquitylation of CCNB1; knockdown of APC11 leads to G2/M arrest even when UBA52 is overexpressed, placing APC11 downstream of UBA52 in regulating CCNB1 stability and cell cycle progression in NSCLC cells.","method":"Co-immunoprecipitation, shRNA knockdown and gene overexpression, cell cycle analysis, xenograft tumor assays","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP plus epistatic knockdown/overexpression experiments with cell cycle readout, single lab","pmids":["31814919"],"is_preprint":false},{"year":2021,"finding":"Circ-CCNB1 acts as a sponge for miR-223, leading to elevated SIAH1 expression; SIAH1 in turn inhibits CCNB1 nuclear translocation. This circ-CCNB1/miR-223/SIAH1 axis suppresses trophoblast proliferation and invasion, establishing that CCNB1 nuclear translocation is regulated through SIAH1.","method":"RNA pull-down, dual luciferase reporter assay, siRNA knockdown, nuclear-cytoplasmic fractionation, Co-IP/immunofluorescence for CCNB1 localization","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNA pull-down plus luciferase plus fractionation assays; single lab, but multiple orthogonal methods","pmids":["35731831"],"is_preprint":false},{"year":2017,"finding":"CCNB1 is required for normal proliferation of gonocytes and spermatogonia in mouse testes; conditional knockout of CCNB1 in male germ cells causes male sterility due to germ cell depletion and increased apoptosis, and also promotes spermatogonial differentiation by downregulating Lin28a and upregulating let-7 miRNA. Notably, ablation of CCNB1 in premeiotic cells (spermatocytes) did not affect meiosis or male fertility, suggesting CCNB1 is dispensable for meiosis in spermatocytes.","method":"Conditional knockout mice, immunofluorescence, TUNEL assay, Lin28a/let-7 expression analysis, fertility assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout with multiple cellular readouts including fertility phenotype, single lab","pmids":["29072697"],"is_preprint":false},{"year":2021,"finding":"SIN3A regulates CCNB1 expression in porcine early embryos; SIN3A depletion causes a two-cell developmental block associated with dramatically reduced CCNB1 transcript levels, and injection of exogenous CCNB1 mRNA into SIN3A-depleted embryos partially rescues development past the two-cell stage, placing SIN3A upstream of CCNB1 in early embryonic cell cycle progression.","method":"siRNA knockdown, RNA-seq, mRNA microinjection rescue, immunofluorescence","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with mRNA rescue establishing epistasis, single lab","pmids":["33692994"],"is_preprint":false},{"year":2021,"finding":"Septin 4 regulates CCNB1 accumulation in mouse oocytes via APC/C-CDC20: depletion of Septin 4 increases CDC20 expression, reduces CCNB1 accumulation, and causes GV arrest; this arrest can be rescued by CCNB1 overexpression or CDC20 depletion, placing Septin 4 upstream of APC/C-CDC20-mediated CCNB1 stabilization at the meiotic G2/M transition.","method":"siRNA knockdown, mRNA microinjection rescue, immunoprecipitation, immunofluorescence, time-lapse live imaging, immunoblotting","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue experiments with multiple orthogonal methods, single lab","pmids":["34189751"],"is_preprint":false},{"year":2022,"finding":"Septin 9 depletion in mouse oocytes causes MI arrest with persistent SAC signaling (Mad1, BubR1 on kinetochores), failure of CDC20 upregulation and CCNB1 degradation, and disrupted kinetochore-microtubule connections; CDC20 mRNA microinjection partially rescues the arrest, establishing that Septin 9 promotes MI-AI transition through SAC/APC/C-CDC20-dependent CCNB1 degradation.","method":"siRNA knockdown, mRNA microinjection rescue, time-lapse live imaging, immunofluorescence for SAC proteins, immunoblotting for CDC20/CCNB1","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue and multiple protein-level readouts, single lab","pmids":["36354207"],"is_preprint":false},{"year":2021,"finding":"Human separase is inhibited by CDK1-CCNB1-CKS1 complex; structural analysis defined molecular mechanisms by which this complex blocks separase's cohesin-cleavage activity, in parallel with inhibition by securin.","method":"Structural biology (cryo-EM/crystallography implied by 'structures') of human separase bound to CDK1-CCNB1-CKS1 complex","journal":"Molecular & cellular oncology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural determination reported but only a commentary/brief communication; references primary structural paper not directly in this corpus","pmids":["34616878"],"is_preprint":false},{"year":2023,"finding":"SQLE (squalene epoxidase) directly interacts with CCNB1 and alleviates its ubiquitination modification, enhancing CCNB1 protein stability; this SQLE-CCNB1 interaction was demonstrated to promote breast cancer cell cycle progression and inhibit ferroptosis.","method":"Co-immunoprecipitation, immunofluorescence colocalization, ubiquitination assay, SQLE overexpression/knockdown with CCNB1 protein-level readout, xenograft","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP plus ubiquitination assay plus functional rescue, single lab","pmids":["37839786"],"is_preprint":false},{"year":2024,"finding":"UCHL1 (deubiquitinase) directly binds CCNB1, prolongs its half-life and inhibits its degradation, thereby promoting granulosa cell proliferation; the flavonoid isovitexin enhances UCHL1 enzymatic activity and downstream CCNB1 stabilization.","method":"Co-immunoprecipitation, half-life (cycloheximide chase) assays, UCHL1 overexpression/knockdown with CCNB1 protein-level readout, enzyme activity assay","journal":"Journal of animal science and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding by Co-IP, half-life assay establishing stabilization mechanism, single lab","pmids":["38858680"],"is_preprint":false},{"year":2025,"finding":"METTL3 mediates m6A modification of CCNB1 mRNA, upregulating its stability and expression; METTL3-modified ASC-exosomes transfer this activity to dermal fibroblasts, enhancing their proliferation and migration in a CCNB1-dependent manner.","method":"Methylated RNA immunoprecipitation (MeRIP), actinomycin D mRNA stability assay, qPCR, METTL3 overexpression/knockdown, CCNB1 knockdown rescue experiments","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP assay plus mRNA stability and functional rescue, single lab","pmids":["39954139"],"is_preprint":false},{"year":2024,"finding":"AURKA interacts with transcription factor E2F1 and recruits it to the CCNB1 promoter to drive CCNB1 transcription; CCNB1 expression is required for AURKA-induced renal cell carcinoma progression.","method":"Co-immunoprecipitation (AURKA-E2F1 interaction), ChIP (E2F1 at CCNB1 promoter), luciferase reporter assay, AURKA/CCNB1 knockdown with functional rescue","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and luciferase with functional rescue, single lab","pmids":["38655290"],"is_preprint":false},{"year":2025,"finding":"SNRPB regulates CCNB1 expression through FOXM1-mediated transcriptional activation: SNRPB interacts with FOXM1 (shown by Co-IP), and this complex drives CCNB1 promoter activity (shown by ChIP). CCNB1 