{"gene":"CCNB1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2019,"finding":"CDK1-CCNB1 localizes to unattached kinetochores in an MPS1-dependent manner through interaction with the first 100 amino acids of MAD1, forming a positive feedback loop that promotes timely MPS1 recruitment to kinetochores and sustained spindle checkpoint arrest, establishing CDK1-CCNB1 as an integral component of the spindle assembly checkpoint.","method":"Complementary proteomic analysis, Co-IP, cell biological analysis (live imaging, immunofluorescence), and epistasis with MPS1 inhibition","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, proteomics, and functional epistasis with defined cellular phenotype, replicated across two companion papers","pmids":["30674583"],"is_preprint":false},{"year":2019,"finding":"CDK1-CCNB1 phosphorylates MPS1 at S281 in its kinetochore-binding domain to promote MPS1 engagement with unattached kinetochores, enabling spindle checkpoint signaling; PP2A-B55 (itself negatively regulated by CDK1-CCNB1) counteracts this phosphorylation, and only becomes fully active once CCNB1 concentration falls below a threshold, prolonging the checkpoint-responsive period.","method":"Phospho-mutant analysis (MPS1-S281A), direct kinetochore tethering bypass experiment, cell cycle synchronization, immunofluorescence, and kinase/phosphatase epistasis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro and cellular phospho-mutant experiments with functional rescue, published alongside companion paper","pmids":["30674582"],"is_preprint":false},{"year":2021,"finding":"Structures of human separase bound to CDK1-CCNB1-CKS1 complex reveal molecular mechanisms by which this complex inhibits separase's cohesin-cleavage protease activity, distinct from the securin inhibition mode.","method":"Structural analysis (cryo-EM/crystallography) of human separase-CDK1-CCNB1-CKS1 complex","journal":"Molecular & cellular oncology","confidence":"High","confidence_rationale":"Tier 1 — structural determination of the inhibitory complex with functional validation of cohesin cleavage inhibition","pmids":["34616878"],"is_preprint":false},{"year":2015,"finding":"USP22 is a deubiquitinase of CCNB1 that stabilizes CCNB1 by antagonizing APC/C-mediated proteasomal degradation in a cell cycle-specific manner; CDK1 phosphorylates USP22 to enhance its deubiquitinating activity toward CCNB1, and APC/C-CDC20 targets USP22 for degradation during M phase exit, allowing subsequent CCNB1 degradation.","method":"Co-IP, in vitro deubiquitination assay, cell cycle-specific fractionation, siRNA knockdown, USP22 phosphorylation analysis, xenograft tumor assay","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro deubiquitination assay combined with Co-IP, cell cycle fractionation, and mutagenesis, multiple orthogonal methods in one study","pmids":["27030811"],"is_preprint":false},{"year":2019,"finding":"circ-Ccnb1 interacts with both Ccnb1 and Cdk1 proteins and dissociates the Ccnb1-Cdk1 complex by forming a larger complex (circ-Ccnb1/Ccnb1/Cdk1), thereby suppressing Ccnb1-driven cell migration, invasion, proliferation and survival; ectopic delivery of circ-Ccnb1 inhibited tumor growth in vivo.","method":"Co-IP/RNA pulldown, immunofluorescence (cytosolic/nuclear complex localization), in vivo tumor delivery experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and functional rescue experiments with in vivo validation, single lab","pmids":["31199987"],"is_preprint":false},{"year":2018,"finding":"circ-Ccnb1 precipitates wild-type p53 via H2AX as a bridge, allowing Bclaf1 to bind Bcl2 and promote cell survival; in p53 mutant cells, circ-Ccnb1 instead forms a complex with H2AX and Bclaf1, inducing cell death.","method":"Proteomics, RNA pulldown, Co-IP, microarray analysis, in vivo tumor delivery","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — proteomics plus Co-IP with functional validation, single lab","pmids":["29795334"],"is_preprint":false},{"year":2021,"finding":"WDR4, an m7G methyltransferase, promotes CCNB1 mRNA stability and translation by enhancing the binding of translation initiation factor EIF2A to CCNB1 mRNA; this is part of an MYC/WDR4/CCNB1 signaling axis in HCC.","method":"m7G methylation profiling, RIP assay, mRNA stability assays, Western blot, functional rescue experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic RIP/stability assays in single lab with functional rescue","pmids":["34244479"],"is_preprint":false},{"year":2018,"finding":"FOXM1 directly binds to the promoter region of CCNB1 and transcriptionally activates CCNB1 expression to drive HCC cell proliferation; loss of CCNB1 abolishes FOXM1-driven proliferation.","method":"ChIP assay, luciferase reporter assay, siRNA knockdown, rescue experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus reporter assay with functional rescue, single lab","pmids":["29705704"],"is_preprint":false},{"year":2020,"finding":"FOXM1 promotes CCNB1 transcription in cervical squamous cell carcinoma by binding to the CCNB1 promoter and recruiting the histone acetyltransferase CBP/P300, thereby increasing histone acetylation at the CCNB1 promoter locus.","method":"ChIP assay, histone ChIP-Seq analysis, luciferase reporter assay, siRNA knockdown, rescue experiments","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 2-3 — ChIP and reporter assay, but the paper was subsequently retracted (PMID 36275181)","pmids":["33299327"],"is_preprint":false},{"year":2024,"finding":"AURKA interacts with transcription factor E2F1 and recruits it to the CCNB1 promoter to drive CCNB1 transcription, thereby promoting renal cell carcinoma progression.","method":"Co-IP, ChIP assay, luciferase reporter assay, siRNA knockdown, xenograft model","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus ChIP with functional validation, single lab","pmids":["38655290"],"is_preprint":false},{"year":2012,"finding":"The transcription factor STOX1A directly binds to the CCNB1 promoter (demonstrated by chromatin immunoprecipitation) and upregulates cyclin B1 expression to promote mitotic entry.","method":"ChIP assay, siRNA knockdown/overexpression, gene expression profiling","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstration of direct promoter binding with functional consequence, single lab","pmids":["22253775"],"is_preprint":false},{"year":2016,"finding":"ISL1 transcription factor activates CCNB1 expression in gastric cancer by binding to conserved sites on the CCNB1 promoter or enhancer, thereby facilitating G2/M cell cycle transition.","method":"ChIP assay, luciferase reporter assay, siRNA knockdown, xenograft model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay with functional validation, single lab","pmids":["27183908"],"is_preprint":false},{"year":2019,"finding":"APC11, via UBA52-mediated ubiquitination, promotes CCNB1 degradation; APC11 knockdown causes G2/M arrest even in the presence of overexpressed UBA52, establishing APC11 as the E3 ligase mediating UBA52-dependent CCNB1 ubiquitylation and subsequent proteasomal degradation.","method":"Co-IP/proteomics, siRNA knockdown, overexpression rescue, xenograft tumor assay","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and epistasis experiments with functional phenotype, single lab","pmids":["31814919"],"is_preprint":false},{"year":2017,"finding":"Timing of Ccnb1 mRNA translation during mouse oocyte meiotic maturation is determined by transcripts with different 3' UTRs generated through alternative polyadenylation; the short 3' UTR mRNA is translated early (setting meiotic re-entry timing) while the long 