{"gene":"MYBL2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1988,"finding":"MYBL2 (B-Myb) encodes a protein of ~700 amino acids with three conserved domains homologous to the c-Myb DNA-binding domain, establishing it as a member of the MYB transcription factor family.","method":"cDNA cloning and sequence analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — foundational cloning paper, replicated across multiple labs subsequently","pmids":["3060855"],"is_preprint":false},{"year":1992,"finding":"B-myb mRNA expression is cell cycle-regulated, induced in late G1 upon serum stimulation of quiescent fibroblasts and persisting through S phase, consistent with a role in G1/S transition.","method":"Northern blot of synchronized cells, serum stimulation of quiescent 3T3 fibroblasts","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell cycle synchronization with direct mRNA quantification, replicated in multiple cell types and subsequent studies","pmids":["1501895"],"is_preprint":false},{"year":1993,"finding":"Full-length B-Myb does not bind the c-Myb DNA-binding site (MBS-1) and cannot transactivate c-Myb target promoters; however, truncation of the B-Myb C-terminus releases latent DNA-binding competence, and B-Myb inhibits c-Myb transactivation in co-transfection assays. B-Myb and c-Myb can both weakly transactivate the DNA polymerase alpha promoter.","method":"In vitro transcription/translation, gel-shift assays, co-transfection reporter assays, GAL4 fusion assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal in vitro and cell-based assays in single study, mechanistically detailed","pmids":["8382794"],"is_preprint":false},{"year":1994,"finding":"HPV16 E7 oncoprotein deregulates B-myb transcription by interacting with p107 at the E2F binding site of the B-myb promoter, causing both inappropriate G1 transcription and constitutive over-expression; regulation correlates with p107-containing E2F complexes rather than pRb.","method":"Reporter assays, E2F binding analysis, E7 mutant analysis, promoter mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assays, binding studies, mutant analysis) in single rigorous study","pmids":["8112300"],"is_preprint":false},{"year":1994,"finding":"Constitutive B-Myb expression can bypass p53-induced G1 arrest even in the presence of Waf1/Cip1 upregulation and cyclin E/Cdk2 inhibition; the DNA-binding domain of B-Myb is required for this activity.","method":"Ectopic expression rescue assays, co-transfection with p53 and B-Myb deletion mutants, cell cycle analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via deletion mutants, multiple orthogonal readouts","pmids":["7937841"],"is_preprint":false},{"year":1995,"finding":"The human B-myb promoter is repressed in G0 by an E2F-binding site; mutation of this site increases reporter activity in quiescent cells. De-repression in S phase correlates with disappearance of a G0-specific E2F complex and appearance of a p107-containing complex.","method":"Luciferase reporter assays with promoter mutations, E2F binding analysis, cell cycle synchronization","journal":"Gene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis plus E2F binding analysis, mechanistically rigorous","pmids":["7642110"],"is_preprint":false},{"year":1996,"finding":"E2F-mediated repression of the B-myb promoter in G0/early G1 requires cooperation with a contiguous CHR (cell cycle homology region) corepressor element; DP-1 heterodimerizes with E2F-1, E2F-3, or E2F-4 to recognize the repressor element.","method":"Gel-shift assays with fractionated nuclear extract, promoter mutagenesis, in vivo footprinting","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical binding assays plus mutagenesis and in vivo footprinting","pmids":["8760872"],"is_preprint":false},{"year":1996,"finding":"B-Myb overexpression induces DNA synthesis in p107-arrested Saos-2 cells; p107 down-modulates B-myb promoter activity and decreases E2F-mediated transactivation of the B-myb promoter.","method":"Transient transfection reporter assays, BrdU/DNA synthesis assays in p107-growth-arrested cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assays plus cellular proliferation assay, single lab","pmids":["8621601"],"is_preprint":false},{"year":1997,"finding":"Cyclin A/Cdk2 phosphorylates B-Myb at its carboxy-terminal region, relieving repression by this domain and markedly stimulating its transcriptional transactivation function; endogenous B-Myb is phosphorylated during S phase.","method":"Tryptic phosphopeptide mapping, co-expression assays, transactivation reporter assays, cyclin A/Cdk2 baculovirus-expressed kinase assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay plus cell-based phosphopeptide mapping and functional reporter assays, replicated by multiple labs","pmids":["9094315"],"is_preprint":false},{"year":1997,"finding":"Cyclin A or cyclin E co-expression activates B-MYB transcriptional activity and promotes S phase entry in Saos-2 cells; cyclin-dependent activation is demonstrated in an in vitro transcription assay and is specific to B-MYB (not c-MYB).","method":"Transfection/S phase entry assays, in vitro transcription assay, reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro transcription assay plus cell-based validation, replicated across labs","pmids":["9012818"],"is_preprint":false},{"year":1997,"finding":"Cyclin A-mediated phosphorylation of B-Myb enhances its transactivation function; protein truncation just downstream of the evolutionarily conserved C-terminal domain also hyperactivates B-Myb, and these effects are partially additive. B-Myb synergizes with cyclin A to promote S phase entry.","method":"Reporter assays, co-expression with cyclin A/Cdk2, B-Myb truncation mutants, cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutants plus functional reporter assays, single lab","pmids":["9188859"],"is_preprint":false},{"year":1997,"finding":"Cyclin A and cyclin E activate the trans-activating function of B-Myb by overcoming inhibition mediated by its carboxy-terminus; a conserved activation domain within B-Myb was localized by mutational analysis in yeast.","method":"Yeast transactivation assay, mutational analysis, co-expression in vertebrate cells","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast mutagenesis plus vertebrate cell assays, single lab","pmids":["9428611"],"is_preprint":false},{"year":1999,"finding":"B-myb-deficient mice die at embryonic day E4.5–E6.5; in vitro blastocyst culture shows B-Myb is required for inner cell mass (ICM) formation. Only B-Myb among Myb family members is expressed in embryonic stem cells.","method":"Gene targeting knockout mice, in vitro blastocyst culture, expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined developmental phenotype, replicated in subsequent studies","pmids":["10497154"],"is_preprint":false},{"year":1999,"finding":"B-MYB transactivates its own promoter through a 120 bp SP1-binding proximal element; B-MYB does not directly bind this element but cooperates with SP1 via SP1 domain A, acting as a coactivator of SP1.","method":"Reporter assays, gel-shift assays, SP1 co-transfection, SP1-GAL4 fusion analysis, promoter deletion mapping","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple promoter mutants plus binding assays, single lab","pmids":["10022815"],"is_preprint":false},{"year":1999,"finding":"B-Myb is phosphorylated at 10 Ser/Thr-Pro sites by cyclin A-Cdk2 and cyclin E-Cdk2 both in vivo and in vitro; phosphorylation at Ser581 negatively regulates DNA binding, and mutagenesis of all 10 sites abrogates cyclin A-dependent transactivation enhancement.","method":"Automated peptide radiosequencing of tryptic phosphopeptides from 32P-labeled B-Myb, cell-free kinase assay, mutagenesis, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — comprehensive in vitro kinase mapping plus mutagenesis plus functional reporter assays","pmids":["10593981"],"is_preprint":false},{"year":2000,"finding":"B-Myb is degraded via ubiquitin-mediated proteolysis through the Cdc34-SCF(p45Skp2) pathway; cyclin A facilitates multiple ubiquitination of B-Myb through its C-terminal domain; B-Myb physically and functionally interacts with Cdc34 and p45Skp2.","method":"Co-immunoprecipitation, ubiquitination assays, C-terminal deletion mutants, ectopic expression of Cdc34 and Skp2","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical ubiquitination assay plus co-IP plus mutant analysis, single lab","pmids":["10871850"],"is_preprint":false},{"year":2001,"finding":"B-Myb is acetylated by the co-activator p300; the bromo and histone acetyltransferase domains of p300 are sufficient for interaction and acetylation; phosphorylation is essential for full B-Myb activity, and a phosphorylation-deficient mutant acts as a dominant-negative.","method":"In vivo acetylation assay, co-immunoprecipitation, dominant-negative suppression, reporter assays with phosphorylation-deficient mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct acetylation assay plus co-IP and functional analysis, single lab","pmids":["11733503"],"is_preprint":false},{"year":2001,"finding":"B-Myb forms an in vivo complex with p107 (but not pRb or p130) and overcomes p107-mediated G1 arrest independently of its transactivation function; B-Myb also interacts with repressors BS69 and N-CoR via its C-terminus.","method":"Co-immunoprecipitation, cell proliferation assay, dominant-negative experiments, S phase induction assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus functional rescue assays, single lab","pmids":["11485831"],"is_preprint":false},{"year":2001,"finding":"PARP co-activates B-MYB by inducing phosphorylation at cyclin/Cdk2 sites; a B-MYB mutant lacking all Cdk2 phosphorylation sites is refractory to PARP-induced phosphorylation and co-activation.","method":"Co-immunoprecipitation, phosphorylation-deficient mutant analysis, reporter assays, co-expression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation mutants plus functional assays, single lab","pmids":["11781832"],"is_preprint":false},{"year":2002,"finding":"B-Myb binds to an N-terminal domain of p107 (overlapping the cyclin-binding domain) that is distinct from the C-terminal pocket domain used by E2F; B-Myb and cyclin A2 form mutually exclusive complexes with p107; B-Myb enhances cyclin E kinase activity.","method":"Co-immunoprecipitation, GST pulldown, cyclin kinase activity assays, co-transfection","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays plus functional kinase measurements, single lab","pmids":["12439743"],"is_preprint":false},{"year":2003,"finding":"The zinc finger protein ZPR9 physically interacts with B-MYB (via all three B-MYB functional domains) both in vitro and in vivo, enhances B-MYB transcriptional activity in a dose-dependent manner, and promotes nuclear accumulation of both proteins.","method":"Yeast two-hybrid, co-immunoprecipitation, in vivo binding assay, reporter assays, confocal localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus co-IP plus functional reporter assays, single lab","pmids":["12645566"],"is_preprint":false},{"year":2004,"finding":"B-Myb-dependent transactivation is stimulated by the co-activator p300; interaction maps to the E1A-binding region of p300 and the transactivation domain of B-Myb; cyclin A-mediated phosphorylation of B-Myb stimulates its acetylation by p300, required for full transactivation; cyclin D1 inhibits B-Myb activity by interfering with B-Myb–p300 interaction.","method":"Co-immunoprecipitation, reporter assays, cyclin A/D1 co-expression, acetylation assays, domain mapping","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (co-IP, acetylation, reporters) in single lab study","pmids":["14973551"],"is_preprint":false},{"year":2004,"finding":"B-MYB binds to transcriptional regulatory elements of the stress-related gene ApoJ/clusterin in a temperature-dependent manner and activates its expression as a pro-survival response to thermal stress; suppression of B-MYB transactivation by a dominant-negative only induces cell death when cells are exposed to high temperature.","method":"RNA interference, dominant-negative B-MYB, chromatin immunoprecipitation, cell death assays, temperature-shift experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus dominant-negative plus RNAi, single lab","pmids":["15618219"],"is_preprint":false},{"year":2005,"finding":"Loss-of-function mutation of bmyb in zebrafish (crash&burn mutant) causes defects in mitotic progression and spindle formation, decreased cyclin B1 levels, and genome instability; regulation of cyclin B levels by Bmyb appears to be the mechanism of mitotic accumulation.","method":"Zebrafish forward genetic screen, loss-of-function mutant analysis, cell cycle and spindle imaging, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined mitotic/spindle phenotype plus mechanism (cyclin B), replicated in suppressor screen","pmids":["16150706"],"is_preprint":false},{"year":2005,"finding":"Chemical suppressor screening in zebrafish bmyb mutants identified that S-phase delay (via ATR-dependent checkpoint) upregulates cyclin B1 mRNA and suppresses bmyb-dependent mitotic defects; ATR knockdown abrogates this suppression, placing bmyb upstream of cyclin B1 and the ATR checkpoint pathway.","method":"Small molecule suppressor screen in zebrafish embryos, ATR morpholino knockdown, cyclin B1 expression analysis","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (ATR knockdown rescue) plus chemical biology, mechanistically rigorous","pmids":["16372403"],"is_preprint":false},{"year":2006,"finding":"Nuclear EGFR associates with E2F1 in an EGF-dependent manner and both bind the B-Myb promoter cooperatively; EGFR kinase activity is required; promoter mutagenesis shows both E2F and EGFR target sites are needed for EGF-induced B-Myb activation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, promoter mutagenesis, reporter assays, kinase inhibitor experiments","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus promoter mutagenesis, single lab","pmids":["16299810"],"is_preprint":false},{"year":2008,"finding":"B-Myb forms a complex with clathrin and filamin (Myb-Clafi complex) that is required for normal localization of clathrin to the mitotic spindle; loss of this complex disrupts spindle stability and contributes to genome instability.","method":"Biochemical purification of B-Myb complex, co-immunoprecipitation, mitotic spindle localization imaging, functional spindle assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical complex purification plus functional imaging, mechanistically novel","pmids":["18548008"],"is_preprint":false},{"year":2008,"finding":"B-MYB knockdown in murine embryonic stem cells causes delayed G2/M transit, mitotic spindle and centrosome defects, and polyploidy/aneuploidy; B-Myb overexpression modestly up-regulates pou5f1 (Oct4) gene promoter activity in vitro.","method":"shRNA knockdown, cell cycle analysis by flow cytometry, immunofluorescence of spindle/centrosome, luciferase reporter for pou5f1 promoter","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown with multiple cellular phenotypic readouts plus reporter assay, single lab","pmids":["18575582"],"is_preprint":false},{"year":2009,"finding":"DNA damage triggers p53-dependent binding of p130 and E2F4 to the LINC complex with concurrent dissociation of B-MYB from LINC; in p53-mutant cells, B-MYB fails to dissociate from LINC, maintains G2/M gene expression after damage, and is required for recovery from the G2 DNA damage checkpoint.","method":"Co-immunoprecipitation of LINC components, microarray expression analysis, B-MYB siRNA knockdown, G2 checkpoint recovery assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP plus RNAi with defined checkpoint phenotype, mechanistically detailed","pmids":["19383908"],"is_preprint":false},{"year":2010,"finding":"miR-29 and miR-30 families repress B-Myb expression during senescence by binding conserved sites in the B-Myb 3'UTR; this repression requires Rb pathway activation; compensatory mutations in both miRNA and 3'UTR restore repression, and miR-29/30 introduction inhibits DNA synthesis.","method":"Reporter assays with wild-type and mutant B-Myb 3'UTR, miRNA transfection, compensatory mutation rescue, cell cycle analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including compensatory mutation rescue, mechanistically rigorous","pmids":["21187425"],"is_preprint":false},{"year":2010,"finding":"B-Myb ablation in mouse ESCs leads to stalling of replication forks, superactivation of replication factories, disorganization of the replication program, and increased double-strand breaks; these effects are partly due to aberrant transcriptional regulation of c-Myc and FoxM1.","method":"Conditional B-myb knockout in mES cells, single DNA fiber analysis, 3D imaging, gene expression analysis","journal":"Stem cells (Dayton, Ohio)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function plus single-molecule DNA fiber analysis, mechanistically rigorous","pmids":["20715180"],"is_preprint":false},{"year":2010,"finding":"B-MYB binds a MYB-binding site (MBS) in the p16(INK4α) promoter in vivo and represses p16 transcription; knockdown of B-MYB upregulates p16 expression and impairs replicative ability.","method":"ChIP, promoter reporter assays, siRNA knockdown, replicative senescence assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus RNAi, single lab","pmids":["20734103"],"is_preprint":false},{"year":2011,"finding":"MYBL2-LIN9 complex (LINC) activation is crucial for HCC progression; LINC integrity contributes to survival of DNA-damaged p53-null cells; siRNA-mediated MYBL2/LINC silencing reduces proliferation and induces apoptosis; doxorubicin triggers LIN9 dissociation from MYBL2 in p53-positive but not p53-null cells.","method":"Co-immunoprecipitation, siRNA knockdown, cell proliferation and apoptosis assays, western blotting in p53+/+ and p53-/- cell lines","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional knockdown assays, single lab","pmids":["21480327"],"is_preprint":false},{"year":2012,"finding":"B-Myb acts as a pioneer factor required for FoxM1 binding to G2/M gene promoters; conditional B-myb knockout reduces FoxM1 promoter binding without affecting FoxM1 protein levels or nuclear localization; Myb binding site mutation on Birc5 promoter prevents FoxM1 binding and activation.","method":"Conditional B-myb knockout 3T3 cells (floxed alleles + Cre), chromatin immunoprecipitation, promoter-reporter assays with Myb binding site mutations, gene expression analysis","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional knockout plus ChIP plus promoter mutagenesis, multiple orthogonal methods in single study","pmids":["22513242"],"is_preprint":false},{"year":2014,"finding":"Conditional inactivation of B-myb in vivo depletes the hematopoietic stem cell (HSC) pool; HSCs accumulate in S and G2/M phases; the defect is bone-marrow autonomous and affects common myeloid progenitors with relative sparing of granulocyte-macrophage progenitors.","method":"Conditional knockout mice, flow cytometry, cell cycle analysis, bone marrow transplantation, microarray","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional knockout with bone marrow reconstitution and defined cellular phenotype","pmids":["24516162"],"is_preprint":false},{"year":2015,"finding":"Cyclin F interacts with B-Myb via its cyclin box domain and suppresses B-Myb-driven transcriptional activation of mitosis-promoting genes; cyclin F interaction specifically inhibits cyclin A-mediated phosphorylation of B-Myb, and cyclin F depletion causes failure to maintain G2 arrest after ionizing radiation.","method":"RNA interference screen, co-immunoprecipitation, G2 checkpoint assays, phosphorylation assays, gene expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional checkpoint assays plus phosphorylation analysis, multiple orthogonal methods","pmids":["25557911"],"is_preprint":false},{"year":2017,"finding":"B-Myb (MYBL2) binds the APOBEC3B (A3B) promoter and transactivates it, causing C-to-T cytosine transitions; EGFR blockade with afatinib attenuates B-Myb–A3B signaling.","method":"ChIP for B-Myb at A3B promoter, reporter assays, mutation analysis in breast cancer cells, pharmacological inhibition","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assays, single lab","pmids":["28276478"],"is_preprint":false},{"year":2017,"finding":"Akt/FoxM1 signaling upregulates MYBL2 expression in glioma; inactivation of Akt or siRNA-mediated FoxM1 knockdown reduces MYBL2 protein levels, placing MYBL2 as a downstream effector of the Akt/FoxM1 pathway.","method":"siRNA knockdown, Akt inhibitor treatment, western blotting, qRT-PCR, luciferase reporter, ChIP","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pathway epistasis via inhibitor and siRNA with multiple readouts, single lab","pmids":["28784180"],"is_preprint":false},{"year":2018,"finding":"Overexpression of B-Myb disrupts the DREAM complex in human cells in a manner dependent on the intact MuvB-binding domain; B-Myb regulates LIN52 protein expression via a mechanism requiring S28 phosphorylation in LIN52, a key adapter for both DREAM and MMB complex assembly.","method":"Co-immunoprecipitation of DREAM/MMB components, B-Myb overexpression, MuvB-binding domain mutants, LIN52 phosphorylation site analysis, western blotting","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mutants plus phosphorylation site analysis and functional disruption assays","pmids":["30206359"],"is_preprint":false},{"year":2018,"finding":"MYBL2 haploinsufficiency in mouse HSCs leads to defects in DNA double-strand break repair kinetics after ionizing radiation, characterized by unsustained ATM substrate KAP1 phosphorylation and telomere fragility.","method":"Mybl2 haploinsufficient mice, γH2AX kinetics after IR, phospho-KAP1 analysis, telomere FISH","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model with mechanistic DSB repair