knockdown reverses proliferative and tumorigenic effects of SNRPB overexpression in HCC.","method":"Co-immunoprecipitation (SNRPB-FOXM1), ChIP (FOXM1 at CCNB1 promoter), CCNB1 knockdown rescue in SNRPB-overexpressing cells, in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP plus functional epistasis, single lab","pmids":["40682115"],"is_preprint":false},{"year":2021,"finding":"MEOX1 transcription factor binds the transcriptional initiation site of CCNB1 and suppresses its expression; CCNB1 overexpression rescues the proliferation inhibition caused by MEOX1 overexpression in NSCLC cells, placing MEOX1 upstream of CCNB1 in a suppressive axis.","method":"ChIP or EMSA (binding to CCNB1 transcription initiation site), CCNB1 rescue of MEOX1 overexpression phenotype, in vitro and in vivo functional assays","journal":"Environmental toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single binding assay with functional rescue; method detail limited in abstract","pmids":["34837450"],"is_preprint":false},{"year":2026,"finding":"MAPK1 (ERK2) directly phosphorylates CCNB1 at Ser128; this phosphorylation facilitates CCNB1 nuclear translocation and the G2-to-prophase transition. A phospho-mimetic CCNB1-S128D mutant partially rescues proliferation defects caused by MAPK1 knockdown in TNBC cells.","method":"TurboID proximity labeling + mass spectrometry to identify MAPK1-CCNB1 interaction, Co-IP, in vitro kinase assay, CCNB1-S128A/D mutants, nuclear-cytoplasmic fractionation, immunofluorescence, cell cycle analysis, xenograft","journal":"Life sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay establishing direct phosphorylation, site-directed mutagenesis, nuclear translocation readout, and in vivo xenograft in a single study with multiple orthogonal methods","pmids":["41905453"],"is_preprint":false},{"year":2025,"finding":"HROB suppresses LUAD progression by interacting with ZC3HC1 and reducing its phosphorylation at Ser354; this de-phosphorylation event facilitates K27-linked ubiquitination of CCNB1, promoting its proteasomal degradation and impairing the G2-to-M phase transition.","method":"Co-IP (HROB-ZC3HC1 interaction), phospho-specific analysis of ZC3HC1-Ser354, ubiquitination assay for K27-linked CCNB1 ubiquitination, proteasomal degradation assay, cell cycle analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and cell cycle readout; single lab with multiple biochemical methods","pmids":["40654113"],"is_preprint":false},{"year":2024,"finding":"GADD45G directly interacts with CDK1 and CCNB1 (shown by Co-IP), and negatively regulates CDK1/CCNB1 at transcript and protein levels; reduced GADD45G expression (due to promoter methylation) leads to invasive behavior in endometrial cancer cells through upregulated CDK1/CCNB1.","method":"Co-immunoprecipitation (GADD45G with CDK1 and CCNB1), methylation-specific PCR, qRT-PCR and western blot, functional invasion assays","journal":"Journal of cancer research and therapeutics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with limited functional follow-up, single lab","pmids":["39206984"],"is_preprint":false},{"year":2025,"finding":"Luteolin directly binds CCNB1 (confirmed by molecular docking and surface plasmon resonance), disrupts the CCNB1/CDK1 complex, induces G2/M arrest, and suppresses pancreatic cancer growth in vitro and in vivo.","method":"Surface plasmon resonance (direct binding assay), molecular docking, CCNB1/CDK1 co-immunoprecipitation post-treatment, flow cytometry for cell cycle, xenograft model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — SPR establishes direct binding, Co-IP shows complex disruption, functional in vivo validation; single lab","pmids":["41298459"],"is_preprint":false},{"year":2019,"finding":"hnRNPR stabilizes CCNB1 mRNA; knockdown of CCNB1 abolishes hnRNPR-induced cell growth in gastric cancer, placing hnRNPR-CCNB1 as a functional axis regulating proliferation.","method":"hnRNPR knockdown with mRNA-level CCNB1 readout (mRNA stability implied), CCNB1 knockdown rescue of hnRNPR overexpression phenotype","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mRNA stabilization mechanism inferred from expression changes without direct RNA-binding or stability assay described in abstract; single lab","pmids":["31527303"],"is_preprint":false},{"year":2022,"finding":"RAD6A (E2 ubiquitin-conjugating enzyme) positively regulates CCNB1 expression through upregulation of H2B ubiquitination, promoting ESCC progression; RAD6A knockdown reduces both H2B ubiquitination and CCNB1 levels.","method":"RAD6A shRNA knockdown with H2B ubiquitination and CCNB1 protein-level readout, correlation analysis in tissues, xenograft","journal":"Biological procedures online","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect epigenetic mechanism inferred from knockdown correlations without direct chromatin or recruitment assay for CCNB1 promoter; single lab","pmids":["35321657"],"is_preprint":false},{"year":2026,"finding":"N-glycosylation of ERLIN2 at asparagine 106 enhances its interaction with CCNB1, leading to dysregulated (elevated) CCNB1 expression and accelerating HCC progression; MARCHF6 E3 ligase mediates ubiquitination degradation of ERLIN2, an effect more pronounced when N106 glycosylation is inhibited.","method":"Co-immunoprecipitation (ERLIN2-CCNB1 interaction), N106Q mutant analysis, MARCHF6 knockdown, N-glycosylation inhibition with CCNB1 protein readout","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with mutant analysis; mechanism of how ERLIN2 elevates CCNB1 is not fully established from the abstract; single lab","pmids":["42166002"],"is_preprint":false}],"current_model":"Cyclin B1 (CCNB1) is the regulatory subunit of the CDK1-CCNB1 (MPF) kinase complex that drives mitotic and meiotic G2/M entry; its levels are tightly controlled through a balance of transcriptional activation (by FOXM1, ISL1, STOX1A, AURKA-E2F1, SNRPB-FOXM1), post-transcriptional regulation (3' UTR-dependent translational timing via alternative polyadenylation during oocyte meiosis; mRNA stabilization by hnRNPR and METTL3-mediated m6A modification; WDR4-m7G-EIF2A-dependent translation), and protein stability control (deubiquitination by USP22 activated by CDK1 phosphorylation; deubiquitination by UCHL1; stabilization by SQLE; degradation via APC/C-CDC20/UBA52-APC11 and HROB-ZC3HC1-K27-ubiquitin pathways); at kinetochores, CDK1-CCNB1 is recruited by MPS1-dependent interaction with MAD1 where it phosphorylates MPS1-S281 to enable spindle assembly checkpoint signaling, forming a positive feedback loop that sustains checkpoint arrest until CCNB1 levels fall below the threshold that fully activates the counteracting PP2A-B55 phosphatase; MAPK1 (ERK2) directly phosphorylates CCNB1 at Ser128 to promote its nuclear translocation and mitotic entry; CCNB1 also inhibits separase by forming an inhibitory CDK1-CCNB1-CKS1 complex, and promotes p53 ubiquitination/degradation, PI3K/AKT signaling, and EMT-related gene expression downstream of its cell-cycle kinase activity."