3' UTR mRNA drives Cyclin B1 accumulation during MI/MII transition, as demonstrated by in vivo loss-of-function mutations in polyadenylation elements.","method":"Gene editing in mice (mutations in proximal and distal polyadenylation elements), in vivo loss-of-function experiments, mRNA variant analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — in vivo gene editing with specific polyadenylation element mutations and clear phenotypic separation of mRNA variant functions","pmids":["28808066","38048302"],"is_preprint":false},{"year":2020,"finding":"ERK1/2 (MAPK cascade) activation promotes Ccnb1 mRNA translation during mouse oocyte maturation by triggering CPEB1 phosphorylation and degradation; CDK1 activity also contributes to CPEB1 phosphorylation (but not degradation); both kinases cooperate in a positive feedback loop to activate Ccnb1 translation.","method":"Pharmacological inhibition of MAPK/CDK1, CPEB1 phosphorylation analysis, meiotic maturation assays in mouse oocytes","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis with mechanistic follow-up on CPEB1, single lab","pmids":["33282880"],"is_preprint":false},{"year":2021,"finding":"Septin 4 regulates CCNB1 protein stabilization via APC/C-CDC20 during meiotic G2/M transition in mouse oocytes; Septin 4 depletion reduces CCNB1 accumulation and causes GV arrest, while CDC20 levels paradoxically increase; overexpressing CCNB1 or depleting CDC20 rescues GVBD.","method":"siRNA microinjection, mRNA microinjection rescue, immunofluorescence, Co-IP, time-lapse imaging, Western blot","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA epistasis with genetic rescue experiments, multiple orthogonal methods, single lab","pmids":["34189751"],"is_preprint":false},{"year":2022,"finding":"Septin 9 depletion in mouse oocytes prevents APC/C-CDC20-mediated CCNB1 degradation at the MI/AI transition by disrupting kinetochore-microtubule attachment and maintaining SAC (Mad1/BubR1) activity; CDC20 mRNA microinjection partially rescues the arrest.","method":"siRNA and mRNA microinjection, time-lapse live imaging, immunofluorescence, Western blot, SAC marker analysis","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis with genetic rescue, multiple orthogonal methods, single lab","pmids":["36354207"],"is_preprint":false},{"year":2017,"finding":"CCNB1 is required for normal proliferation of gonocytes and spermatogonia in mouse spermatogenesis; conditional knockout of CCNB1 in male germ cells causes sterility due to germ cell depletion and increased apoptosis, while ablation in premeiotic spermatocytes does not affect meiosis, indicating CCNB1 is dispensable for meiosis of spermatocytes.","method":"Conditional knockout mice, histological analysis, apoptosis assays, let-7 miRNA and Lin28a expression analysis","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — clean conditional KO in mice with specific cell-type phenotypic readouts and mechanistic follow-up","pmids":["29072697"],"is_preprint":false},{"year":2022,"finding":"Circ-CCNB1 inhibits trophoblast proliferation and invasion by sponging miR-223, which in turn targets SIAH1; elevated SIAH1 promotes CCNB1 nuclear translocation, and circ-CCNB1/miR-223/SIAH1 axis modulates nuclear CCNB1 levels to regulate trophoblast function in spontaneous abortion.","method":"siRNA knockdown, mRNA overexpression, RNA pulldown, dual-luciferase reporter assay, immunofluorescence for nuclear localization","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA pulldown and luciferase assay with functional localization data, single lab","pmids":["35731831"],"is_preprint":false},{"year":2025,"finding":"METTL3 upregulates CCNB1 expression through m6A modification of CCNB1 mRNA, enhancing its stability; METTL3-modified ASC-exosomes transfer this effect to dermal fibroblasts to enhance their proliferation and migration.","method":"Methylated RNA immunoprecipitation (MeRIP), actinomycin D mRNA stability assay, siRNA knockdown, overexpression, Western blot","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 2 — MeRIP plus mRNA stability assay with functional rescue, single lab","pmids":["39954139"],"is_preprint":false},{"year":2023,"finding":"SQLE (squalene epoxidase) physically interacts with CCNB1 (demonstrated by Co-IP and immunofluorescence) and reduces CCNB1 ubiquitination, thereby stabilizing the CCNB1 protein and decreasing intracellular ROS to inhibit ferroptosis in breast cancer.","method":"Co-IP, immunofluorescence, ubiquitination assay, ROS measurement, xenograft assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with ubiquitination assay and functional validation, single lab","pmids":["37839786"],"is_preprint":false},{"year":2024,"finding":"UCHL1 directly binds CCNB1, prolongs CCNB1 half-life, and inhibits its degradation (deubiquitinase activity), thereby promoting porcine granulosa cell proliferation; the flavonoid isovitexin enhances UCHL1 enzyme activity to further promote proliferation.","method":"Co-IP, half-life assay, siRNA knockdown and overexpression, cell proliferation assays","journal":"Journal of animal science and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with half-life/stability assay and functional validation, single lab","pmids":["38858680"],"is_preprint":false},{"year":2021,"finding":"SIN3A depletion in porcine early embryos drastically reduces CCNB1 transcript levels; injection of exogenous CCNB1 mRNA into SIN3A-depleted embryos partially rescues development past the two-cell block, placing SIN3A upstream of CCNB1 in embryonic genome activation.","method":"siRNA knockdown, RNA-seq, mRNA microinjection rescue, immunofluorescence","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis with genetic rescue (mRNA injection), single lab","pmids":["33692994"],"is_preprint":false},{"year":2025,"finding":"SNRPB regulates CCNB1 expression through FOXM1-mediated transcriptional activation; SNRPB interacts with FOXM1 (demonstrated by Co-IP), and SNRPB/FOXM1 promote CCNB1 transcription (demonstrated by ChIP); CCNB1 knockdown reverses proliferative and tumorigenic effects of SNRPB overexpression.","method":"ChIP, Co-IP, siRNA knockdown, functional assays, in vivo experiments","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and Co-IP with functional rescue, single lab","pmids":["40682115"],"is_preprint":false},{"year":2024,"finding":"GADD45G physically interacts with CDK1 and CCNB1 (demonstrated by Co-IP), and negatively regulates their expression; reduced GADD45G expression (due to promoter methylation) leads to CDK1/CCNB1 upregulation and enhanced invasive behavior in endometrial cancer.","method":"Co-immunoprecipitation, methylation-specific PCR, siRNA knockdown, in vitro and in vivo functional assays","journal":"Journal of cancer research and therapeutics","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional assays, single lab","pmids":["39206984"],"is_preprint":false},{"year":2025,"finding":"HROB interacts with ZC3HC1 and reduces ZC3HC1 phosphorylation at Ser354, which facilitates K27-linked ubiquitination of CCNB1 and promotes its proteasomal degradation, impairing G2-to-M transition and suppressing cell proliferation in lung adenocarcinoma.","method":"Co-IP, ubiquitination assay, phospho-mutant analysis, cell cycle analysis, xenograft model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical epistasis with ubiquitination assays and functional validation, single lab","pmids":["40654113"],"is_preprint":false},{"year":2026,"finding":"MAPK1 (ERK2) directly phosphorylates CCNB1 at serine 128 (demonstrated by in vitro kinase assay and co-IP), promoting 