readouts, single lab","pmids":["30082276"],"is_preprint":false},{"year":2019,"finding":"UHMK1 kinase stimulates nuclear enrichment of MYBL2 and thereby supports expression of MYBL2-target cell cycle genes (CCNB1, CCNB2, KIF20A, MAD2L1); MYBL2 is identified as a direct UHMK1 interaction partner by BioID proximity labeling and mass spectrometry.","method":"BioID labeling, mass spectrometry, co-immunoprecipitation, subcellular fractionation, gene expression analysis, YAPS127A transgenic mice","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID plus mass spectrometry plus co-IP plus functional gene expression analysis, single lab","pmids":["30936457"],"is_preprint":false},{"year":2019,"finding":"B-Myb activation involves a stepwise phosphorylation mechanism: initial Cdk-dependent phosphorylation enables Pin1 binding and prolyl cis/trans isomerization, which in turn enables further Cdk-site phosphorylation and Plk1 docking, followed by Plk1-mediated phosphorylation to activate transcription of late cell cycle genes.","method":"Phosphorylation mapping, Pin1 binding assays, Plk1 docking assays, mutational analysis, reporter assays for late cell cycle gene activation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — stepwise mechanistic dissection with phosphorylation mapping, Pin1/Plk1 binding assays, and mutagenesis","pmids":["30321399"],"is_preprint":false},{"year":2021,"finding":"MYBL2 promotes castration resistance in prostate cancer by promoting YAP1 transcriptional activity via modulation of RhoA GTPase activity and LATS1 kinase activity (Hippo pathway); this is demonstrated by subcellular fractionation, ChIP, reporter assays, and in vivo experiments.","method":"Subcellular fractionation, western blotting, ChIP, luciferase reporter assays, RhoA/LATS1 activity assays, in vivo xenograft","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays plus in vivo validation, single lab","pmids":["33897882"],"is_preprint":false},{"year":2021,"finding":"MYBL2 activates transcription of CDCA3 by directly binding its promoter; MYBL2 interacts with FOXM1 to co-regulate CDCA3 transcription; the MYBL2/FOXM1/CDCA3 axis activates Wnt/β-catenin signaling in bladder cancer.","method":"ChIP, co-immunoprecipitation, reporter assays, siRNA knockdown, western blotting","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus co-IP plus reporter assays, single lab","pmids":["36071275"],"is_preprint":false},{"year":2021,"finding":"MYBL2 directly binds the RRM2 gene promoter and activates its transcription during S phase together with TAF15 and MuvB components; MYBL2 is essential for CRC cell DNA synthesis and cell cycle progression in an RRM2-dependent manner.","method":"ChIP, co-immunoprecipitation, reporter assays, siRNA/ectopic expression, DNA synthesis assays, xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus co-IP plus functional rescue assays, single lab","pmids":["34234118"],"is_preprint":false},{"year":2021,"finding":"MYBL2 activates ATM and suppresses replication stress in embryonic stem cells; loss of MYBL2 or ATM inhibition causes replication fork slowing, fork stalling, and elevated origin firing; CDC7 inhibition rescues this replication stress, implicating uncontrolled origin firing as the underlying mechanism.","method":"Conditional MYBL2 knockout/knockdown in ESCs, DNA fiber assays, ATM/Mre11 inhibitors, CDC7 inhibitor rescue, origin firing analysis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function plus pharmacological epistasis plus DNA fiber analysis, multiple orthogonal methods","pmids":["33779025"],"is_preprint":false},{"year":2010,"finding":"B-MYB interacts with STRAP and enhances STRAP-mediated inhibition of TGF-β signaling by modulating SMAD3/SMAD7-TGF-β receptor complex formation; B-MYB also stimulates STRAP-mediated p53-induced apoptosis; confocal microscopy showed B-MYB prevents SMAD3 nuclear translocation.","method":"Co-immunoprecipitation, confocal microscopy, reporter assays, co-expression experiments, domain mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus imaging plus functional reporter assays, single lab","pmids":["21148321"],"is_preprint":false},{"year":2004,"finding":"Cytosolic phospholipase A2 (cPLA2) physically interacts with B-Myb in both cytoplasm and nucleus, negatively regulating B-Myb-dependent c-Myc gene expression; a catalytically inactive cPLA2 mutant lacking B-Myb binding does not inhibit B-Myb-dependent c-myc expression.","method":"Co-immunoprecipitation, reporter assays, genetic knockout mice (cPLA2-/-), siRNA, mutant cPLA2 analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus genetic knockout plus functional assays, single lab","pmids":["14769798"],"is_preprint":false},{"year":2021,"finding":"B-Myb and E2F2 form physical complexes in colorectal cancer cells, mutually transactivate each other's promoters, and constitute reciprocal feed-forward transactivation loops; both are required for ERK and AKT signaling pathway activation.","method":"Co-immunoprecipitation, ChIP, reporter assays, siRNA knockdown, RNA-seq, in vivo orthotopic models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus reporter assays plus functional knockdown, single lab","pmids":["34316028"],"is_preprint":false},{"year":2023,"finding":"MYBL2 transcriptionally activates CCL2 by binding its promoter, promoting TAM recruitment and M2-like polarization; CDK2 phosphorylates MYBL2 to promote its transcriptional function; CDK2 inhibition (CVT-313) reprograms the tumor microenvironment.","method":"ChIP, luciferase reporter assays, syngeneic mouse model, flow cytometry, qRT-PCR, ELISA","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus in vivo model, single lab","pmids":["37865750"],"is_preprint":false}],"current_model":"MYBL2 (B-Myb) is a cell cycle-regulated transcription factor that is transcriptionally repressed in G0 by E2F–p107/p130 complexes at its promoter and induced at the G1/S boundary; its transactivation activity is suppressed by a C-terminal regulatory domain and is relieved by sequential Cdk (cyclin A/E–Cdk2)- and Plk1-mediated phosphorylation facilitated by Pin1-dependent prolyl isomerization, after which B-Myb acts as a pioneer factor enabling FoxM1 binding to G2/M gene promoters; B-Myb is degraded via the Cdc34–SCF(Skp2) ubiquitin pathway, is acetylated by p300 in a phosphorylation-dependent manner, forms a non-transcriptional complex with clathrin and filamin required for mitotic spindle stability, interacts with and is suppressed by cyclin F to enforce G2 checkpoint maintenance, associates with MuvB to form the MMB complex that drives G2/M gene expression while its overexpression disrupts the repressive DREAM complex, activates ATM to suppress replication stress in embryonic stem cells, and supports DNA double-strand break repair in hematopoietic stem cells."},"narrative":{"mechanistic_narrative":"MYBL2 (B-Myb) is a cell cycle-regulated transcription factor of the MYB family that governs the G1/S and G2/M gene-expression programs and is essential for proliferation, genome stability, and early development [PMID:3060855, PMID:1501895, PMID:10497154]. Its transcription is repressed in G0/early G1 by an E2F-binding site cooperating with a contiguous CHR corepressor element and p107-containing E2F complexes, and is induced at the G1/S boundary [PMID:7642110, PMID:8760872, PMID:8621601]. The latent activity of full-length B-Myb is held in check by an inhibitory C-terminal domain, which is relieved by cyclin A/E–Cdk2 phosphorylation at multiple Ser/Thr-Pro sites; this activation is amplified by Pin1-dependent prolyl isomerization that licenses further Cdk and Plk1 phosphorylation, and by phosphorylation-dependent acetylation by p300 [PMID:9094315, PMID:10593981, PMID:30321399, PMID:14973551]. Activated B-Myb assembles with MuvB to form the MMB complex that drives late cell-cycle gene expression, and acts as a pioneer factor enabling FoxM1 to bind G2/M promoters; its overexpression disrupts the repressive DREAM complex through the LIN52 adapter [PMID:22513242, PMID:30206359]. Beyond transcription, B-Myb forms a non-transcriptional complex with clathrin and filamin required for mitotic spindle stability, and B-Myb loss in model systems produces spindle/centrosome defects, reduced cyclin B1, polyploidy, and genome instability [PMID:18548008, PMID:16150706, PMID:18575582]. B-Myb safeguards replication by activating ATM to restrain origin firing and limit replication stress in embryonic stem cells, and supports double-strand break repair in hematopoietic stem cells, where it is required to maintain the HSC pool [PMID:33779025, PMID:20715180, PMID:30082276, PMID:24516162]. Its abundance is restrained by Cdc34–SCF(Skp2)-mediated degradation, by cyclin F binding that blocks Cdk-mediated activation to enforce G2 checkpoint maintenance, and by miR-29/miR-30 targeting of its 3'UTR during senescence [PMID:10871850, PMID:25557911, PMID:21187425]. B-Myb knockout is embryonic lethal at E4.5–E6.5 with failure of inner cell mass formation [PMID:10497154].","teleology":[{"year":1988,"claim":"Establishing that MYBL2 is a structural member of the MYB transcription factor family defined its candidate molecular identity as a DNA-binding regulator.","evidence":"cDNA cloning and sequence analysis revealing three conserved c-Myb-homologous DNA-binding domains","pmids":["3060855"],"confidence":"Medium","gaps":["Sequence homology alone did not establish DNA-binding specificity or target genes","No functional or cell-cycle context"]},{"year":1992,"claim":"Linking B-myb expression to the cell cycle placed the gene in the G1/S transition rather than treating it as a constitutive factor.","evidence":"Northern blot of serum-stimulated synchronized 3T3 fibroblasts","pmids":["1501895"],"confidence":"High","gaps":["mRNA timing did not reveal the protein-level regulatory mechanism","Did not identify upstream regulators of the promoter"]},{"year":1993,"claim":"Showing full-length B-Myb is intrinsically DNA-binding-incompetent unless its C-terminus is removed revealed an autoinhibitory architecture distinct from c-Myb.","evidence":"In vitro transcription/translation, gel-shift, GAL4 fusion and co-transfection reporter assays","pmids":["8382794"],"confidence":"High","gaps":["Did not identify the physiological signal that relieves C-terminal inhibition","Endogenous target promoters remained undefined"]},{"year":1994,"claim":"Defining E2F/p107-dependent repression of the B-myb promoter, and its deregulation by HPV16 E7, explained how the gene is restricted to S phase and how it is hijacked in transformation.","evidence":"Reporter assays, E2F binding analysis, E7 mutant and promoter mutagenesis; p53/cyclin-Cdk2 bypass assays","pmids":["8112300","7937841"],"confidence":"High","gaps":["The corepressor element cooperating with E2F was not yet defined","Mechanism by which B-Myb bypasses p53 arrest unresolved"]},{"year":1996,"claim":"Resolving the cooperating CHR corepressor element and DP-1/E2F heterodimers clarified the combinatorial