},"narrative":{"mechanistic_narrative":"Cyclin B1 (CCNB1) is the regulatory subunit of the CDK1-CCNB1 mitotic kinase that drives the G2/M transition in mitotic and meiotic cell cycles, and its activity is gated by exquisitely tight control of its abundance, localization, and timing [PMID:30674583, PMID:28808066]. Beyond simply activating CDK1, CDK1-CCNB1 is an integral component of the spindle assembly checkpoint: it localizes to unattached kinetochores in an MPS1-dependent manner through direct interaction with the N-terminal 100 residues of MAD1, and phosphorylates MPS1 at Ser281 to sustain its kinetochore binding, creating a positive feedback loop that maintains checkpoint arrest until CCNB1 levels fall below the threshold that fully activates the counteracting PP2A-B55 phosphatase to permit mitotic exit [PMID:30674583, PMID:30674582]. CDK1-CCNB1 also inhibits separase by forming an inhibitory CDK1-CCNB1-CKS1 complex that blocks cohesin cleavage [PMID:34616878]. Nuclear translocation of CCNB1 — a prerequisite for mitotic entry — is promoted by direct MAPK1 (ERK2) phosphorylation at Ser128 [PMID:41905453]. CCNB1 abundance is set transcriptionally by activators that bind its promoter, including FOXM1, ISL1, STOX1A, and E2F1 recruited by AURKA [PMID:29705704, PMID:27183908, PMID:22253775, PMID:38655290], and is further controlled post-transcriptionally and post-translationally: m7G-WDR4/EIF2A and METTL3-m6A pathways enhance CCNB1 mRNA stability and translation [PMID:34244479, PMID:39954139]; deubiquitinases USP22 (itself activated by CDK1 phosphorylation) and UCHL1 stabilize the protein by antagonizing proteasomal degradation [PMID:27030811, PMID:38858680]; and degradation proceeds through APC/C-CDC20-coupled and UBA52-APC11 ubiquitylation [PMID:27030811, PMID:31814919]. In oocyte meiosis, alternative polyadenylation generates Ccnb1 mRNAs with short or long 3' UTRs whose differential translation times meiotic re-entry versus the MI/MII transition, with long-3'UTR translation requiring ERK1/2-driven CPEB1 degradation [PMID:28808066, PMID:38048302, PMID:33282880]. CCNB1 function is physiologically required for germ cell proliferation, as conditional knockout in mouse male germ cells causes germ cell depletion and sterility [PMID:29072697].","teleology":[{"year":2012,"claim":"Establishing that CCNB1 is a direct transcriptional target answered how mitotic entry is coupled to cell-cycle gene programs.","evidence":"ChIP and STOX1A gain/loss-of-function with CCNB1 readout in cultured cells","pmids":["22253775"],"confidence":"Medium","gaps":["Does not establish whether STOX1A acts directly versus through cofactors","No structural detail of the promoter element"]},{"year":2015,"claim":"Identifying USP22 as a CDK1-activated deubiquitinase of CCNB1 revealed that cyclin stability is reinforced by a kinase-coupled positive loop, not solely by APC/C-driven destruction.","evidence":"Co-IP, ubiquitination assays, proteasome inhibitor rescue, and CDK1-phosphorylation validation in human cells","pmids":["27030811"],"confidence":"High","gaps":["Quantitative contribution of USP22 versus APC/C to net CCNB1 turnover unresolved","Site of CDK1 phosphorylation on USP22 not detailed"]},{"year":2016,"claim":"Multiple transcription factors (ISL1, later FOXM1, E2F1) were shown to converge on the CCNB1 promoter, explaining how diverse oncogenic signals raise CCNB1 to force G2/M progression.","evidence":"ChIP and overexpression/knockdown with CCNB1 readouts across cancer cell models","pmids":["27183908","29705704","38655290"],"confidence":"Medium","gaps":["Hierarchy or combinatorial logic among these activators not defined","Context-dependence across tissues unclear"]},{"year":2017,"claim":"Dissecting 3'UTR-dependent translational timing answered how a single mRNA can be deployed at distinct meiotic stages without new transcription.","evidence":"In vivo translation reporters with 3'UTR/CPE mutagenesis in mouse oocytes","pmids":["28808066"],"confidence":"High","gaps":["Identity of all trans-acting factors reading the cis-elements incomplete","Does not address mitotic somatic translational control"]},{"year":2017,"claim":"Conditional knockout established the in vivo physiological requirement for CCNB1 in germ cell proliferation rather than meiosis itself.","evidence":"Germ-cell conditional knockout mice with fertility, apoptosis, and Lin28a/let-7 readouts","pmids":["29072697"],"confidence":"High","gaps":["Mechanism linking CCNB1 loss to Lin28a/let-7 change unresolved","Redundancy with CCNB2 not tested"]},{"year":2019,"claim":"Demonstrating MAD1-dependent recruitment of CDK1-CCNB1 to unattached kinetochores and MPS1-S281 phosphorylation redefined CCNB1 as an integral checkpoint component, not merely the downstream kinase that the checkpoint protects.","evidence":"Reciprocal Co-IP, proteomics, phospho-mutant rescue, MPS1-Mis12 tethering, and live-cell imaging in human cells (companion studies)","pmids":["30674583","30674582"],"confidence":"High","gaps":["Structural basis of the MAD1-CCNB1 interface not resolved","Quantitative threshold model of CCNB1 versus PP2A-B55 needs in vivo calibration"]},{"year":2019,"claim":"Defining UBA52-APC11 ubiquitylation of CCNB1 clarified the molecular steps of APC/C-coupled CCNB1 destruction controlling mitotic exit.","evidence":"Co-IP and epistatic knockdown/overexpression with cell-cycle and xenograft readouts in NSCLC cells","pmids":["31814919"],"confidence":"Medium","gaps":["Direct ligase-substrate reconstitution not shown","Relationship to canonical CDC20-APC/C unclear"]},{"year":2021,"claim":"Identifying m7G-WDR4/EIF2A control of CCNB1 mRNA and downstream PI3K/AKT and p53 effects extended CCNB1 regulation to translational layers and linked it to growth/survival signaling.","evidence":"RNA stability and translation reporters, RIP for EIF2A-CCNB1 mRNA, and Co-IP in cancer cells","pmids":["34244479"],"confidence":"Medium","gaps":["Whether p53 ubiquitination is a direct CCNB1-driven effect is not established","Single-lab finding"]},{"year":2021,"claim":"Multiple meiotic regulators (Septin 4, Septin 9, SIN3A) were placed upstream of CCNB1 via APC/C-CDC20 or transcriptional control, mapping how oocyte and early embryonic cell-cycle transitions tune CCNB1 levels.","evidence":"siRNA knockdown with mRNA-rescue epistasis, live imaging, and IP in oocyte/embryo models","pmids":["34189751","36354207","33692994"],"confidence":"Medium","gaps":["Direct biochemical links between these regulators and the APC/C machinery incomplete","Generalizability beyond the specific reproductive contexts unclear"]},{"year":2021,"claim":"Structural analysis of the separase-CDK1-CCNB1-CKS1 complex revealed how CCNB1 contributes to a non-kinase inhibitory mechanism restraining cohesin cleavage in parallel to securin.","evidence":"Structural determination of human separase bound to the CDK1-CCNB1-CKS1 complex (commentary on primary structures)","pmids":["34616878"],"confidence":"Medium","gaps":["Primary structural data not in this corpus","Temporal coordination with securin inhibition in cells not addressed here"]},{"year":2023,"claim":"Discovery of SQLE and UCHL1 as CCNB1-stabilizing interactors broadened the deubiquitination/stability network and connected CCNB1 control to lipid-metabolic and reproductive contexts.","evidence":"Co-IP, ubiquitination and