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.","method":"TurboID proximity labeling + mass spectrometry, Co-IP, in vitro kinase assay, phospho-mutant analysis, nuclear-cytoplasmic fractionation, immunofluorescence, cell cycle analysis, xenograft model","journal":"Life sciences","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus Co-IP, phospho-mutant rescue experiments, multiple orthogonal methods","pmids":["41905453"],"is_preprint":false},{"year":2014,"finding":"Chk1 positively regulates CCNB1 protein expression in colorectal cancer cells; Chk1 repression leads to decreased CCNB1 protein and mRNA levels, and CCNB1 knockdown causes G2/M arrest with associated changes in CDC25c and CDK1 expression.","method":"siRNA knockdown, Western blot, flow cytometry, xenograft tumor growth assay","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 — siRNA epistasis with defined cell cycle phenotype, single lab","pmids":["24971465"],"is_preprint":false},{"year":2017,"finding":"NF-Y (NF-YA) is a key transcriptional activator of the Ccnb1 promoter; a dominant-negative NF-YA mutant increases the promoter 'OFF'/'ON' time ratio without altering Pol II firing rates during the 'ON' period, suggesting NF-Y controls promoter activation frequency rather than elongation rate at the Ccnb1 gene.","method":"Single-copy promoter transgene system, live single-molecule mRNA imaging, ChIP (H3K4me2, H3K79me2), dominant-negative NF-YA expression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 — single-molecule imaging plus ChIP with dominant-negative approach, single lab","pmids":["28522800"],"is_preprint":false},{"year":1992,"finding":"Human CCNB1 was mapped to chromosome 5 (region q13-qter) by Southern blot analysis of human × Chinese hamster somatic cell hybrid panels.","method":"Somatic cell hybrid panel analysis, Southern blot","journal":"Somatic cell and molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct chromosomal mapping by somatic cell hybrid analysis","pmids":["1386686"],"is_preprint":false}],"current_model":"CCNB1 (Cyclin B1) is the regulatory subunit of the CDK1-CCNB1 kinase complex (MPF/maturation-promoting factor) that drives the G2-to-M phase transition; its levels are controlled by a balance of synthesis (transcriptionally activated by FOXM1, NF-Y, ISL1, STOX1A; translationally regulated by APA-dependent 3' UTR variants and CPEB1/MAPK/CDK1 positive feedback in oocytes; stabilized at the mRNA level by m7G methylation via WDR4/EIF2A and m6A via METTL3) and targeted proteasomal degradation (ubiquitinated by APC/C-CDC20 via UBA52/APC11 and counteracted by deubiquitinases USP22 and UCHL1); CDK1-CCNB1 also functions as an integral component of the spindle assembly checkpoint by localizing to unattached kinetochores through MAD1 to phosphorylate MPS1-S281, and inhibits separase (cohesin cleavage protease) by forming a CDK1-CCNB1-CKS1 inhibitory complex; additionally, MAPK1 phosphorylates CCNB1 at Ser128 to promote its nuclear translocation and mitotic entry."},"narrative":{"teleology":[{"year":1992,"claim":"Mapping CCNB1 to human chromosome 5q13-qter established its genomic location, a prerequisite for genetic and functional studies.","evidence":"Southern blot of human × Chinese hamster somatic cell hybrid panels","pmids":["1386686"],"confidence":"Medium","gaps":["Precise chromosomal band assignment not yet defined","No functional data at this stage"]},{"year":2012,"claim":"Identification of STOX1A as a direct transcriptional activator of CCNB1 via promoter binding began to define the transcription factor network controlling CCNB1 expression and mitotic entry.","evidence":"ChIP assay and overexpression/knockdown in human cells","pmids":["22253775"],"confidence":"Medium","gaps":["No combinatorial analysis with other CCNB1 transcription factors","Single lab without independent replication"]},{"year":2015,"claim":"Discovery that USP22 deubiquitinates CCNB1 to antagonize APC/C-mediated degradation—and that CDK1 phosphorylates USP22 to enhance this activity—revealed a positive-feedback stabilization loop governing mitotic CCNB1 levels.","evidence":"In vitro deubiquitination assay, Co-IP, cell cycle fractionation, siRNA knockdown","pmids":["27030811"],"confidence":"High","gaps":["Structural basis of USP22–CCNB1 interaction unknown","Relative contribution of USP22 vs. other DUBs in vivo uncharacterized"]},{"year":2016,"claim":"ISL1 was shown to directly bind the CCNB1 promoter and activate transcription, expanding the set of tissue-specific transcription factors (alongside STOX1A) that drive CCNB1 in proliferating cells.","evidence":"ChIP assay, luciferase reporter, siRNA knockdown in gastric cancer cells","pmids":["27183908"],"confidence":"Medium","gaps":["Relative hierarchy among CCNB1 transcription factors not established","Single cancer type tested"]},{"year":2017,"claim":"Alternative polyadenylation was shown to generate CCNB1 mRNA isoforms with distinct 3′ UTRs that are translated at different meiotic stages, establishing a post-transcriptional timing mechanism for Cyclin B1 accumulation in oocytes.","evidence":"Gene editing of proximal/distal polyadenylation elements in mouse oocytes with phenotypic analysis","pmids":["28808066"],"confidence":"High","gaps":["Trans-acting factors for each APA variant incompletely defined","Whether similar APA control operates in somatic cells unknown"]},{"year":2017,"claim":"Conditional CCNB1 knockout in mouse male germ cells demonstrated that CCNB1 is essential for gonocyte and spermatogonia proliferation but dispensable for spermatocyte meiosis, delineating its cell-type-specific requirement.","evidence":"Conditional knockout mice with histology, apoptosis assays, and gene expression analysis","pmids":["29072697"],"confidence":"High","gaps":["Whether CCNB2 compensates during meiosis not formally tested","Molecular targets of CDK1–CCNB1 in spermatogonia not identified"]},{"year":2017,"claim":"NF-Y was established as a key activator of the CCNB1 promoter that controls the frequency of promoter activation (ON/OFF cycling) rather than Pol II elongation rate, providing a mechanistic basis for transcriptional burst regulation.","evidence":"Single-molecule mRNA imaging with dominant-negative NF-YA and histone ChIP","pmids":["28522800"],"confidence":"Medium","gaps":["How NF-Y cooperates with FOXM1 and other factors at the endogenous locus not resolved","Single-copy transgene may not fully recapitulate endogenous chromatin context"]},{"year":2018,"claim":"FOXM1 was shown to directly bind the CCNB1 promoter and activate its transcription, with loss of CCNB1 abolishing FOXM1-driven proliferation, establishing FOXM1 as a critical upstream transcriptional regulator.","evidence":"ChIP, luciferase reporter, siRNA knockdown and rescue in HCC cells","pmids":["29705704"],"confidence":"Medium","gaps":["Whether FOXM1 is the dominant transcription factor for CCNB1 across tissues unknown","Epigenetic co-regulators beyond CBP/P300 not characterized"]},{"year":2019,"claim":"Two companion studies established CDK1–CCNB1 as an integral spindle assembly checkpoint component: it localizes to unattached kinetochores via MAD1 and phosphorylates MPS1 at S281 to sustain checkpoint signaling, with PP2A-B55 acting as the opposing phosphatase that becomes active only when CCNB1 falls below a threshold.","evidence":"Reciprocal Co-IP, proteomics, phospho-mutant analysis, kinetochore tethering bypass, epistasis with MPS1 inhibition in human cells","pmids":["30674583","30674582"],"confidence":"High","gaps":["Precise stoichiometry of CDK1–CCNB1 at kinetochores not determined","Whether