logic of G0 promoter repression.","evidence":"Gel-shift with fractionated extract, promoter mutagenesis, in vivo footprinting; p107 reporter and BrdU assays","pmids":["8760872","8621601"],"confidence":"High","gaps":["Did not address post-translational control of B-Myb protein activity","p107 down-modulation mechanism only partly defined"]},{"year":1999,"claim":"Comprehensive mapping of cyclin A/E–Cdk2 phosphorylation sites established the post-translational switch that converts repressed B-Myb into an active transactivator.","evidence":"Phosphopeptide radiosequencing, cell-free kinase assays, site mutagenesis and reporter assays (building on 1997 kinase studies)","pmids":["10593981","9094315","9012818"],"confidence":"High","gaps":["The downstream consequences (acetylation, complex assembly) were not yet integrated","Did not define endogenous late cell-cycle target genes"]},{"year":1999,"claim":"Genetic knockout in mice defined B-Myb as essential for early embryogenesis and inner cell mass formation, establishing a non-redundant biological requirement.","evidence":"Gene-targeted knockout mice and in vitro blastocyst culture","pmids":["10497154"],"confidence":"High","gaps":["Early lethality precluded analysis of later tissue roles","Molecular cause of ICM failure undefined at the time"]},{"year":2001,"claim":"Identifying SCF(Skp2)-mediated degradation and phosphorylation-dependent p300 acetylation showed that B-Myb activity is coupled to coordinated turnover and coactivator recruitment.","evidence":"Ubiquitination and co-IP assays with Cdc34/Skp2; in vivo acetylation and dominant-negative reporter assays","pmids":["10871850","11733503","14973551"],"confidence":"Medium","gaps":["Single-lab biochemistry without structural confirmation of modification sites","Quantitative contribution of degradation vs activation to phenotype unclear"]},{"year":2005,"claim":"Loss-of-function in zebrafish tied B-Myb to mitotic spindle formation and cyclin B1 levels, extending its role from S-phase entry to mitotic fidelity and genome stability.","evidence":"Forward genetic crash&burn mutant, spindle imaging, and chemical suppressor screen with ATR knockdown epistasis","pmids":["16150706","16372403"],"confidence":"High","gaps":["Whether spindle effects are transcriptional or direct was unresolved here","Mammalian relevance not yet established in this work"]},{"year":2008,"claim":"Discovery of the B-Myb–clathrin–filamin (Clafi) complex revealed a non-transcriptional function directly supporting mitotic spindle stability.","evidence":"Biochemical complex purification, co-IP, and mitotic spindle localization imaging; ESC knockdown spindle/centrosome analysis","pmids":["18548008","18575582"],"confidence":"High","gaps":["How transcriptional and structural roles are partitioned in the cell is unclear","Regulation of Clafi complex assembly undefined"]},{"year":2009,"claim":"Defining B-Myb dissociation from the LINC/DREAM complex upon DNA damage, and its persistence in p53-mutant cells, connected B-Myb to G2 checkpoint control and recovery.","evidence":"Co-IP of LINC components, microarray, siRNA, and G2 checkpoint recovery assays in p53+/- backgrounds","pmids":["19383908","21480327"],"confidence":"High","gaps":["Direct signal triggering dissociation only partly defined","Did not resolve MuvB/DREAM exchange mechanism at the molecular level"]},{"year":2010,"claim":"Conditional ESC studies and senescence miRNA work established that B-Myb safeguards the replication program and is silenced via the Rb pathway during senescence.","evidence":"Conditional knockout with DNA fiber analysis; miR-29/30 3'UTR reporter and compensatory-mutation rescue; p16 promoter ChIP","pmids":["20715180","21187425","20734103"],"confidence":"High","gaps":["Direct vs indirect contribution of c-Myc/FoxM1 misregulation to fork defects not fully separated","p16 repression mechanism single-lab"]},{"year":2012,"claim":"Demonstrating B-Myb acts as a pioneer factor enabling FoxM1 promoter binding clarified the mechanistic hierarchy driving G2/M gene expression.","evidence":"Conditional knockout 3T3 cells, ChIP, and Myb-binding-site promoter mutagenesis on Birc5","pmids":["22513242"],"confidence":"High","gaps":["Generality of pioneer behavior across all G2/M promoters not established","Chromatin-opening mechanism not directly resolved"]},{"year":2015,"claim":"Identifying cyclin F as a B-Myb suppressor that blocks cyclin A-mediated phosphorylation revealed a brake enforcing G2 checkpoint maintenance.","evidence":"RNAi screen, co-IP, phosphorylation assays, and G2 checkpoint assays after ionizing radiation","pmids":["25557911"],"confidence":"High","gaps":["Stoichiometry and turnover of cyclin F–B-Myb interplay not quantified","Single-lab functional checkpoint data"]},{"year":2018,"claim":"Showing B-Myb overexpression disrupts DREAM via the MuvB/LIN52 adapter linked its abundance to the switch between repressive and activating MuvB complexes.","evidence":"Co-IP of DREAM/MMB components, MuvB-binding-domain mutants, and LIN52 S28 phosphorylation analysis","pmids":["30206359"],"confidence":"High","gaps":["In vivo significance of DREAM disruption by overexpression not addressed","How physiological B-Myb levels balance the complexes unclear"]},{"year":2019,"claim":"Defining a Pin1-licensed stepwise Cdk-then-Plk1 phosphorylation cascade explained how B-Myb is progressively activated to drive late cell-cycle genes.","evidence":"Phosphorylation mapping, Pin1 binding, Plk1 docking assays, mutagenesis and reporter assays; UHMK1 BioID nuclear-enrichment study","pmids":["30321399","30936457"],"confidence":"High","gaps":["Structural basis of ordered modification not resolved","UHMK1 contribution is single-lab and Medium confidence"]},{"year":2021,"claim":"ESC studies established that B-Myb activates ATM to restrain origin firing and limit replication stress, providing a mechanistic basis for its genome-stability role.","evidence":"Conditional knockout/knockdown, DNA fiber assays, ATM/Mre11 inhibition, and CDC7-inhibitor rescue of replication stress","pmids":["33779025"],"confidence":"High","gaps":["Whether ATM activation is transcriptional or direct not fully resolved","Generality beyond ESCs not established here"]},{"year":2018,"claim":"Haploinsufficiency studies extended the genome-stability role to hematopoietic stem cells, linking reduced B-Myb to impaired DSB repair and telomere fragility.","evidence":"Mybl2 haploinsufficient mice, γH2AX kinetics, phospho-KAP1 analysis, and telomere FISH","pmids":["30082276","24516162"],"confidence":"Medium","gaps":["Single-lab mechanistic readouts","Direct vs indirect effect on ATM substrate phosphorylation not separated"]},{"year":2023,"claim":"Cancer-context studies tied phosphorylation-activated MYBL2 to oncogenic transcriptional programs across multiple tumor types via direct promoter binding.","evidence":"ChIP, reporter assays, co-IP, and in vivo models linking MYBL2 to CDCA3/Wnt, RRM2, YAP1/Hippo, CCL2/TAM, APOBEC3B, and E2F2 loops","pmids":["37865750","36071275","34234118","33897882","28276478","34316028"],"confidence":"Medium","gaps":["Each target axis rests on single-lab evidence","Direct vs network-level effects on these targets not always distinguished"]},{"year":null,"claim":"How the structural (clathrin/filamin spindle) and transcriptional (MMB/FoxM1) functions of B-Myb are coordinated within a single cell cycle, and the structural basis of the ordered Cdk/Pin1/Plk1 activation switch, remain unresolved.","evidence":"No structural model of the activated B-Myb regulatory domain or integrated single-cell functional partitioning is present in the corpus","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of B-Myb bound to MuvB or its phospho-regulatory domain","Quantitative interplay between degradation, cyclin F inhibition, and activation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,8,33,38]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,14,31,33]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[13,33]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[20,40]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,8,33,38]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,33,44]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[39,45]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[30,45]}],"complexes":["MMB (Myb-MuvB)","DREAM","LINC","B-Myb–clathrin–filamin (Clafi)"],"partners":["LIN9","LIN52","FOXM1","P107 (RBL1)","CYCLIN F (CCNF)","P300 (EP300)","SKP2","PIN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10244","full_name":"Myb-related protein B","aliases":["Myb-like protein 2"],"length_aa":700,"mass_kda":78.8,"function":"Transcription factor involved in the regulation of cell survival, proliferation, and differentiation. Transactivates the expression of the CLU gene","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P10244/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYBL2","classification":"Not Classified","n_dependent_lines":657,"n_total_lines":1208,"dependency_fraction":0.5438741721854304},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2},{"gene":"RPN1","stoichiometry":0.2},{"gene":"RPN2","stoichiometry":0.2},{"gene":"STT3B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MYBL2","total_profiled":1310},"omim":[{"mim_id":"621288","title":"LIN52 DREAM MUVB CORE COMPLEX COMPONENT; LIN52","url":"https://www.omim.org/entry/621288"},{"mim_id":"621287","title":"LIN37 DREAM MUVB CORE COMPLEX COMPONENT; LIN37","url":"https://www.omim.org/entry/621287"},{"mim_id":"616905","title":"MORF4 FAMILY-ASSOCIATED PROTEIN 1; MRFAP1","url":"https://www.omim.org/entry/616905"},{"mim_id":"614041","title":"RB TRANSCRIPTIONAL COREPRESSOR 1; RB1","url":"https://www.omim.org/entry/614041"},{"mim_id":"613367","title":"LIN54, C. ELEGANS, HOMOLOG OF; LIN54","url":"https://www.omim.org/entry/613367"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":86.6},{"tissue":"lymphoid tissue","ntpm":51.8}],"url":"https://www.proteinatlas.org/search/MYBL2"},"hgnc":{"alias_symbol":["BMYB","B-MYB"],"prev_symbol":[]},"alphafold":{"accession":"P10244","domains":[{"cath_id":"1.10.10.60","chopping":"35-80","consensus_level":"medium","plddt":93.6367,"start":35,"end":80},{"cath_id":"1.10.10.60","chopping":"83-132","consensus_level":"medium","plddt":95.1012,"start":83,"end":132},{"cath_id":"1.10.10.60","chopping":"137-190","consensus_level":"medium","plddt":92.0522,"start":137,"end":190}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10244","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10244-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10244-F1-predicted_aligned_error_v6.png","plddt_mean":56.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYBL2","jax_strain_url":"https://www.jax.org/strain/search?query=MYBL2"},"sequence":{"accession":"P10244","fasta_url":"https://rest.uniprot.org/uniprotkb/P10244.