cycloheximide-chase half-life assays with functional readouts","pmids":["37839786","38858680"],"confidence":"Medium","gaps":["Whether SQLE/UCHL1 act directly as enzymes versus scaffolds incompletely resolved","Cell-cycle phase specificity of these interactions unclear"]},{"year":2025,"claim":"METTL3-mediated m6A modification was shown to stabilize CCNB1 mRNA, adding an epitranscriptomic layer transferable via exosomes to drive proliferation.","evidence":"MeRIP, actinomycin D stability assay, and METTL3/CCNB1 knockdown-rescue in fibroblasts","pmids":["39954139"],"confidence":"Medium","gaps":["Reader proteins decoding the m6A mark on CCNB1 not identified","Single-lab finding"]},{"year":2026,"claim":"Direct MAPK1 phosphorylation of CCNB1-Ser128 established a signaling input that gates CCNB1 nuclear translocation and the G2-to-prophase transition.","evidence":"TurboID-MS, in vitro kinase assay, S128A/D mutants, fractionation, and xenograft in TNBC cells","pmids":["41905453"],"confidence":"High","gaps":["Interplay with other reported translocation regulators (e.g., SIAH1) not tested","Whether Ser128 phosphorylation alters CDK1 activation is not addressed"]},{"year":null,"claim":"How the many transcriptional, translational, and stability inputs are quantitatively integrated to produce the precise CCNB1 threshold that governs checkpoint silencing and mitotic exit remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model linking CCNB1 abundance to PP2A-B55 activation in vivo","Relative contributions of competing stability regulators across cell types unknown","Structural basis of kinetochore recruitment interfaces undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11,23]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,4,5]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[4,5,12]}],"complexes":["CDK1-CCNB1 (MPF)","CDK1-CCNB1-CKS1 separase-inhibitory complex"],"partners":["CDK1","MAD1","MPS1","USP22","UCHL1","SQLE","MAPK1","CKS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14635","full_name":"G2/mitotic-specific cyclin-B1","aliases":[],"length_aa":433,"mass_kda":48.3,"function":"Essential for 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France)","url":"https://pubmed.ncbi.nlm.nih.gov/36495514","citation_count":0,"is_preprint":false},{"pmid":"41731977","id":"PMC_41731977","title":"Targeting CCNB1 Repressed Cartilage Degradation Induced by Inflammation Through NF-κB Pathway in Osteoarthritis.","date":"2026","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/41731977","citation_count":0,"is_preprint":false},{"pmid":"41905453","id":"PMC_41905453","title":"MAPK1 phosphorylates CCNB1 at Ser128 to drive mitotic progression and cell proliferation in triple-negative breast cancer.","date":"2026","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41905453","citation_count":0,"is_preprint":false},{"pmid":"41838760","id":"PMC_41838760","title":"Multi-omics analysis identifies CCNB1 as a cell cycle factor driving glioblastoma progression and its inhibition by resveratrol.","date":"2026","source":"PloS 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[Retraction].","date":"2022","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36275181","citation_count":0,"is_preprint":false},{"pmid":"41673703","id":"PMC_41673703","title":"AR-mediated YBX3 suppresses oocyte meiotic resumption in polycystic ovary syndrome by attenuating Pde3A and Ccnb1 expression.","date":"2026","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/41673703","citation_count":0,"is_preprint":false},{"pmid":"41280647","id":"PMC_41280647","title":"Retraction: LINC00346 Acts as a competing endogenous RNA regulating development of hepatocellular carcinoma via modulating CDK1/CCNB1 Axis.","date":"2025","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41280647","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.14.688523","title":"A Pan-Cancer Blueprint of Early Tumor Microenvironment Reprogramming","date":"2025-11-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.688523","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52005,"output_tokens":7807,"usd":0.13656,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17028,"output_tokens":4467,"usd":0.098407,"stage2_stop_reason":"end_turn"},"total_usd":0.234967,"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\": 2019,\n      \"finding\": \"CDK1-CCNB1 localizes to unattached kinetochores (lost upon microtubule attachment) and is recruited there in an MPS1-dependent fashion through direct interaction with the first 100 amino acids of MAD1. This pool of CDK1-CCNB1 creates a positive feedback loop for timely MPS1 kinetochore recruitment and sustained spindle checkpoint arrest, making CDK1-CCNB1 an integral component of the spindle checkpoint.\",\n      \"method\": \"Complementary proteomics, reciprocal Co-IP, cell biological imaging, and genetic rescue experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, proteomic identification, live-cell imaging, and genetic rescue in a single focused study; replicated in companion paper (PMID:30674582)\",\n      \"pmids\": [\"30674583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDK1-CCNB1 phosphorylates MPS1 at S281 to enable its kinetochore binding during mitotic entry; a counteracting phosphatase PP2A-B55 (itself negatively regulated by CDK1-CCNB1) dephosphorylates S281 to promote mitotic exit. This creates a spindle checkpoint-permissive state that persists until CCNB1 concentration falls below a threshold that fully activates PP2A-B55.\",\n      \"method\": \"Phospho-specific mutant analysis (MPS1-S281A/D), tethering bypass experiments (MPS1-Mis12 fusion), quantitative live-cell imaging, and genetic epistasis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in-cell phospho-mutant rescue, direct tethering bypass, and quantitative imaging; companion to PMID:30674583 providing orthogonal mechanistic validation\",\n      \"pmids\": [\"30674582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP22 is a deubiquitinase of CCNB1: it directly interacts with CCNB1, stabilizes it by antagonizing proteasome-mediated degradation in a cell-cycle-specific manner, and its deubiquitinating activity toward CCNB1 is enhanced by CDK1-mediated phosphorylation of USP22. APC/C-CDC20 targets USP22 for degradation during mitotic exit, thereby permitting CCNB1 degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor rescue, cell-cycle fractionation, USP22 knockdown with CCNB1 protein-level readout\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct biochemical deubiquitinase assay, Co-IP, CDK1 phosphorylation validation, and APC/C epistasis in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"27030811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR4 (m7G methyltransferase) promotes CCNB1 mRNA stability and translation by enhancing binding of EIF2A to CCNB1 mRNA. CCNB1 in turn promotes PI3K/AKT phosphorylation and reduces p53 protein expression by promoting p53 ubiquitination.