CDK1–CCNB1 phosphorylates additional SAC substrates at kinetochores not fully explored"]},{"year":2019,"claim":"APC11 was identified as the E3 ligase component mediating UBA52-dependent CCNB1 ubiquitination for proteasomal degradation, defining a specific ubiquitin-chain initiation mechanism for CCNB1 turnover.","evidence":"Co-IP/proteomics, siRNA epistasis, and xenograft assays","pmids":["31814919"],"confidence":"Medium","gaps":["Ubiquitin chain type specificity beyond K27 linkage not clarified in this study","Relationship to canonical APC/C-CDC20 D-box recognition pathway needs integration"]},{"year":2020,"claim":"ERK1/2 and CDK1 were shown to cooperate in a positive-feedback loop that activates CCNB1 mRNA translation in oocytes by phosphorylating and degrading the translational repressor CPEB1, connecting signaling cascades to the APA-based translational timing mechanism.","evidence":"Pharmacological inhibition of MAPK/CDK1 with CPEB1 phosphorylation analysis in mouse oocytes","pmids":["33282880"],"confidence":"Medium","gaps":["Direct phosphorylation sites on CPEB1 by each kinase not fully mapped","Whether this loop operates in somatic G2/M not tested"]},{"year":2021,"claim":"Cryo-EM structures of the human separase–CDK1–CCNB1–CKS1 complex revealed the molecular basis of separase inhibition by CDK1–CCNB1, distinct from securin-mediated inhibition, explaining how two independent inhibitory mechanisms safeguard sister chromatid cohesion.","evidence":"Cryo-EM/crystallographic structure determination with functional validation","pmids":["34616878"],"confidence":"High","gaps":["Dynamic interconversion between securin-bound and CDK1-CCNB1-bound separase states in vivo not characterized","How the two inhibitory modes are coordinated during mitotic exit remains unclear"]},{"year":2021,"claim":"WDR4-mediated m7G methylation of CCNB1 mRNA was shown to enhance its stability and translation via EIF2A recruitment, revealing an epitranscriptomic layer of CCNB1 regulation.","evidence":"m7G profiling, RIP assay, mRNA stability assays in HCC cells","pmids":["34244479"],"confidence":"Medium","gaps":["Whether m7G and m6A modifications on CCNB1 mRNA interact or are mutually exclusive unknown","In vivo validation lacking"]},{"year":2024,"claim":"UCHL1 was identified as a second deubiquitinase (in addition to USP22) that directly stabilizes CCNB1 protein by inhibiting its proteasomal degradation, indicating redundant DUB-mediated protection of Cyclin B1.","evidence":"Co-IP, half-life assay, siRNA knockdown/overexpression in porcine granulosa cells","pmids":["38858680"],"confidence":"Medium","gaps":["Whether UCHL1 and USP22 act on the same or different ubiquitin chain types on CCNB1 unknown","Relevance in human somatic cells not confirmed"]},{"year":2025,"claim":"METTL3-mediated m6A modification was shown to stabilize CCNB1 mRNA, adding a second epitranscriptomic control layer alongside m7G modification and linking CCNB1 regulation to intercellular communication via exosomes.","evidence":"MeRIP, mRNA stability assay, functional rescue in dermal fibroblasts","pmids":["39954139"],"confidence":"Medium","gaps":["m6A reader identity for CCNB1 mRNA not identified","Relative contribution of m6A vs. m7G to CCNB1 mRNA stability not compared"]},{"year":2026,"claim":"MAPK1 was shown to directly phosphorylate CCNB1 at Ser128 to promote its nuclear translocation and G2-to-prophase transition, establishing a direct kinase–substrate link between mitogenic signaling and mitotic entry.","evidence":"In vitro kinase assay, TurboID proximity labeling, phospho-mutant rescue, nuclear-cytoplasmic fractionation in TNBC cells and xenografts","pmids":["41905453"],"confidence":"High","gaps":["Whether Ser128 phosphorylation affects CDK1 binding or catalytic activity unknown","Interplay with CRM1/importin-mediated nuclear transport not defined"]},{"year":null,"claim":"How the multiple transcriptional, epitranscriptomic, translational, and post-translational inputs converge quantitatively to set the threshold of CDK1–CCNB1 activity required for mitotic commitment remains an open systems-level question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated quantitative model of CCNB1 accumulation combining transcription, RNA modification, translation, and degradation","In vivo contribution of individual DUBs and E3 ligases to CCNB1 steady-state levels not compared","Structural basis of MAPK1-mediated Ser128 phosphorylation and its effect on CDK1–CCNB1 complex dynamics unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,26]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[18,26]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,26]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,2,3,12,13,17,26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,12,21,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,26]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,9,10,11,28]}],"complexes":["CDK1-CCNB1 (MPF)","CDK1-CCNB1-CKS1-separase inhibitory complex","APC/C-CDC20 (substrate)"],"partners":["CDK1","MAD1","USP22","UCHL1","FOXM1","MAPK1","GADD45G","SQLE"],"other_free_text":[]},"mechanistic_narrative":"CCNB1 (Cyclin B1) is the regulatory subunit of the CDK1–CCNB1 (MPF) kinase complex that drives the G2-to-M phase transition, with essential roles in mitotic entry, spindle assembly checkpoint (SAC) signaling, and separase inhibition. CDK1–CCNB1 localizes to unattached kinetochores via the MAD1 N-terminus and phosphorylates MPS1 at S281 to sustain SAC arrest, while also forming a CDK1–CCNB1–CKS1 inhibitory complex that directly blocks separase-mediated cohesin cleavage [PMID:30674583, PMID:30674582, PMID:34616878]. CCNB1 abundance is tightly controlled: transcription is activated by FOXM1 (recruiting CBP/P300), NF-Y, E2F1 (recruited by AURKA), ISL1, and STOX1A [PMID:29705704, PMID:28522800, PMID:38655290, PMID:27183908, PMID:22253775]; mRNA stability is modulated by m7G (WDR4/EIF2A) and m6A (METTL3) modifications [PMID:34244479, PMID:39954139]; translational timing in oocytes depends on alternative polyadenylation-generated 3′-UTR variants regulated by a CPEB1/MAPK/CDK1 positive-feedback loop [PMID:28808066, PMID:33282880]; and protein turnover is governed by APC/C–CDC20-mediated ubiquitination counteracted by the deubiquitinases USP22 and UCHL1 [PMID:27030811, PMID:38858680]. MAPK1 directly phosphorylates CCNB1 at Ser128 to promote its nuclear translocation and mitotic entry, and conditional CCNB1 knockout in mouse male germ cells causes sterility through gonocyte/spermatogonia depletion, demonstrating its essential role in germ-cell proliferation [PMID:41905453, PMID:29072697]."},"prefetch_data":{"uniprot":{"accession":"P14635","full_name":"G2/mitotic-specific cyclin-B1","aliases":[],"length_aa":433,"mass_kda":48.3,"function":"Essential for the control of the cell cycle at the G2/M (mitosis) transition","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/P14635/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNB1","classification":"Common 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the International Society for Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41871736","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":"36275181","id":"PMC_36275181","title":"CCNB1 Expedites the Progression of Cervical Squamous Cell Carcinoma via the Regulation by FOXM1 [Retraction].","date":"2022","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36275181","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 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proteomic analysis, Co-IP, cell biological analysis (live imaging, immunofluorescence), and epistasis with MPS1 inhibition\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, proteomics, and functional epistasis with defined cellular phenotype, replicated across two companion papers\",\n      \"pmids\": [\"30674583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDK1-CCNB1 phosphorylates MPS1 at S281 in its kinetochore-binding domain to promote MPS1 engagement with unattached kinetochores, enabling spindle checkpoint signaling; PP2A-B55 (itself negatively regulated by CDK1-CCNB1) counteracts this phosphorylation, and only becomes fully active once CCNB1 concentration falls below a threshold, prolonging the checkpoint-responsive period.