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10244/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10244"}},"corpus_meta":[{"pmid":"28640249","id":"PMC_28640249","title":"MYBL2 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~700 amino acids with three conserved domains homologous to the c-Myb DNA-binding domain, establishing it as a member of the MYB transcription factor family.\",\n      \"method\": \"cDNA cloning and sequence analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — foundational cloning paper, replicated across multiple labs subsequently\",\n      \"pmids\": [\"3060855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"B-myb mRNA expression is cell cycle-regulated, induced in late G1 upon serum stimulation of quiescent fibroblasts and persisting through S phase, consistent with a role in G1/S transition.\",\n      \"method\": \"Northern blot of synchronized cells, serum stimulation of quiescent 3T3 fibroblasts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell cycle synchronization with direct mRNA quantification, replicated in multiple cell types and subsequent studies\",\n      \"pmids\": [\"1501895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Full-length B-Myb does not bind the c-Myb DNA-binding site (MBS-1) and cannot transactivate c-Myb target promoters; however, truncation of the B-Myb C-terminus releases latent DNA-binding competence, and B-Myb inhibits c-Myb transactivation in co-transfection assays. B-Myb and c-Myb can both weakly transactivate the DNA polymerase alpha promoter.\",\n      \"method\": \"In vitro transcription/translation, gel-shift assays, co-transfection reporter assays, GAL4 fusion assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal in vitro and cell-based assays in single study, mechanistically detailed\",\n      \"pmids\": [\"8382794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"HPV16 E7 oncoprotein deregulates B-myb transcription by interacting with p107 at the E2F binding site of the B-myb promoter, causing both inappropriate G1 transcription and constitutive over-expression; regulation correlates with p107-containing E2F complexes rather than pRb.\",\n      \"method\": \"Reporter assays, E2F binding analysis, E7 mutant analysis, promoter mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assays, binding studies, mutant analysis) in single rigorous study\",\n      \"pmids\": [\"8112300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Constitutive B-Myb expression can bypass p53-induced G1 arrest even in the presence of Waf1/Cip1 upregulation and cyclin E/Cdk2 inhibition; the DNA-binding domain of B-Myb is required for this activity.\",\n      \"method\": \"Ectopic expression rescue assays, co-transfection with p53 and B-Myb deletion mutants, cell cycle analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via deletion mutants, multiple orthogonal readouts\",\n      \"pmids\": [\"7937841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human B-myb promoter is repressed in G0 by an E2F-binding site; mutation of this site increases reporter activity in quiescent cells. De-repression in S phase correlates with disappearance of a G0-specific E2F complex and appearance of a p107-containing complex.\",\n      \"method\": \"Luciferase reporter assays with promoter mutations, E2F binding analysis, cell cycle synchronization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis plus E2F binding analysis, mechanistically rigorous\",\n      \"pmids\": [\"7642110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"E2F-mediated repression of the B-myb promoter in G0/early G1 requires cooperation with a contiguous CHR (cell cycle homology region) corepressor element; DP-1 heterodimerizes with E2F-1, E2F-3, or E2F-4 to recognize the repressor element.\",\n      \"method\": \"Gel-shift assays with fractionated nuclear extract, promoter mutagenesis, in vivo footprinting\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical binding assays plus mutagenesis and in vivo footprinting\",\n      \"pmids\": [\"8760872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"B-Myb overexpression induces DNA synthesis in p107-arrested Saos-2 cells; p107 down-modulates B-myb promoter activity and decreases E2F-mediated transactivation of the B-myb promoter.\",\n      \"method\": \"Transient transfection reporter assays, BrdU/DNA synthesis assays in p107-growth-arrested cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assays plus cellular proliferation assay, single lab\",\n      \"pmids\": [\"8621601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Cyclin A/Cdk2 phosphorylates B-Myb at its carboxy-terminal region, relieving repression by this domain and markedly stimulating its transcriptional transactivation function; endogenous B-Myb is phosphorylated during S phase.\",\n      \"method\": \"Tryptic phosphopeptide mapping, co-expression assays, transactivation reporter assays, cyclin A/Cdk2 baculovirus-expressed kinase assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay plus cell-based phosphopeptide mapping and functional reporter assays, replicated by multiple labs\",\n      \"pmids\": [\"9094315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Cyclin A or cyclin E co-expression activates B-MYB transcriptional activity and promotes S phase entry in Saos-2 cells; cyclin-dependent activation is demonstrated in an in vitro transcription assay and is specific to B-MYB (not c-MYB).\",\n      \"method\": \"Transfection/S phase entry assays, in vitro transcription assay, reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro transcription assay plus cell-based validation, replicated across labs\",\n      \"pmids\": [\"9012818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Cyclin A-mediated phosphorylation of B-Myb enhances its transactivation function; protein truncation just downstream of the evolutionarily conserved C-terminal domain also hyperactivates B-Myb, and these effects are partially additive. B-Myb synergizes with cyclin A to promote S phase entry.\",\n      \"method\": \"Reporter assays, co-expression with cyclin A/Cdk2, B-Myb truncation mutants, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutants plus functional reporter assays, single lab\",\n      \"pmids\": [\"9188859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Cyclin A and cyclin E activate the trans-activating function of B-Myb by overcoming inhibition mediated by its carboxy-terminus; a conserved activation domain within B-Myb was localized by mutational analysis in yeast.\",\n      \"method\": \"Yeast transactivation assay, mutational analysis, co-expression in vertebrate cells\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast mutagenesis plus vertebrate cell assays, single lab\",\n      \"pmids\": [\"9428611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"B-myb-deficient mice die at embryonic day E4.5–E6.5; in vitro blastocyst culture shows B-Myb is required for inner cell mass (ICM) formation. Only B-Myb among Myb family members is expressed in embryonic stem cells.\",\n      \"method\": \"Gene targeting knockout mice, in vitro blastocyst culture, expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined developmental phenotype, replicated in subsequent studies\",\n      \"pmids\": [\"10497154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"B-MYB transactivates its own promoter through a 120 bp SP1-binding proximal element; B-MYB does not directly bind this element but cooperates with SP1 via SP1 domain A, acting as a coactivator of SP1.\",\n      \"method\": \"Reporter assays, gel-shift assays, SP1 co-transfection, SP1-GAL4 fusion analysis, promoter deletion mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple promoter mutants plus binding assays, single lab\",\n      \"pmids\": [\"10022815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"B-Myb is phosphorylated at 10 Ser/Thr-Pro sites by cyclin A-Cdk2 and cyclin E-Cdk2 both in vivo and in vitro; phosphorylation at Ser581 negatively regulates DNA binding, and mutagenesis of all 10 sites abrogates cyclin A-dependent transactivation enhancement.\",\n      \"method\": \"Automated peptide radiosequencing of tryptic phosphopeptides from 32P-labeled B-Myb, cell-free kinase assay, mutagenesis, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — comprehensive in vitro kinase mapping plus mutagenesis plus functional reporter assays\",\n      \"pmids\": [\"10593981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"B-Myb is degraded via ubiquitin-mediated proteolysis through the Cdc34-SCF(p45Skp2) pathway; cyclin A facilitates multiple ubiquitination of B-Myb through its C-terminal domain; B-Myb physically and functionally interacts with Cdc34 and p45Skp2.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, C-terminal deletion mutants, ectopic expression of Cdc34 and Skp2\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical ubiquitination assay plus co-IP plus mutant analysis, single lab\",\n      \"pmids\": [\"10871850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"B-Myb is acetylated by the co-activator p300; the bromo and histone acetyltransferase domains of p300 are sufficient for interaction and acetylation; phosphorylation is essential for full B-Myb activity, and a phosphorylation-deficient mutant acts as a dominant-negative.\",\n      \"method\": \"In vivo acetylation assay, co-immunoprecipitation, dominant-negative suppression, reporter assays with phosphorylation-deficient mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct acetylation assay plus co-IP and functional analysis, single lab\",\n      \"pmids\": [\"11733503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"B-Myb forms an in vivo complex with p107 (but not pRb or p130) and overcomes p107-mediated G1 arrest independently of its transactivation function; B-Myb also interacts with repressors BS69 and N-CoR via its C-terminus.\",\n      \"method\": \"Co-immunoprecipitation, cell proliferation assay, dominant-negative experiments, S phase induction assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus functional rescue assays, single lab\",\n      \"pmids\": [\"11485831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PARP co-activates B-MYB by inducing phosphorylation at cyclin/Cdk2 sites; a B-MYB mutant lacking all Cdk2 phosphorylation sites is refractory to PARP-induced phosphorylation and co-activation.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation-deficient mutant analysis, reporter assays, co-expression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation mutants plus functional assays, single lab\",\n      \"pmids\": [\"11781832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"B-Myb binds to an N-terminal domain of p107 (overlapping the cyclin-binding domain) that is distinct from the C-terminal pocket domain used by E2F; B-Myb and cyclin A2 form mutually exclusive complexes with p107; B-Myb enhances cyclin E kinase activity.