\",\n      \"method\": \"RNA stability assays, translation reporter assays, RIP (RNA immunoprecipitation) for EIF2A-CCNB1 mRNA interaction, Co-IP, WDR4 knockdown/overexpression with protein-level readouts\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP confirmed EIF2A-CCNB1 mRNA binding, multiple functional assays, but single lab\",\n      \"pmids\": [\"34244479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The timing of Ccnb1 mRNA translation in mouse oocytes is determined by the presence of transcripts with distinct 3' UTRs generated by alternative polyadenylation: inclusion or exclusion of specific cis-acting elements directs early vs. late translational activation during meiotic maturation.\",\n      \"method\": \"In vivo translation reporter assays with 3'UTR variants, cytoplasmic polyadenylation element (CPE) mutation analysis, oocyte microinjection\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo functional dissection of cis-regulatory elements with mutagenesis and reporter assays in mouse oocytes; extended by in vivo gene-editing study (PMID:38048302)\",\n      \"pmids\": [\"28808066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Alternative cleavage and polyadenylation (APA) generates Ccnb1 mRNA variants with short or long 3' UTRs; in vivo mutation of proximal (short) polyadenylation elements showed that short-3'UTR mRNA translation specifies the Cyclin B1 levels that set the timing of meiotic re-entry, whereas long-3'UTR mRNA translation drives Cyclin B1 accumulation during the MI/MII transition.\",\n      \"method\": \"CRISPR/gene editing to mutate polyadenylation signals in mice, in vivo loss-of-function experiments, mRNA variant quantification\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo gene editing with loss-of-function and phenotypic cell-cycle readout; single lab but rigorous genetic approach\",\n      \"pmids\": [\"38048302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERK1/2 (MAPK) activation is required for translational activation of Ccnb1 long-3'UTR transcripts during meiotic resumption in mouse oocytes. CDK1 activity also contributes to Ccnb1 mRNA translational activation. ERK1/2-driven degradation (not just phosphorylation) of CPEB1 is the principal mechanism, whereas CDK1 only phosphorylates CPEB1 without triggering its degradation.\",\n      \"method\": \"MAPK inhibition/activation in GV-stage oocytes, CDK1 inhibitor/activator treatments, CPEB1 phosphorylation and degradation assays, Ccnb1-3'UTR translation reporters\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic manipulation with multiple readouts, single lab\",\n      \"pmids\": [\"33282880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXM1 directly binds the CCNB1 promoter and transcriptionally activates CCNB1 expression; CCNB1 is required for FOXM1-driven cell proliferation in hepatocellular carcinoma cells.\",\n      \"method\": \"ChIP (chromatin immunoprecipitation) demonstrating FOXM1 binding to CCNB1 promoter, FOXM1 knockdown with mRNA/protein-level readouts, CCNB1 rescue experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus loss-of-function/rescue functional assays, single lab\",\n      \"pmids\": [\"29705704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ISL1 transcription factor directly binds conserved sites in the CCNB1 (and CCNB2, c-MYC) promoters/enhancers to activate their expression, promoting G2/M cell cycle transition in gastric cancer cells.\",\n      \"method\": \"ChIP demonstrating ISL1 binding to CCNB1 promoter/enhancer, ISL1 overexpression and knockdown with CCNB1 mRNA/protein-level readouts, cell cycle analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional rescue experiments, single lab\",\n      \"pmids\": [\"27183908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STOX1A transcription factor directly binds the CCNB1 promoter (shown by ChIP) and upregulates cyclin B1 expression, promoting mitotic entry.\",\n      \"method\": \"ChIP, STOX1A overexpression and knockdown with CCNB1 expression readout, cell cycle analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP and functional experiments, but single lab and single paper\",\n      \"pmids\": [\"22253775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCNB1 degradation by APC11 is mediated through UBA52-driven ubiquitylation of CCNB1; knockdown of APC11 leads to G2/M arrest even when UBA52 is overexpressed, placing APC11 downstream of UBA52 in regulating CCNB1 stability and cell cycle progression in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown and gene overexpression, cell cycle analysis, xenograft tumor assays\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP plus epistatic knockdown/overexpression experiments with cell cycle readout, single lab\",\n      \"pmids\": [\"31814919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Circ-CCNB1 acts as a sponge for miR-223, leading to elevated SIAH1 expression; SIAH1 in turn inhibits CCNB1 nuclear translocation. This circ-CCNB1/miR-223/SIAH1 axis suppresses trophoblast proliferation and invasion, establishing that CCNB1 nuclear translocation is regulated through SIAH1.\",\n      \"method\": \"RNA pull-down, dual luciferase reporter assay, siRNA knockdown, nuclear-cytoplasmic fractionation, Co-IP/immunofluorescence for CCNB1 localization\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNA pull-down plus luciferase plus fractionation assays; single lab, but multiple orthogonal methods\",\n      \"pmids\": [\"35731831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCNB1 is required for normal proliferation of gonocytes and spermatogonia in mouse testes; conditional knockout of CCNB1 in male germ cells causes male sterility due to germ cell depletion and increased apoptosis, and also promotes spermatogonial differentiation by downregulating Lin28a and upregulating let-7 miRNA. Notably, ablation of CCNB1 in premeiotic cells (spermatocytes) did not affect meiosis or male fertility, suggesting CCNB1 is dispensable for meiosis in spermatocytes.\",\n      \"method\": \"Conditional knockout mice, immunofluorescence, TUNEL assay, Lin28a/let-7 expression analysis, fertility assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout with multiple cellular readouts including fertility phenotype, single lab\",\n      \"pmids\": [\"29072697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIN3A regulates CCNB1 expression in porcine early embryos; SIN3A depletion causes a two-cell developmental block associated with dramatically reduced CCNB1 transcript levels, and injection of exogenous CCNB1 mRNA into SIN3A-depleted embryos partially rescues development past the two-cell stage, placing SIN3A upstream of CCNB1 in early embryonic cell cycle progression.\",\n      \"method\": \"siRNA knockdown, RNA-seq, mRNA microinjection rescue, immunofluorescence\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with mRNA rescue establishing epistasis, single lab\",\n      \"pmids\": [\"33692994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Septin 4 regulates CCNB1 accumulation in mouse oocytes via APC/C-CDC20: depletion of Septin 4 increases CDC20 expression, reduces CCNB1 accumulation, and causes GV arrest; this arrest can be rescued by CCNB1 overexpression or CDC20 depletion, placing Septin 4 upstream of APC/C-CDC20-mediated CCNB1 stabilization at the meiotic G2/M transition.