\",\n      \"method\": \"Phospho-mutant analysis (MPS1-S281A), direct kinetochore tethering bypass experiment, cell cycle synchronization, immunofluorescence, and kinase/phosphatase epistasis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro and cellular phospho-mutant experiments with functional rescue, published alongside companion paper\",\n      \"pmids\": [\"30674582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Structures of human separase bound to CDK1-CCNB1-CKS1 complex reveal molecular mechanisms by which this complex inhibits separase's cohesin-cleavage protease activity, distinct from the securin inhibition mode.\",\n      \"method\": \"Structural analysis (cryo-EM/crystallography) of human separase-CDK1-CCNB1-CKS1 complex\",\n      \"journal\": \"Molecular & cellular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination of the inhibitory complex with functional validation of cohesin cleavage inhibition\",\n      \"pmids\": [\"34616878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP22 is a deubiquitinase of CCNB1 that stabilizes CCNB1 by antagonizing APC/C-mediated proteasomal degradation in a cell cycle-specific manner; CDK1 phosphorylates USP22 to enhance its deubiquitinating activity toward CCNB1, and APC/C-CDC20 targets USP22 for degradation during M phase exit, allowing subsequent CCNB1 degradation.\",\n      \"method\": \"Co-IP, in vitro deubiquitination assay, cell cycle-specific fractionation, siRNA knockdown, USP22 phosphorylation analysis, xenograft tumor assay\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro deubiquitination assay combined with Co-IP, cell cycle fractionation, and mutagenesis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27030811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"circ-Ccnb1 interacts with both Ccnb1 and Cdk1 proteins and dissociates the Ccnb1-Cdk1 complex by forming a larger complex (circ-Ccnb1/Ccnb1/Cdk1), thereby suppressing Ccnb1-driven cell migration, invasion, proliferation and survival; ectopic delivery of circ-Ccnb1 inhibited tumor growth in vivo.\",\n      \"method\": \"Co-IP/RNA pulldown, immunofluorescence (cytosolic/nuclear complex localization), in vivo tumor delivery experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and functional rescue experiments with in vivo validation, single lab\",\n      \"pmids\": [\"31199987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"circ-Ccnb1 precipitates wild-type p53 via H2AX as a bridge, allowing Bclaf1 to bind Bcl2 and promote cell survival; in p53 mutant cells, circ-Ccnb1 instead forms a complex with H2AX and Bclaf1, inducing cell death.\",\n      \"method\": \"Proteomics, RNA pulldown, Co-IP, microarray analysis, in vivo tumor delivery\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics plus Co-IP with functional validation, single lab\",\n      \"pmids\": [\"29795334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR4, an m7G methyltransferase, promotes CCNB1 mRNA stability and translation by enhancing the binding of translation initiation factor EIF2A to CCNB1 mRNA; this is part of an MYC/WDR4/CCNB1 signaling axis in HCC.\",\n      \"method\": \"m7G methylation profiling, RIP assay, mRNA stability assays, Western blot, functional rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic RIP/stability assays in single lab with functional rescue\",\n      \"pmids\": [\"34244479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXM1 directly binds to the promoter region of CCNB1 and transcriptionally activates CCNB1 expression to drive HCC cell proliferation; loss of CCNB1 abolishes FOXM1-driven proliferation.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, siRNA knockdown, rescue experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assay with functional rescue, single lab\",\n      \"pmids\": [\"29705704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXM1 promotes CCNB1 transcription in cervical squamous cell carcinoma by binding to the CCNB1 promoter and recruiting the histone acetyltransferase CBP/P300, thereby increasing histone acetylation at the CCNB1 promoter locus.\",\n      \"method\": \"ChIP assay, histone ChIP-Seq analysis, luciferase reporter assay, siRNA knockdown, rescue experiments\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and reporter assay, but the paper was subsequently retracted (PMID 36275181)\",\n      \"pmids\": [\"33299327\"],\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, thereby promoting renal cell carcinoma progression.\",\n      \"method\": \"Co-IP, ChIP assay, luciferase reporter assay, siRNA knockdown, xenograft model\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ChIP with functional validation, single lab\",\n      \"pmids\": [\"38655290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The transcription factor STOX1A directly binds to the CCNB1 promoter (demonstrated by chromatin immunoprecipitation) and upregulates cyclin B1 expression to promote mitotic entry.\",\n      \"method\": \"ChIP assay, siRNA knockdown/overexpression, gene expression profiling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstration of direct promoter binding with functional consequence, single lab\",\n      \"pmids\": [\"22253775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ISL1 transcription factor activates CCNB1 expression in gastric cancer by binding to conserved sites on the CCNB1 promoter or enhancer, thereby facilitating G2/M cell cycle transition.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, siRNA knockdown, xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay with functional validation, single lab\",\n      \"pmids\": [\"27183908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"APC11, via UBA52-mediated ubiquitination, promotes CCNB1 degradation; APC11 knockdown causes G2/M arrest even in the presence of overexpressed UBA52, establishing APC11 as the E3 ligase mediating UBA52-dependent CCNB1 ubiquitylation and subsequent proteasomal degradation.\",\n      \"method\": \"Co-IP/proteomics, siRNA knockdown, overexpression rescue, xenograft tumor assay\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and epistasis experiments with functional phenotype, single lab\",\n      \"pmids\": [\"31814919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Timing of Ccnb1 mRNA translation during mouse oocyte meiotic maturation is determined by transcripts with different 3' UTRs generated through alternative polyadenylation; the short 3' UTR mRNA is translated early (setting meiotic re-entry timing) while the long 3' UTR mRNA drives Cyclin B1 accumulation during MI/MII transition, as demonstrated by in vivo loss-of-function mutations in polyadenylation elements.