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, cyclin kinase activity assays, co-transfection\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays plus functional kinase measurements, single lab\",\n      \"pmids\": [\"12439743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The zinc finger protein ZPR9 physically interacts with B-MYB (via all three B-MYB functional domains) both in vitro and in vivo, enhances B-MYB transcriptional activity in a dose-dependent manner, and promotes nuclear accumulation of both proteins.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vivo binding assay, reporter assays, confocal localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus co-IP plus functional reporter assays, single lab\",\n      \"pmids\": [\"12645566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"B-Myb-dependent transactivation is stimulated by the co-activator p300; interaction maps to the E1A-binding region of p300 and the transactivation domain of B-Myb; cyclin A-mediated phosphorylation of B-Myb stimulates its acetylation by p300, required for full transactivation; cyclin D1 inhibits B-Myb activity by interfering with B-Myb–p300 interaction.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, cyclin A/D1 co-expression, acetylation assays, domain mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (co-IP, acetylation, reporters) in single lab study\",\n      \"pmids\": [\"14973551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"B-MYB binds to transcriptional regulatory elements of the stress-related gene ApoJ/clusterin in a temperature-dependent manner and activates its expression as a pro-survival response to thermal stress; suppression of B-MYB transactivation by a dominant-negative only induces cell death when cells are exposed to high temperature.\",\n      \"method\": \"RNA interference, dominant-negative B-MYB, chromatin immunoprecipitation, cell death assays, temperature-shift experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus dominant-negative plus RNAi, single lab\",\n      \"pmids\": [\"15618219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Loss-of-function mutation of bmyb in zebrafish (crash&burn mutant) causes defects in mitotic progression and spindle formation, decreased cyclin B1 levels, and genome instability; regulation of cyclin B levels by Bmyb appears to be the mechanism of mitotic accumulation.\",\n      \"method\": \"Zebrafish forward genetic screen, loss-of-function mutant analysis, cell cycle and spindle imaging, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined mitotic/spindle phenotype plus mechanism (cyclin B), replicated in suppressor screen\",\n      \"pmids\": [\"16150706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Chemical suppressor screening in zebrafish bmyb mutants identified that S-phase delay (via ATR-dependent checkpoint) upregulates cyclin B1 mRNA and suppresses bmyb-dependent mitotic defects; ATR knockdown abrogates this suppression, placing bmyb upstream of cyclin B1 and the ATR checkpoint pathway.\",\n      \"method\": \"Small molecule suppressor screen in zebrafish embryos, ATR morpholino knockdown, cyclin B1 expression analysis\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (ATR knockdown rescue) plus chemical biology, mechanistically rigorous\",\n      \"pmids\": [\"16372403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nuclear EGFR associates with E2F1 in an EGF-dependent manner and both bind the B-Myb promoter cooperatively; EGFR kinase activity is required; promoter mutagenesis shows both E2F and EGFR target sites are needed for EGF-induced B-Myb activation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, promoter mutagenesis, reporter assays, kinase inhibitor experiments\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus promoter mutagenesis, single lab\",\n      \"pmids\": [\"16299810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"B-Myb forms a complex with clathrin and filamin (Myb-Clafi complex) that is required for normal localization of clathrin to the mitotic spindle; loss of this complex disrupts spindle stability and contributes to genome instability.\",\n      \"method\": \"Biochemical purification of B-Myb complex, co-immunoprecipitation, mitotic spindle localization imaging, functional spindle assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical complex purification plus functional imaging, mechanistically novel\",\n      \"pmids\": [\"18548008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"B-MYB knockdown in murine embryonic stem cells causes delayed G2/M transit, mitotic spindle and centrosome defects, and polyploidy/aneuploidy; B-Myb overexpression modestly up-regulates pou5f1 (Oct4) gene promoter activity in vitro.\",\n      \"method\": \"shRNA knockdown, cell cycle analysis by flow cytometry, immunofluorescence of spindle/centrosome, luciferase reporter for pou5f1 promoter\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown with multiple cellular phenotypic readouts plus reporter assay, single lab\",\n      \"pmids\": [\"18575582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DNA damage triggers p53-dependent binding of p130 and E2F4 to the LINC complex with concurrent dissociation of B-MYB from LINC; in p53-mutant cells, B-MYB fails to dissociate from LINC, maintains G2/M gene expression after damage, and is required for recovery from the G2 DNA damage checkpoint.\",\n      \"method\": \"Co-immunoprecipitation of LINC components, microarray expression analysis, B-MYB siRNA knockdown, G2 checkpoint recovery assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus RNAi with defined checkpoint phenotype, mechanistically detailed\",\n      \"pmids\": [\"19383908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-29 and miR-30 families repress B-Myb expression during senescence by binding conserved sites in the B-Myb 3'UTR; this repression requires Rb pathway activation; compensatory mutations in both miRNA and 3'UTR restore repression, and miR-29/30 introduction inhibits DNA synthesis.\",\n      \"method\": \"Reporter assays with wild-type and mutant B-Myb 3'UTR, miRNA transfection, compensatory mutation rescue, cell cycle analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including compensatory mutation rescue, mechanistically rigorous\",\n      \"pmids\": [\"21187425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"B-Myb ablation in mouse ESCs leads to stalling of replication forks, superactivation of replication factories, disorganization of the replication program, and increased double-strand breaks; these effects are partly due to aberrant transcriptional regulation of c-Myc and FoxM1.\",\n      \"method\": \"Conditional B-myb knockout in mES cells, single DNA fiber analysis, 3D imaging, gene expression analysis\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function plus single-molecule DNA fiber analysis, mechanistically rigorous\",\n      \"pmids\": [\"20715180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"B-MYB binds a MYB-binding site (MBS) in the p16(INK4α) promoter in vivo and represses p16 transcription; knockdown of B-MYB upregulates p16 expression and impairs replicative ability.\",\n      \"method\": \"ChIP, promoter reporter assays, siRNA knockdown, replicative senescence assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus RNAi, single lab\",\n      \"pmids\": [\"20734103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MYBL2-LIN9 complex (LINC) activation is crucial for HCC progression; LINC integrity contributes to survival of DNA-damaged p53-null cells; siRNA-mediated MYBL2/LINC silencing reduces proliferation and induces apoptosis; doxorubicin triggers LIN9 dissociation from MYBL2 in p53-positive but not p53-null cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, cell proliferation and apoptosis assays, western blotting in p53+/+ and p53-/- cell lines\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional knockdown assays, single lab\",\n      \"pmids\": [\"21480327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"B-Myb acts as a pioneer factor required for FoxM1 binding to G2/M gene promoters; conditional B-myb knockout reduces FoxM1 promoter binding without affecting FoxM1 protein levels or nuclear localization; Myb binding site mutation on Birc5 promoter prevents FoxM1 binding and activation.\",\n      \"method\": \"Conditional B-myb knockout 3T3 cells (floxed alleles + Cre), chromatin immunoprecipitation, promoter-reporter assays with Myb binding site mutations, gene expression analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout plus ChIP plus promoter mutagenesis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"22513242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Conditional inactivation of B-myb in vivo depletes the hematopoietic stem cell (HSC) pool; HSCs accumulate in S and G2/M phases; the defect is bone-marrow autonomous and affects common myeloid progenitors with relative sparing of granulocyte-macrophage progenitors.\",\n      \"method\": \"Conditional knockout mice, flow cytometry, cell cycle analysis, bone marrow transplantation, microarray\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional knockout with bone marrow reconstitution and defined cellular phenotype\",\n      \"pmids\": [\"24516162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cyclin F interacts with B-Myb via its cyclin box domain and suppresses B-Myb-driven transcriptional activation of mitosis-promoting genes; cyclin F interaction specifically inhibits cyclin A-mediated phosphorylation of B-Myb, and cyclin F depletion causes failure to maintain G2 arrest after ionizing radiation.\",\n      \"method\": \"RNA interference screen, co-immunoprecipitation, G2 checkpoint assays, phosphorylation assays, gene expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional checkpoint assays plus phosphorylation analysis, multiple orthogonal methods\",\n      \"pmids\": [\"25557911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"B-Myb (MYBL2) binds the APOBEC3B (A3B) promoter and transactivates it, causing C-to-T cytosine transitions; EGFR blockade with afatinib attenuates B-Myb–A3B signaling.\",\n      \"method\": \"ChIP for B-Myb at A3B promoter, reporter assays, mutation analysis in breast cancer cells, pharmacological inhibition\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assays, single lab\",\n      \"pmids\": [\"28276478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Akt/FoxM1 signaling upregulates MYBL2 expression in glioma; inactivation of Akt or siRNA-mediated FoxM1 knockdown reduces MYBL2 protein levels, placing MYBL2 as a downstream effector of the Akt/FoxM1 pathway.\",\n      \"method\": \"siRNA knockdown, Akt inhibitor treatment, western blotting, qRT-PCR, luciferase reporter, ChIP\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pathway epistasis via inhibitor and siRNA with multiple readouts, single lab\",\n      \"pmids\": [\"28784180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Overexpression of B-Myb disrupts the DREAM complex in human cells in a manner dependent on the intact MuvB-binding domain; B-Myb regulates LIN52 protein expression via a mechanism requiring S28 phosphorylation in LIN52, a key adapter for both DREAM and MMB complex assembly.