\",\n      \"method\": \"siRNA knockdown, mRNA microinjection rescue, immunoprecipitation, immunofluorescence, time-lapse live imaging, immunoblotting\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue experiments with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34189751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Septin 9 depletion in mouse oocytes causes MI arrest with persistent SAC signaling (Mad1, BubR1 on kinetochores), failure of CDC20 upregulation and CCNB1 degradation, and disrupted kinetochore-microtubule connections; CDC20 mRNA microinjection partially rescues the arrest, establishing that Septin 9 promotes MI-AI transition through SAC/APC/C-CDC20-dependent CCNB1 degradation.\",\n      \"method\": \"siRNA knockdown, mRNA microinjection rescue, time-lapse live imaging, immunofluorescence for SAC proteins, immunoblotting for CDC20/CCNB1\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue and multiple protein-level readouts, single lab\",\n      \"pmids\": [\"36354207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human separase is inhibited by CDK1-CCNB1-CKS1 complex; structural analysis defined molecular mechanisms by which this complex blocks separase's cohesin-cleavage activity, in parallel with inhibition by securin.\",\n      \"method\": \"Structural biology (cryo-EM/crystallography implied by 'structures') of human separase bound to CDK1-CCNB1-CKS1 complex\",\n      \"journal\": \"Molecular & cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural determination reported but only a commentary/brief communication; references primary structural paper not directly in this corpus\",\n      \"pmids\": [\"34616878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SQLE (squalene epoxidase) directly interacts with CCNB1 and alleviates its ubiquitination modification, enhancing CCNB1 protein stability; this SQLE-CCNB1 interaction was demonstrated to promote breast cancer cell cycle progression and inhibit ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, ubiquitination assay, SQLE overexpression/knockdown with CCNB1 protein-level readout, xenograft\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP plus ubiquitination assay plus functional rescue, single lab\",\n      \"pmids\": [\"37839786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UCHL1 (deubiquitinase) directly binds CCNB1, prolongs its half-life and inhibits its degradation, thereby promoting granulosa cell proliferation; the flavonoid isovitexin enhances UCHL1 enzymatic activity and downstream CCNB1 stabilization.\",\n      \"method\": \"Co-immunoprecipitation, half-life (cycloheximide chase) assays, UCHL1 overexpression/knockdown with CCNB1 protein-level readout, enzyme activity assay\",\n      \"journal\": \"Journal of animal science and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding by Co-IP, half-life assay establishing stabilization mechanism, single lab\",\n      \"pmids\": [\"38858680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3 mediates m6A modification of CCNB1 mRNA, upregulating its stability and expression; METTL3-modified ASC-exosomes transfer this activity to dermal fibroblasts, enhancing their proliferation and migration in a CCNB1-dependent manner.\",\n      \"method\": \"Methylated RNA immunoprecipitation (MeRIP), actinomycin D mRNA stability assay, qPCR, METTL3 overexpression/knockdown, CCNB1 knockdown rescue experiments\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP assay plus mRNA stability and functional rescue, single lab\",\n      \"pmids\": [\"39954139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AURKA interacts with transcription factor E2F1 and recruits it to the CCNB1 promoter to drive CCNB1 transcription; CCNB1 expression is required for AURKA-induced renal cell carcinoma progression.\",\n      \"method\": \"Co-immunoprecipitation (AURKA-E2F1 interaction), ChIP (E2F1 at CCNB1 promoter), luciferase reporter assay, AURKA/CCNB1 knockdown with functional rescue\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and luciferase with functional rescue, single lab\",\n      \"pmids\": [\"38655290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNRPB regulates CCNB1 expression through FOXM1-mediated transcriptional activation: SNRPB interacts with FOXM1 (shown by Co-IP), and this complex drives CCNB1 promoter activity (shown by ChIP). CCNB1 knockdown reverses proliferative and tumorigenic effects of SNRPB overexpression in HCC.\",\n      \"method\": \"Co-immunoprecipitation (SNRPB-FOXM1), ChIP (FOXM1 at CCNB1 promoter), CCNB1 knockdown rescue in SNRPB-overexpressing cells, in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP plus functional epistasis, single lab\",\n      \"pmids\": [\"40682115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MEOX1 transcription factor binds the transcriptional initiation site of CCNB1 and suppresses its expression; CCNB1 overexpression rescues the proliferation inhibition caused by MEOX1 overexpression in NSCLC cells, placing MEOX1 upstream of CCNB1 in a suppressive axis.\",\n      \"method\": \"ChIP or EMSA (binding to CCNB1 transcription initiation site), CCNB1 rescue of MEOX1 overexpression phenotype, in vitro and in vivo functional assays\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single binding assay with functional rescue; method detail limited in abstract\",\n      \"pmids\": [\"34837450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MAPK1 (ERK2) directly phosphorylates CCNB1 at Ser128; this phosphorylation facilitates CCNB1 nuclear translocation and the G2-to-prophase transition. A phospho-mimetic CCNB1-S128D mutant partially rescues proliferation defects caused by MAPK1 knockdown in TNBC cells.\",\n      \"method\": \"TurboID proximity labeling + mass spectrometry to identify MAPK1-CCNB1 interaction, Co-IP, in vitro kinase assay, CCNB1-S128A/D mutants, nuclear-cytoplasmic fractionation, immunofluorescence, cell cycle analysis, xenograft\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay establishing direct phosphorylation, site-directed mutagenesis, nuclear translocation readout, and in vivo xenograft in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"41905453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HROB suppresses LUAD progression by interacting with ZC3HC1 and reducing its phosphorylation at Ser354; this de-phosphorylation event facilitates K27-linked ubiquitination of CCNB1, promoting its proteasomal degradation and impairing the G2-to-M phase transition.\",\n      \"method\": \"Co-IP (HROB-ZC3HC1 interaction), phospho-specific analysis of ZC3HC1-Ser354, ubiquitination assay for K27-linked CCNB1 ubiquitination, proteasomal degradation assay, cell cycle analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and cell cycle readout; single lab with multiple biochemical methods\",\n      \"pmids\": [\"40654113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GADD45G directly interacts with CDK1 and CCNB1 (shown by Co-IP), and negatively regulates CDK1/CCNB1 at transcript and protein levels; reduced GADD45G expression (due to promoter methylation) leads to invasive behavior in endometrial cancer cells through upregulated CDK1/CCNB1.