\",\n      \"method\": \"Gene editing in mice (mutations in proximal and distal polyadenylation elements), in vivo loss-of-function experiments, mRNA variant analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo gene editing with specific polyadenylation element mutations and clear phenotypic separation of mRNA variant functions\",\n      \"pmids\": [\"28808066\", \"38048302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERK1/2 (MAPK cascade) activation promotes Ccnb1 mRNA translation during mouse oocyte maturation by triggering CPEB1 phosphorylation and degradation; CDK1 activity also contributes to CPEB1 phosphorylation (but not degradation); both kinases cooperate in a positive feedback loop to activate Ccnb1 translation.\",\n      \"method\": \"Pharmacological inhibition of MAPK/CDK1, CPEB1 phosphorylation analysis, meiotic maturation assays in mouse oocytes\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis with mechanistic follow-up on CPEB1, single lab\",\n      \"pmids\": [\"33282880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Septin 4 regulates CCNB1 protein stabilization via APC/C-CDC20 during meiotic G2/M transition in mouse oocytes; Septin 4 depletion reduces CCNB1 accumulation and causes GV arrest, while CDC20 levels paradoxically increase; overexpressing CCNB1 or depleting CDC20 rescues GVBD.\",\n      \"method\": \"siRNA microinjection, mRNA microinjection rescue, immunofluorescence, Co-IP, time-lapse imaging, Western blot\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA epistasis with genetic rescue experiments, 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 prevents APC/C-CDC20-mediated CCNB1 degradation at the MI/AI transition by disrupting kinetochore-microtubule attachment and maintaining SAC (Mad1/BubR1) activity; CDC20 mRNA microinjection partially rescues the arrest.\",\n      \"method\": \"siRNA and mRNA microinjection, time-lapse live imaging, immunofluorescence, Western blot, SAC marker analysis\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with genetic rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36354207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCNB1 is required for normal proliferation of gonocytes and spermatogonia in mouse spermatogenesis; conditional knockout of CCNB1 in male germ cells causes sterility due to germ cell depletion and increased apoptosis, while ablation in premeiotic spermatocytes does not affect meiosis, indicating CCNB1 is dispensable for meiosis of spermatocytes.\",\n      \"method\": \"Conditional knockout mice, histological analysis, apoptosis assays, let-7 miRNA and Lin28a expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — clean conditional KO in mice with specific cell-type phenotypic readouts and mechanistic follow-up\",\n      \"pmids\": [\"29072697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Circ-CCNB1 inhibits trophoblast proliferation and invasion by sponging miR-223, which in turn targets SIAH1; elevated SIAH1 promotes CCNB1 nuclear translocation, and circ-CCNB1/miR-223/SIAH1 axis modulates nuclear CCNB1 levels to regulate trophoblast function in spontaneous abortion.\",\n      \"method\": \"siRNA knockdown, mRNA overexpression, RNA pulldown, dual-luciferase reporter assay, immunofluorescence for nuclear localization\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA pulldown and luciferase assay with functional localization data, single lab\",\n      \"pmids\": [\"35731831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3 upregulates CCNB1 expression through m6A modification of CCNB1 mRNA, enhancing its stability; METTL3-modified ASC-exosomes transfer this effect to dermal fibroblasts to enhance their proliferation and migration.\",\n      \"method\": \"Methylated RNA immunoprecipitation (MeRIP), actinomycin D mRNA stability assay, siRNA knockdown, overexpression, Western blot\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MeRIP plus mRNA stability assay with functional rescue, single lab\",\n      \"pmids\": [\"39954139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SQLE (squalene epoxidase) physically interacts with CCNB1 (demonstrated by Co-IP and immunofluorescence) and reduces CCNB1 ubiquitination, thereby stabilizing the CCNB1 protein and decreasing intracellular ROS to inhibit ferroptosis in breast cancer.\",\n      \"method\": \"Co-IP, immunofluorescence, ubiquitination assay, ROS measurement, xenograft assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with ubiquitination assay and functional validation, single lab\",\n      \"pmids\": [\"37839786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UCHL1 directly binds CCNB1, prolongs CCNB1 half-life, and inhibits its degradation (deubiquitinase activity), thereby promoting porcine granulosa cell proliferation; the flavonoid isovitexin enhances UCHL1 enzyme activity to further promote proliferation.\",\n      \"method\": \"Co-IP, half-life assay, siRNA knockdown and overexpression, cell proliferation assays\",\n      \"journal\": \"Journal of animal science and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with half-life/stability assay and functional validation, single lab\",\n      \"pmids\": [\"38858680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIN3A depletion in porcine early embryos drastically reduces CCNB1 transcript levels; injection of exogenous CCNB1 mRNA into SIN3A-depleted embryos partially rescues development past the two-cell block, placing SIN3A upstream of CCNB1 in embryonic genome activation.\",\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 — epistasis with genetic rescue (mRNA injection), single lab\",\n      \"pmids\": [\"33692994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNRPB regulates CCNB1 expression through FOXM1-mediated transcriptional activation; SNRPB interacts with FOXM1 (demonstrated by Co-IP), and SNRPB/FOXM1 promote CCNB1 transcription (demonstrated by ChIP); CCNB1 knockdown reverses proliferative and tumorigenic effects of SNRPB overexpression.\",\n      \"method\": \"ChIP, Co-IP, siRNA knockdown, functional assays, in vivo experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and Co-IP with functional rescue, single lab\",\n      \"pmids\": [\"40682115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GADD45G physically interacts with CDK1 and CCNB1 (demonstrated by Co-IP), and negatively regulates their expression; reduced GADD45G expression (due to promoter methylation) leads to CDK1/CCNB1 upregulation and enhanced invasive behavior in endometrial cancer.\",\n      \"method\": \"Co-immunoprecipitation, methylation-specific PCR, siRNA knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"Journal of cancer research and therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional assays, single lab\",\n      \"pmids\": [\"39206984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HROB interacts with ZC3HC1 and reduces ZC3HC1 phosphorylation at Ser354, which facilitates K27-linked ubiquitination of CCNB1 and promotes its proteasomal degradation, impairing G2-to-M transition and suppressing cell proliferation in lung adenocarcinoma.\",\n      \"method\": \"Co-IP, ubiquitination assay, phospho-mutant analysis, cell cycle analysis, xenograft model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical epistasis with ubiquitination assays and functional validation, single lab\",\n      \"pmids\": [\"40654113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MAPK1 (ERK2) directly phosphorylates CCNB1 at serine 128 (demonstrated by in vitro kinase assay and co-IP), promoting 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.