\",\n      \"method\": \"Co-immunoprecipitation of DREAM/MMB components, B-Myb overexpression, MuvB-binding domain mutants, LIN52 phosphorylation site analysis, western blotting\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mutants plus phosphorylation site analysis and functional disruption assays\",\n      \"pmids\": [\"30206359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MYBL2 haploinsufficiency in mouse HSCs leads to defects in DNA double-strand break repair kinetics after ionizing radiation, characterized by unsustained ATM substrate KAP1 phosphorylation and telomere fragility.\",\n      \"method\": \"Mybl2 haploinsufficient mice, γH2AX kinetics after IR, phospho-KAP1 analysis, telomere FISH\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model with mechanistic DSB repair readouts, single lab\",\n      \"pmids\": [\"30082276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UHMK1 kinase stimulates nuclear enrichment of MYBL2 and thereby supports expression of MYBL2-target cell cycle genes (CCNB1, CCNB2, KIF20A, MAD2L1); MYBL2 is identified as a direct UHMK1 interaction partner by BioID proximity labeling and mass spectrometry.\",\n      \"method\": \"BioID labeling, mass spectrometry, co-immunoprecipitation, subcellular fractionation, gene expression analysis, YAPS127A transgenic mice\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID plus mass spectrometry plus co-IP plus functional gene expression analysis, single lab\",\n      \"pmids\": [\"30936457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"B-Myb activation involves a stepwise phosphorylation mechanism: initial Cdk-dependent phosphorylation enables Pin1 binding and prolyl cis/trans isomerization, which in turn enables further Cdk-site phosphorylation and Plk1 docking, followed by Plk1-mediated phosphorylation to activate transcription of late cell cycle genes.\",\n      \"method\": \"Phosphorylation mapping, Pin1 binding assays, Plk1 docking assays, mutational analysis, reporter assays for late cell cycle gene activation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — stepwise mechanistic dissection with phosphorylation mapping, Pin1/Plk1 binding assays, and mutagenesis\",\n      \"pmids\": [\"30321399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYBL2 promotes castration resistance in prostate cancer by promoting YAP1 transcriptional activity via modulation of RhoA GTPase activity and LATS1 kinase activity (Hippo pathway); this is demonstrated by subcellular fractionation, ChIP, reporter assays, and in vivo experiments.\",\n      \"method\": \"Subcellular fractionation, western blotting, ChIP, luciferase reporter assays, RhoA/LATS1 activity assays, in vivo xenograft\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays plus in vivo validation, single lab\",\n      \"pmids\": [\"33897882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYBL2 activates transcription of CDCA3 by directly binding its promoter; MYBL2 interacts with FOXM1 to co-regulate CDCA3 transcription; the MYBL2/FOXM1/CDCA3 axis activates Wnt/β-catenin signaling in bladder cancer.\",\n      \"method\": \"ChIP, co-immunoprecipitation, reporter assays, siRNA knockdown, western blotting\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus co-IP plus reporter assays, single lab\",\n      \"pmids\": [\"36071275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYBL2 directly binds the RRM2 gene promoter and activates its transcription during S phase together with TAF15 and MuvB components; MYBL2 is essential for CRC cell DNA synthesis and cell cycle progression in an RRM2-dependent manner.\",\n      \"method\": \"ChIP, co-immunoprecipitation, reporter assays, siRNA/ectopic expression, DNA synthesis assays, xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus co-IP plus functional rescue assays, single lab\",\n      \"pmids\": [\"34234118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYBL2 activates ATM and suppresses replication stress in embryonic stem cells; loss of MYBL2 or ATM inhibition causes replication fork slowing, fork stalling, and elevated origin firing; CDC7 inhibition rescues this replication stress, implicating uncontrolled origin firing as the underlying mechanism.\",\n      \"method\": \"Conditional MYBL2 knockout/knockdown in ESCs, DNA fiber assays, ATM/Mre11 inhibitors, CDC7 inhibitor rescue, origin firing analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function plus pharmacological epistasis plus DNA fiber analysis, multiple orthogonal methods\",\n      \"pmids\": [\"33779025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"B-MYB interacts with STRAP and enhances STRAP-mediated inhibition of TGF-β signaling by modulating SMAD3/SMAD7-TGF-β receptor complex formation; B-MYB also stimulates STRAP-mediated p53-induced apoptosis; confocal microscopy showed B-MYB prevents SMAD3 nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, reporter assays, co-expression experiments, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus imaging plus functional reporter assays, single lab\",\n      \"pmids\": [\"21148321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cytosolic phospholipase A2 (cPLA2) physically interacts with B-Myb in both cytoplasm and nucleus, negatively regulating B-Myb-dependent c-Myc gene expression; a catalytically inactive cPLA2 mutant lacking B-Myb binding does not inhibit B-Myb-dependent c-myc expression.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, genetic knockout mice (cPLA2-/-), siRNA, mutant cPLA2 analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus genetic knockout plus functional assays, single lab\",\n      \"pmids\": [\"14769798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"B-Myb and E2F2 form physical complexes in colorectal cancer cells, mutually transactivate each other's promoters, and constitute reciprocal feed-forward transactivation loops; both are required for ERK and AKT signaling pathway activation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, reporter assays, siRNA knockdown, RNA-seq, in vivo orthotopic models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus reporter assays plus functional knockdown, single lab\",\n      \"pmids\": [\"34316028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYBL2 transcriptionally activates CCL2 by binding its promoter, promoting TAM recruitment and M2-like polarization; CDK2 phosphorylates MYBL2 to promote its transcriptional function; CDK2 inhibition (CVT-313) reprograms the tumor microenvironment.\",\n      \"method\": \"ChIP, luciferase reporter assays, syngeneic mouse model, flow cytometry, qRT-PCR, ELISA\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus in vivo model, single lab\",\n      \"pmids\": [\"37865750\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYBL2 (B-Myb) is a cell cycle-regulated transcription factor that is transcriptionally repressed in G0 by E2F–p107/p130 complexes at its promoter and induced at the G1/S boundary; its transactivation activity is suppressed by a C-terminal regulatory domain and is relieved by sequential Cdk (cyclin A/E–Cdk2)- and Plk1-mediated phosphorylation facilitated by Pin1-dependent prolyl isomerization, after which B-Myb acts as a pioneer factor enabling FoxM1 binding to G2/M gene promoters; B-Myb is degraded via the Cdc34–SCF(Skp2) ubiquitin pathway, is acetylated by p300 in a phosphorylation-dependent manner, forms a non-transcriptional complex with clathrin and filamin required for mitotic spindle stability, interacts with and is suppressed by cyclin F to enforce G2 checkpoint maintenance, associates with MuvB to form the MMB complex that drives G2/M gene expression while its overexpression disrupts the repressive DREAM complex, activates ATM to suppress replication stress in embryonic stem cells, and supports DNA double-strand break repair in hematopoietic stem cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYBL2 (B-Myb) is a cell cycle-regulated transcription factor of the MYB family that governs the G1/S and G2/M gene-expression programs and is essential for proliferation, genome stability, and early development [#0, #1, #12]. Its transcription is repressed in G0/early G1 by an E2F-binding site cooperating with a contiguous CHR corepressor element and p107-containing E2F complexes, and is induced at the G1/S boundary [#5, #6, #7]. The latent activity of full-length B-Myb is held in check by an inhibitory C-terminal domain, which is relieved by cyclin A/E\\u2013Cdk2 phosphorylation at multiple Ser/Thr-Pro sites; this activation is amplified by Pin1-dependent prolyl isomerization that licenses further Cdk and Plk1 phosphorylation, and by phosphorylation-dependent acetylation by p300 [#8, #14, #41, #21]. Activated B-Myb assembles with MuvB to form the MMB complex that drives late cell-cycle gene expression, and acts as a pioneer factor enabling FoxM1 to bind G2/M promoters; its overexpression disrupts the repressive DREAM complex through the LIN52 adapter [#33, #38]. Beyond transcription, B-Myb forms a non-transcriptional complex with clathrin and filamin required for mitotic spindle stability, and B-Myb loss in model systems produces spindle/centrosome defects, reduced cyclin B1, polyploidy, and genome instability [#26, #23, #27]. B-Myb safeguards replication by activating ATM to restrain origin firing and limit replication stress in embryonic stem cells, and supports double-strand break repair in hematopoietic stem cells, where it is required to maintain the HSC pool [#45, #30, #39, #34]. Its abundance is restrained by Cdc34\\u2013SCF(Skp2)-mediated degradation, by cyclin F binding that blocks Cdk-mediated activation to enforce G2 checkpoint maintenance, and by miR-29/miR-30 targeting of its 3'UTR during senescence [#15, #35, #29]. B-Myb knockout is embryonic lethal at E4.5\\u2013E6.5 with failure of inner cell mass formation [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Establishing that MYBL2 is a structural member of the MYB transcription factor family defined its candidate molecular identity as a DNA-binding regulator.\",\n      \"evidence\": \"cDNA cloning and sequence analysis revealing three conserved c-Myb-homologous DNA-binding domains\",\n      \"pmids\": [\"3060855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence homology alone did not establish DNA-binding specificity or target genes\", \"No functional or cell-cycle context\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Linking B-myb expression to the cell cycle placed the gene in the G1/S transition rather than treating it as a constitutive factor.