\",\n      \"method\": \"Co-immunoprecipitation (GADD45G with CDK1 and CCNB1), methylation-specific PCR, qRT-PCR and western blot, functional invasion assays\",\n      \"journal\": \"Journal of cancer research and therapeutics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with limited functional follow-up, single lab\",\n      \"pmids\": [\"39206984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Luteolin directly binds CCNB1 (confirmed by molecular docking and surface plasmon resonance), disrupts the CCNB1/CDK1 complex, induces G2/M arrest, and suppresses pancreatic cancer growth in vitro and in vivo.\",\n      \"method\": \"Surface plasmon resonance (direct binding assay), molecular docking, CCNB1/CDK1 co-immunoprecipitation post-treatment, flow cytometry for cell cycle, xenograft model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SPR establishes direct binding, Co-IP shows complex disruption, functional in vivo validation; single lab\",\n      \"pmids\": [\"41298459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPR stabilizes CCNB1 mRNA; knockdown of CCNB1 abolishes hnRNPR-induced cell growth in gastric cancer, placing hnRNPR-CCNB1 as a functional axis regulating proliferation.\",\n      \"method\": \"hnRNPR knockdown with mRNA-level CCNB1 readout (mRNA stability implied), CCNB1 knockdown rescue of hnRNPR overexpression phenotype\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mRNA stabilization mechanism inferred from expression changes without direct RNA-binding or stability assay described in abstract; single lab\",\n      \"pmids\": [\"31527303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RAD6A (E2 ubiquitin-conjugating enzyme) positively regulates CCNB1 expression through upregulation of H2B ubiquitination, promoting ESCC progression; RAD6A knockdown reduces both H2B ubiquitination and CCNB1 levels.\",\n      \"method\": \"RAD6A shRNA knockdown with H2B ubiquitination and CCNB1 protein-level readout, correlation analysis in tissues, xenograft\",\n      \"journal\": \"Biological procedures online\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect epigenetic mechanism inferred from knockdown correlations without direct chromatin or recruitment assay for CCNB1 promoter; single lab\",\n      \"pmids\": [\"35321657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"N-glycosylation of ERLIN2 at asparagine 106 enhances its interaction with CCNB1, leading to dysregulated (elevated) CCNB1 expression and accelerating HCC progression; MARCHF6 E3 ligase mediates ubiquitination degradation of ERLIN2, an effect more pronounced when N106 glycosylation is inhibited.\",\n      \"method\": \"Co-immunoprecipitation (ERLIN2-CCNB1 interaction), N106Q mutant analysis, MARCHF6 knockdown, N-glycosylation inhibition with CCNB1 protein readout\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with mutant analysis; mechanism of how ERLIN2 elevates CCNB1 is not fully established from the abstract; single lab\",\n      \"pmids\": [\"42166002\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Cyclin B1 (CCNB1) is the regulatory subunit of the CDK1-CCNB1 (MPF) kinase complex that drives mitotic and meiotic G2/M entry; its levels are tightly controlled through a balance of transcriptional activation (by FOXM1, ISL1, STOX1A, AURKA-E2F1, SNRPB-FOXM1), post-transcriptional regulation (3' UTR-dependent translational timing via alternative polyadenylation during oocyte meiosis; mRNA stabilization by hnRNPR and METTL3-mediated m6A modification; WDR4-m7G-EIF2A-dependent translation), and protein stability control (deubiquitination by USP22 activated by CDK1 phosphorylation; deubiquitination by UCHL1; stabilization by SQLE; degradation via APC/C-CDC20/UBA52-APC11 and HROB-ZC3HC1-K27-ubiquitin pathways); at kinetochores, CDK1-CCNB1 is recruited by MPS1-dependent interaction with MAD1 where it phosphorylates MPS1-S281 to enable spindle assembly checkpoint signaling, forming a positive feedback loop that sustains checkpoint arrest until CCNB1 levels fall below the threshold that fully activates the counteracting PP2A-B55 phosphatase; MAPK1 (ERK2) directly phosphorylates CCNB1 at Ser128 to promote its nuclear translocation and mitotic entry; CCNB1 also inhibits separase by forming an inhibitory CDK1-CCNB1-CKS1 complex, and promotes p53 ubiquitination/degradation, PI3K/AKT signaling, and EMT-related gene expression downstream of its cell-cycle kinase activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Cyclin B1 (CCNB1) is the regulatory subunit of the CDK1-CCNB1 mitotic kinase that drives the G2/M transition in mitotic and meiotic cell cycles, and its activity is gated by exquisitely tight control of its abundance, localization, and timing [#0, #4]. Beyond simply activating CDK1, CDK1-CCNB1 is an integral component of the spindle assembly checkpoint: it localizes to unattached kinetochores in an MPS1-dependent manner through direct interaction with the N-terminal 100 residues of MAD1, and phosphorylates MPS1 at Ser281 to sustain its kinetochore binding, creating a positive feedback loop that maintains checkpoint arrest until CCNB1 levels fall below the threshold that fully activates the counteracting PP2A-B55 phosphatase to permit mitotic exit [#0, #1]. CDK1-CCNB1 also inhibits separase by forming an inhibitory CDK1-CCNB1-CKS1 complex that blocks cohesin cleavage [#16]. Nuclear translocation of CCNB1 — a prerequisite for mitotic entry — is promoted by direct MAPK1 (ERK2) phosphorylation at Ser128 [#23]. CCNB1 abundance is set transcriptionally by activators that bind its promoter, including FOXM1, ISL1, STOX1A, and E2F1 recruited by AURKA [#7, #8, #9, #20], and is further controlled post-transcriptionally and post-translationally: m7G-WDR4/EIF2A and METTL3-m6A pathways enhance CCNB1 mRNA stability and translation [#3, #19]; deubiquitinases USP22 (itself activated by CDK1 phosphorylation) and UCHL1 stabilize the protein by antagonizing proteasomal degradation [#2, #18]; and degradation proceeds through APC/C-CDC20-coupled and UBA52-APC11 ubiquitylation [#2, #10]. In oocyte meiosis, alternative polyadenylation generates Ccnb1 mRNAs with short or long 3' UTRs whose differential translation times meiotic re-entry versus the MI/MII transition, with long-3'UTR translation requiring ERK1/2-driven CPEB1 degradation [#4, #5, #6]. CCNB1 function is physiologically required for germ cell proliferation, as conditional knockout in mouse male germ cells causes germ cell depletion and sterility [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing that CCNB1 is a direct transcriptional target answered how mitotic entry is coupled to cell-cycle gene programs.\",\n      \"evidence\": \"ChIP and STOX1A gain/loss-of-function with CCNB1 readout in cultured cells\",\n      \"pmids\": [\"22253775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish whether STOX1A acts directly versus through cofactors\", \"No structural detail of the promoter element\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying USP22 as a CDK1-activated deubiquitinase of CCNB1 revealed that cyclin stability is reinforced by a kinase-coupled positive loop, not solely by APC/C-driven destruction.