\",\n      \"method\": \"TurboID proximity labeling + mass spectrometry, Co-IP, in vitro kinase assay, phospho-mutant analysis, nuclear-cytoplasmic fractionation, immunofluorescence, cell cycle analysis, xenograft model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus Co-IP, phospho-mutant rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"41905453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Chk1 positively regulates CCNB1 protein expression in colorectal cancer cells; Chk1 repression leads to decreased CCNB1 protein and mRNA levels, and CCNB1 knockdown causes G2/M arrest with associated changes in CDC25c and CDK1 expression.\",\n      \"method\": \"siRNA knockdown, Western blot, flow cytometry, xenograft tumor growth assay\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — siRNA epistasis with defined cell cycle phenotype, single lab\",\n      \"pmids\": [\"24971465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NF-Y (NF-YA) is a key transcriptional activator of the Ccnb1 promoter; a dominant-negative NF-YA mutant increases the promoter 'OFF'/'ON' time ratio without altering Pol II firing rates during the 'ON' period, suggesting NF-Y controls promoter activation frequency rather than elongation rate at the Ccnb1 gene.\",\n      \"method\": \"Single-copy promoter transgene system, live single-molecule mRNA imaging, ChIP (H3K4me2, H3K79me2), dominant-negative NF-YA expression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — single-molecule imaging plus ChIP with dominant-negative approach, single lab\",\n      \"pmids\": [\"28522800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Human CCNB1 was mapped to chromosome 5 (region q13-qter) by Southern blot analysis of human × Chinese hamster somatic cell hybrid panels.\",\n      \"method\": \"Somatic cell hybrid panel analysis, Southern blot\",\n      \"journal\": \"Somatic cell and molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping by somatic cell hybrid analysis\",\n      \"pmids\": [\"1386686\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCNB1 (Cyclin B1) is the regulatory subunit of the CDK1-CCNB1 kinase complex (MPF/maturation-promoting factor) that drives the G2-to-M phase transition; its levels are controlled by a balance of synthesis (transcriptionally activated by FOXM1, NF-Y, ISL1, STOX1A; translationally regulated by APA-dependent 3' UTR variants and CPEB1/MAPK/CDK1 positive feedback in oocytes; stabilized at the mRNA level by m7G methylation via WDR4/EIF2A and m6A via METTL3) and targeted proteasomal degradation (ubiquitinated by APC/C-CDC20 via UBA52/APC11 and counteracted by deubiquitinases USP22 and UCHL1); CDK1-CCNB1 also functions as an integral component of the spindle assembly checkpoint by localizing to unattached kinetochores through MAD1 to phosphorylate MPS1-S281, and inhibits separase (cohesin cleavage protease) by forming a CDK1-CCNB1-CKS1 inhibitory complex; additionally, MAPK1 phosphorylates CCNB1 at Ser128 to promote its nuclear translocation and mitotic entry.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCNB1 (Cyclin B1) is the regulatory subunit of the CDK1–CCNB1 (MPF) kinase complex that drives the G2-to-M phase transition, with essential roles in mitotic entry, spindle assembly checkpoint (SAC) signaling, and separase inhibition. CDK1–CCNB1 localizes to unattached kinetochores via the MAD1 N-terminus and phosphorylates MPS1 at S281 to sustain SAC arrest, while also forming a CDK1–CCNB1–CKS1 inhibitory complex that directly blocks separase-mediated cohesin cleavage [PMID:30674583, PMID:30674582, PMID:34616878]. CCNB1 abundance is tightly controlled: transcription is activated by FOXM1 (recruiting CBP/P300), NF-Y, E2F1 (recruited by AURKA), ISL1, and STOX1A [PMID:29705704, PMID:28522800, PMID:38655290, PMID:27183908, PMID:22253775]; mRNA stability is modulated by m7G (WDR4/EIF2A) and m6A (METTL3) modifications [PMID:34244479, PMID:39954139]; translational timing in oocytes depends on alternative polyadenylation-generated 3′-UTR variants regulated by a CPEB1/MAPK/CDK1 positive-feedback loop [PMID:28808066, PMID:33282880]; and protein turnover is governed by APC/C–CDC20-mediated ubiquitination counteracted by the deubiquitinases USP22 and UCHL1 [PMID:27030811, PMID:38858680]. MAPK1 directly phosphorylates CCNB1 at Ser128 to promote its nuclear translocation and mitotic entry, and conditional CCNB1 knockout in mouse male germ cells causes sterility through gonocyte/spermatogonia depletion, demonstrating its essential role in germ-cell proliferation [PMID:41905453, PMID:29072697].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Mapping CCNB1 to human chromosome 5q13-qter established its genomic location, a prerequisite for genetic and functional studies.\",\n      \"evidence\": \"Southern blot of human × Chinese hamster somatic cell hybrid panels\",\n      \"pmids\": [\"1386686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise chromosomal band assignment not yet defined\", \"No functional data at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of STOX1A as a direct transcriptional activator of CCNB1 via promoter binding began to define the transcription factor network controlling CCNB1 expression and mitotic entry.\",\n      \"evidence\": \"ChIP assay and overexpression/knockdown in human cells\",\n      \"pmids\": [\"22253775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No combinatorial analysis with other CCNB1 transcription factors\", \"Single lab without independent replication\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that USP22 deubiquitinates CCNB1 to antagonize APC/C-mediated degradation—and that CDK1 phosphorylates USP22 to enhance this activity—revealed a positive-feedback stabilization loop governing mitotic CCNB1 levels.\",\n      \"evidence\": \"In vitro deubiquitination assay, Co-IP, cell cycle fractionation, siRNA knockdown\",\n      \"pmids\": [\"27030811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of USP22–CCNB1 interaction unknown\", \"Relative contribution of USP22 vs. other DUBs in vivo uncharacterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"ISL1 was shown to directly bind the CCNB1 promoter and activate transcription, expanding the set of tissue-specific transcription factors (alongside STOX1A) that drive CCNB1 in proliferating cells.\",\n      \"evidence\": \"ChIP assay, luciferase reporter, siRNA knockdown in gastric cancer cells\",\n      \"pmids\": [\"27183908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative hierarchy among CCNB1 transcription factors not established\", \"Single cancer type tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Alternative polyadenylation was shown to generate CCNB1 mRNA isoforms with distinct 3′ UTRs that are translated at different meiotic stages, establishing a post-transcriptional timing mechanism for Cyclin B1 accumulation in oocytes.\",\n      \"evidence\": \"Gene editing of proximal/distal polyadenylation elements in mouse oocytes with phenotypic analysis\",\n      \"pmids\": [\"28808066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-acting factors for each APA variant incompletely defined\", \"Whether similar APA control operates in somatic cells unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional CCNB1 knockout in mouse male germ cells demonstrated that CCNB1 is essential for gonocyte and spermatogonia proliferation but dispensable for spermatocyte meiosis, delineating its cell-type-specific requirement.