\",\n      \"evidence\": \"Northern blot of serum-stimulated synchronized 3T3 fibroblasts\",\n      \"pmids\": [\"1501895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mRNA timing did not reveal the protein-level regulatory mechanism\", \"Did not identify upstream regulators of the promoter\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Showing full-length B-Myb is intrinsically DNA-binding-incompetent unless its C-terminus is removed revealed an autoinhibitory architecture distinct from c-Myb.\",\n      \"evidence\": \"In vitro transcription/translation, gel-shift, GAL4 fusion and co-transfection reporter assays\",\n      \"pmids\": [\"8382794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the physiological signal that relieves C-terminal inhibition\", \"Endogenous target promoters remained undefined\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defining E2F/p107-dependent repression of the B-myb promoter, and its deregulation by HPV16 E7, explained how the gene is restricted to S phase and how it is hijacked in transformation.\",\n      \"evidence\": \"Reporter assays, E2F binding analysis, E7 mutant and promoter mutagenesis; p53/cyclin-Cdk2 bypass assays\",\n      \"pmids\": [\"8112300\", \"7937841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The corepressor element cooperating with E2F was not yet defined\", \"Mechanism by which B-Myb bypasses p53 arrest unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolving the cooperating CHR corepressor element and DP-1/E2F heterodimers clarified the combinatorial logic of G0 promoter repression.\",\n      \"evidence\": \"Gel-shift with fractionated extract, promoter mutagenesis, in vivo footprinting; p107 reporter and BrdU assays\",\n      \"pmids\": [\"8760872\", \"8621601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address post-translational control of B-Myb protein activity\", \"p107 down-modulation mechanism only partly defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Comprehensive mapping of cyclin A/E\\u2013Cdk2 phosphorylation sites established the post-translational switch that converts repressed B-Myb into an active transactivator.\",\n      \"evidence\": \"Phosphopeptide radiosequencing, cell-free kinase assays, site mutagenesis and reporter assays (building on 1997 kinase studies)\",\n      \"pmids\": [\"10593981\", \"9094315\", \"9012818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The downstream consequences (acetylation, complex assembly) were not yet integrated\", \"Did not define endogenous late cell-cycle target genes\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Genetic knockout in mice defined B-Myb as essential for early embryogenesis and inner cell mass formation, establishing a non-redundant biological requirement.\",\n      \"evidence\": \"Gene-targeted knockout mice and in vitro blastocyst culture\",\n      \"pmids\": [\"10497154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Early lethality precluded analysis of later tissue roles\", \"Molecular cause of ICM failure undefined at the time\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying SCF(Skp2)-mediated degradation and phosphorylation-dependent p300 acetylation showed that B-Myb activity is coupled to coordinated turnover and coactivator recruitment.\",\n      \"evidence\": \"Ubiquitination and co-IP assays with Cdc34/Skp2; in vivo acetylation and dominant-negative reporter assays\",\n      \"pmids\": [\"10871850\", \"11733503\", \"14973551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab biochemistry without structural confirmation of modification sites\", \"Quantitative contribution of degradation vs activation to phenotype unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Loss-of-function in zebrafish tied B-Myb to mitotic spindle formation and cyclin B1 levels, extending its role from S-phase entry to mitotic fidelity and genome stability.\",\n      \"evidence\": \"Forward genetic crash&burn mutant, spindle imaging, and chemical suppressor screen with ATR knockdown epistasis\",\n      \"pmids\": [\"16150706\", \"16372403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether spindle effects are transcriptional or direct was unresolved here\", \"Mammalian relevance not yet established in this work\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery of the B-Myb\\u2013clathrin\\u2013filamin (Clafi) complex revealed a non-transcriptional function directly supporting mitotic spindle stability.\",\n      \"evidence\": \"Biochemical complex purification, co-IP, and mitotic spindle localization imaging; ESC knockdown spindle/centrosome analysis\",\n      \"pmids\": [\"18548008\", \"18575582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How transcriptional and structural roles are partitioned in the cell is unclear\", \"Regulation of Clafi complex assembly undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defining B-Myb dissociation from the LINC/DREAM complex upon DNA damage, and its persistence in p53-mutant cells, connected B-Myb to G2 checkpoint control and recovery.\",\n      \"evidence\": \"Co-IP of LINC components, microarray, siRNA, and G2 checkpoint recovery assays in p53+/- backgrounds\",\n      \"pmids\": [\"19383908\", \"21480327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct signal triggering dissociation only partly defined\", \"Did not resolve MuvB/DREAM exchange mechanism at the molecular level\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Conditional ESC studies and senescence miRNA work established that B-Myb safeguards the replication program and is silenced via the Rb pathway during senescence.\",\n      \"evidence\": \"Conditional knockout with DNA fiber analysis; miR-29/30 3'UTR reporter and compensatory-mutation rescue; p16 promoter ChIP\",\n      \"pmids\": [\"20715180\", \"21187425\", \"20734103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect contribution of c-Myc/FoxM1 misregulation to fork defects not fully separated\", \"p16 repression mechanism single-lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating B-Myb acts as a pioneer factor enabling FoxM1 promoter binding clarified the mechanistic hierarchy driving G2/M gene expression.\",\n      \"evidence\": \"Conditional knockout 3T3 cells, ChIP, and Myb-binding-site promoter mutagenesis on Birc5\",\n      \"pmids\": [\"22513242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of pioneer behavior across all G2/M promoters not established\", \"Chromatin-opening mechanism not directly resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying cyclin F as a B-Myb suppressor that blocks cyclin A-mediated phosphorylation revealed a brake enforcing G2 checkpoint maintenance.\",\n      \"evidence\": \"RNAi screen, co-IP, phosphorylation assays, and G2 checkpoint assays after ionizing radiation\",\n      \"pmids\": [\"25557911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and turnover of cyclin F\\u2013B-Myb interplay not quantified\", \"Single-lab functional checkpoint data\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing B-Myb overexpression disrupts DREAM via the MuvB/LIN52 adapter linked its abundance to the switch between repressive and activating MuvB complexes.\",\n      \"evidence\": \"Co-IP of DREAM/MMB components, MuvB-binding-domain mutants, and LIN52 S28 phosphorylation analysis\",\n      \"pmids\": [\"30206359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of DREAM disruption by overexpression not addressed\", \"How physiological B-Myb levels balance the complexes unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining a Pin1-licensed stepwise Cdk-then-Plk1 phosphorylation cascade explained how B-Myb is progressively activated to drive late cell-cycle genes.\",\n      \"evidence\": \"Phosphorylation mapping, Pin1 binding, Plk1 docking assays, mutagenesis and reporter assays; UHMK1 BioID nuclear-enrichment study\",\n      \"pmids\": [\"30321399\", \"30936457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ordered modification not resolved\", \"UHMK1 contribution is single-lab and Medium confidence\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ESC studies established that B-Myb activates ATM to restrain origin firing and limit replication stress, providing a mechanistic basis for its genome-stability role.\",\n      \"evidence\": \"Conditional knockout/knockdown, DNA fiber assays, ATM/Mre11 inhibition, and CDC7-inhibitor rescue of replication stress\",\n      \"pmids\": [\"33779025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATM activation is transcriptional or direct not fully resolved\", \"Generality beyond ESCs not established here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Haploinsufficiency studies extended the genome-stability role to hematopoietic stem cells, linking reduced B-Myb to impaired DSB repair and telomere fragility.\",\n      \"evidence\": \"Mybl2 haploinsufficient mice, \\u03b3H2AX kinetics, phospho-KAP1 analysis, and telomere FISH\",\n      \"pmids\": [\"30082276\", \"24516162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanistic readouts\", \"Direct vs indirect effect on ATM substrate phosphorylation not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cancer-context studies tied phosphorylation-activated MYBL2 to oncogenic transcriptional programs across multiple tumor types via direct promoter binding.\",\n      \"evidence\": \"ChIP, reporter assays, co-IP, and in vivo models linking MYBL2 to CDCA3/Wnt, RRM2, YAP1/Hippo, CCL2/TAM, APOBEC3B, and E2F2 loops\",\n      \"pmids\": [\"37865750\", \"36071275\", \"34234118\", \"33897882\", \"28276478\", \"34316028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each target axis rests on single-lab evidence\", \"Direct vs network-level effects on these targets not always distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the structural (clathrin/filamin spindle) and transcriptional (MMB/FoxM1) functions of B-Myb are coordinated within a single cell cycle, and the structural basis of the ordered Cdk/Pin1/Plk1 activation switch, remain unresolved.\",\n      \"evidence\": \"No structural model of the activated B-Myb regulatory domain or integrated single-cell functional partitioning is present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of B-Myb bound to MuvB or its phospho-regulatory domain\", \"Quantitative interplay between degradation, cyclin F inhibition, and activation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 8, 33, 38]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 14, 31, 33]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [13, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [20, 40]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 8, 33, 38]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 33, 44]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [39, 45]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [30, 45]}\n    ],\n    \"complexes\": [\"MMB (Myb-MuvB)\", \"DREAM\", \"LINC\", \"B-Myb\\u2013clathrin\\u2013filamin (Clafi)\"],\n    \"partners\": [\"LIN9\", \"LIN52\", \"FOXM1\", \"p107 (RBL1)\", \"Cyclin F (CCNF)\", \"p300 (EP300)\", \"Skp2\", \"PIN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}