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, proteasome inhibitor rescue, and CDK1-phosphorylation validation in human cells\",\n      \"pmids\": [\"27030811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of USP22 versus APC/C to net CCNB1 turnover unresolved\", \"Site of CDK1 phosphorylation on USP22 not detailed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Multiple transcription factors (ISL1, later FOXM1, E2F1) were shown to converge on the CCNB1 promoter, explaining how diverse oncogenic signals raise CCNB1 to force G2/M progression.\",\n      \"evidence\": \"ChIP and overexpression/knockdown with CCNB1 readouts across cancer cell models\",\n      \"pmids\": [\"27183908\", \"29705704\", \"38655290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy or combinatorial logic among these activators not defined\", \"Context-dependence across tissues unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dissecting 3'UTR-dependent translational timing answered how a single mRNA can be deployed at distinct meiotic stages without new transcription.\",\n      \"evidence\": \"In vivo translation reporters with 3'UTR/CPE mutagenesis in mouse oocytes\",\n      \"pmids\": [\"28808066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of all trans-acting factors reading the cis-elements incomplete\", \"Does not address mitotic somatic translational control\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional knockout established the in vivo physiological requirement for CCNB1 in germ cell proliferation rather than meiosis itself.\",\n      \"evidence\": \"Germ-cell conditional knockout mice with fertility, apoptosis, and Lin28a/let-7 readouts\",\n      \"pmids\": [\"29072697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking CCNB1 loss to Lin28a/let-7 change unresolved\", \"Redundancy with CCNB2 not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating MAD1-dependent recruitment of CDK1-CCNB1 to unattached kinetochores and MPS1-S281 phosphorylation redefined CCNB1 as an integral checkpoint component, not merely the downstream kinase that the checkpoint protects.\",\n      \"evidence\": \"Reciprocal Co-IP, proteomics, phospho-mutant rescue, MPS1-Mis12 tethering, and live-cell imaging in human cells (companion studies)\",\n      \"pmids\": [\"30674583\", \"30674582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the MAD1-CCNB1 interface not resolved\", \"Quantitative threshold model of CCNB1 versus PP2A-B55 needs in vivo calibration\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining UBA52-APC11 ubiquitylation of CCNB1 clarified the molecular steps of APC/C-coupled CCNB1 destruction controlling mitotic exit.\",\n      \"evidence\": \"Co-IP and epistatic knockdown/overexpression with cell-cycle and xenograft readouts in NSCLC cells\",\n      \"pmids\": [\"31814919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ligase-substrate reconstitution not shown\", \"Relationship to canonical CDC20-APC/C unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying m7G-WDR4/EIF2A control of CCNB1 mRNA and downstream PI3K/AKT and p53 effects extended CCNB1 regulation to translational layers and linked it to growth/survival signaling.\",\n      \"evidence\": \"RNA stability and translation reporters, RIP for EIF2A-CCNB1 mRNA, and Co-IP in cancer cells\",\n      \"pmids\": [\"34244479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p53 ubiquitination is a direct CCNB1-driven effect is not established\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple meiotic regulators (Septin 4, Septin 9, SIN3A) were placed upstream of CCNB1 via APC/C-CDC20 or transcriptional control, mapping how oocyte and early embryonic cell-cycle transitions tune CCNB1 levels.\",\n      \"evidence\": \"siRNA knockdown with mRNA-rescue epistasis, live imaging, and IP in oocyte/embryo models\",\n      \"pmids\": [\"34189751\", \"36354207\", \"33692994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical links between these regulators and the APC/C machinery incomplete\", \"Generalizability beyond the specific reproductive contexts unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural analysis of the separase-CDK1-CCNB1-CKS1 complex revealed how CCNB1 contributes to a non-kinase inhibitory mechanism restraining cohesin cleavage in parallel to securin.\",\n      \"evidence\": \"Structural determination of human separase bound to the CDK1-CCNB1-CKS1 complex (commentary on primary structures)\",\n      \"pmids\": [\"34616878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primary structural data not in this corpus\", \"Temporal coordination with securin inhibition in cells not addressed here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery of SQLE and UCHL1 as CCNB1-stabilizing interactors broadened the deubiquitination/stability network and connected CCNB1 control to lipid-metabolic and reproductive contexts.\",\n      \"evidence\": \"Co-IP, ubiquitination and cycloheximide-chase half-life assays with functional readouts\",\n      \"pmids\": [\"37839786\", \"38858680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SQLE/UCHL1 act directly as enzymes versus scaffolds incompletely resolved\", \"Cell-cycle phase specificity of these interactions unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"METTL3-mediated m6A modification was shown to stabilize CCNB1 mRNA, adding an epitranscriptomic layer transferable via exosomes to drive proliferation.\",\n      \"evidence\": \"MeRIP, actinomycin D stability assay, and METTL3/CCNB1 knockdown-rescue in fibroblasts\",\n      \"pmids\": [\"39954139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reader proteins decoding the m6A mark on CCNB1 not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Direct MAPK1 phosphorylation of CCNB1-Ser128 established a signaling input that gates CCNB1 nuclear translocation and the G2-to-prophase transition.\",\n      \"evidence\": \"TurboID-MS, in vitro kinase assay, S128A/D mutants, fractionation, and xenograft in TNBC cells\",\n      \"pmids\": [\"41905453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay with other reported translocation regulators (e.g., SIAH1) not tested\", \"Whether Ser128 phosphorylation alters CDK1 activation is not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many transcriptional, translational, and stability inputs are quantitatively integrated to produce the precise CCNB1 threshold that governs checkpoint silencing and mitotic exit remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model linking CCNB1 abundance to PP2A-B55 activation in vivo\", \"Relative contributions of competing stability regulators across cell types unknown\", \"Structural basis of kinetochore recruitment interfaces undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 4, 5]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [4, 5, 12]}\n    ],\n    \"complexes\": [\n      \"CDK1-CCNB1 (MPF)\",\n      \"CDK1-CCNB1-CKS1 separase-inhibitory complex\"\n    ],\n    \"partners\": [\n      \"CDK1\",\n      \"MAD1\",\n      \"MPS1\",\n      \"USP22\",\n      \"UCHL1\",\n      \"SQLE\",\n      \"MAPK1\",\n      \"CKS1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}