\",\n      \"evidence\": \"Conditional knockout mice with histology, apoptosis assays, and gene expression analysis\",\n      \"pmids\": [\"29072697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCNB2 compensates during meiosis not formally tested\", \"Molecular targets of CDK1–CCNB1 in spermatogonia not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"NF-Y was established as a key activator of the CCNB1 promoter that controls the frequency of promoter activation (ON/OFF cycling) rather than Pol II elongation rate, providing a mechanistic basis for transcriptional burst regulation.\",\n      \"evidence\": \"Single-molecule mRNA imaging with dominant-negative NF-YA and histone ChIP\",\n      \"pmids\": [\"28522800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How NF-Y cooperates with FOXM1 and other factors at the endogenous locus not resolved\", \"Single-copy transgene may not fully recapitulate endogenous chromatin context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"FOXM1 was shown to directly bind the CCNB1 promoter and activate its transcription, with loss of CCNB1 abolishing FOXM1-driven proliferation, establishing FOXM1 as a critical upstream transcriptional regulator.\",\n      \"evidence\": \"ChIP, luciferase reporter, siRNA knockdown and rescue in HCC cells\",\n      \"pmids\": [\"29705704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FOXM1 is the dominant transcription factor for CCNB1 across tissues unknown\", \"Epigenetic co-regulators beyond CBP/P300 not characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two companion studies established CDK1–CCNB1 as an integral spindle assembly checkpoint component: it localizes to unattached kinetochores via MAD1 and phosphorylates MPS1 at S281 to sustain checkpoint signaling, with PP2A-B55 acting as the opposing phosphatase that becomes active only when CCNB1 falls below a threshold.\",\n      \"evidence\": \"Reciprocal Co-IP, proteomics, phospho-mutant analysis, kinetochore tethering bypass, epistasis with MPS1 inhibition in human cells\",\n      \"pmids\": [\"30674583\", \"30674582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise stoichiometry of CDK1–CCNB1 at kinetochores not determined\", \"Whether CDK1–CCNB1 phosphorylates additional SAC substrates at kinetochores not fully explored\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"APC11 was identified as the E3 ligase component mediating UBA52-dependent CCNB1 ubiquitination for proteasomal degradation, defining a specific ubiquitin-chain initiation mechanism for CCNB1 turnover.\",\n      \"evidence\": \"Co-IP/proteomics, siRNA epistasis, and xenograft assays\",\n      \"pmids\": [\"31814919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain type specificity beyond K27 linkage not clarified in this study\", \"Relationship to canonical APC/C-CDC20 D-box recognition pathway needs integration\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ERK1/2 and CDK1 were shown to cooperate in a positive-feedback loop that activates CCNB1 mRNA translation in oocytes by phosphorylating and degrading the translational repressor CPEB1, connecting signaling cascades to the APA-based translational timing mechanism.\",\n      \"evidence\": \"Pharmacological inhibition of MAPK/CDK1 with CPEB1 phosphorylation analysis in mouse oocytes\",\n      \"pmids\": [\"33282880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation sites on CPEB1 by each kinase not fully mapped\", \"Whether this loop operates in somatic G2/M not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cryo-EM structures of the human separase–CDK1–CCNB1–CKS1 complex revealed the molecular basis of separase inhibition by CDK1–CCNB1, distinct from securin-mediated inhibition, explaining how two independent inhibitory mechanisms safeguard sister chromatid cohesion.\",\n      \"evidence\": \"Cryo-EM/crystallographic structure determination with functional validation\",\n      \"pmids\": [\"34616878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamic interconversion between securin-bound and CDK1-CCNB1-bound separase states in vivo not characterized\", \"How the two inhibitory modes are coordinated during mitotic exit remains unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"WDR4-mediated m7G methylation of CCNB1 mRNA was shown to enhance its stability and translation via EIF2A recruitment, revealing an epitranscriptomic layer of CCNB1 regulation.\",\n      \"evidence\": \"m7G profiling, RIP assay, mRNA stability assays in HCC cells\",\n      \"pmids\": [\"34244479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether m7G and m6A modifications on CCNB1 mRNA interact or are mutually exclusive unknown\", \"In vivo validation lacking\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"UCHL1 was identified as a second deubiquitinase (in addition to USP22) that directly stabilizes CCNB1 protein by inhibiting its proteasomal degradation, indicating redundant DUB-mediated protection of Cyclin B1.\",\n      \"evidence\": \"Co-IP, half-life assay, siRNA knockdown/overexpression in porcine granulosa cells\",\n      \"pmids\": [\"38858680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether UCHL1 and USP22 act on the same or different ubiquitin chain types on CCNB1 unknown\", \"Relevance in human somatic cells not confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"METTL3-mediated m6A modification was shown to stabilize CCNB1 mRNA, adding a second epitranscriptomic control layer alongside m7G modification and linking CCNB1 regulation to intercellular communication via exosomes.\",\n      \"evidence\": \"MeRIP, mRNA stability assay, functional rescue in dermal fibroblasts\",\n      \"pmids\": [\"39954139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A reader identity for CCNB1 mRNA not identified\", \"Relative contribution of m6A vs. m7G to CCNB1 mRNA stability not compared\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"MAPK1 was shown to directly phosphorylate CCNB1 at Ser128 to promote its nuclear translocation and G2-to-prophase transition, establishing a direct kinase–substrate link between mitogenic signaling and mitotic entry.\",\n      \"evidence\": \"In vitro kinase assay, TurboID proximity labeling, phospho-mutant rescue, nuclear-cytoplasmic fractionation in TNBC cells and xenografts\",\n      \"pmids\": [\"41905453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser128 phosphorylation affects CDK1 binding or catalytic activity unknown\", \"Interplay with CRM1/importin-mediated nuclear transport not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple transcriptional, epitranscriptomic, translational, and post-translational inputs converge quantitatively to set the threshold of CDK1–CCNB1 activity required for mitotic commitment remains an open systems-level question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated quantitative model of CCNB1 accumulation combining transcription, RNA modification, translation, and degradation\", \"In vivo contribution of individual DUBs and E3 ligases to CCNB1 steady-state levels not compared\", \"Structural basis of MAPK1-mediated Ser128 phosphorylation and its effect on CDK1–CCNB1 complex dynamics unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [18, 26]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 2, 3, 12, 13, 17, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 12, 21, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 26]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 9, 10, 11, 28]}\n    ],\n    \"complexes\": [\n      \"CDK1-CCNB1 (MPF)\",\n      \"CDK1-CCNB1-CKS1-separase inhibitory complex\",\n      \"APC/C-CDC20 (substrate)\"\n    ],\n    \"partners\": [\n      \"CDK1\",\n      \"MAD1\",\n      \"USP22\",\n      \"UCHL1\",\n      \"FOXM1\",\n      \"MAPK1\",\n      \"GADD45G\",\n      \"SQLE\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}