{"gene":"FOXM1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2001,"finding":"FOXM1 overexpression stimulates cyclin B1 but not cyclin D1 expression, and activates the cyclin B1 promoter in transient reporter assays, establishing cyclin B1 as a direct transcriptional target of FOXM1.","method":"Doxycycline-inducible stable cell lines, Western blot, Northern blot, flow cytometry, transient luciferase reporter assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (protein/mRNA quantification + promoter reporter), replicated in multiple stable cell lines","pmids":["11682060"],"is_preprint":false},{"year":1997,"finding":"The human FOXM1 gene (then FKHL16/TRIDENT) is located on chromosome 12p13, consists of 10 exons with the winged-helix DNA-binding domain encoded on three exons, and a 300-base promoter fragment drives cell cycle-specific expression in synchronized fibroblasts.","method":"cDNA/gene isolation, chromosomal mapping, promoter analysis in synchronized Rat-1 fibroblasts","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter mapping and chromosomal localization with functional promoter characterization in synchronized cells, single lab","pmids":["9441747"],"is_preprint":false},{"year":2010,"finding":"FOXM1 directly transcribes the tubulin-destabilizing protein Stathmin, and FOXM1 overexpression alters microtubule dynamics to protect breast tumor cells from paclitaxel-induced apoptosis; siRNA knockdown of FOXM1 reversed resistance.","method":"siRNA knockdown, ARF-derived peptide inhibitor, transcriptional target assay, cell viability assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic knockdown with defined phenotype, direct transcriptional target identification, single lab","pmids":["20530690"],"is_preprint":false},{"year":2013,"finding":"FOXM1 regulates NBS1 expression at the transcriptional level through a forkhead response element on the NBS1 promoter; FOXM1 increases NBS1/MRN complex levels and ATM phosphorylation to promote homologous recombination DNA repair; NBS1 is indispensable for the HR function of FOXM1 (FOXM1 overexpression failed to augment HR in NBS1-depleted cells).","method":"ChIP on NBS1 promoter, luciferase reporter, siRNA knockdown/rescue, HR assay, γH2AX foci, senescence assays in breast cancer cells and MEFs","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct promoter binding demonstrated by ChIP, functional epistasis by rescue experiments, multiple orthogonal readouts","pmids":["24141789"],"is_preprint":false},{"year":2013,"finding":"FOXM1 is dynamically modified by SUMO1 (but not SUMO2/3) at multiple consensus conjugation sites; SUMOylation inhibits FOXM1 transcriptional activity, promotes cytoplasmic translocation, and enhances APC/Cdh1-mediated ubiquitination and degradation; a SUMOylation-deficient mutant showed enhanced proliferation while an auto-SUMOylating (FOXM1-Ubc9) fusion caused persistent cyclin B1 expression and mitotic delay.","method":"Mutagenesis of SUMOylation sites, Ubc9 fusion protein (auto-SUMOylating mutant), cell cycle analysis, ubiquitination assays, localization studies","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis plus gain-of-function mutant with multiple orthogonal functional readouts in single rigorous study","pmids":["24362530"],"is_preprint":false},{"year":2016,"finding":"GSK3 phosphorylates FOXM1 at serine 474, inducing FBXW7-mediated ubiquitination and degradation; Wnt signaling activation inhibits GSK3-Axin-mediated FoxM1 phosphorylation, leading to USP5-mediated deubiquitination and FoxM1 stabilization; stabilized nuclear FoxM1 then recruits β-catenin to Wnt target-gene promoters and protects the β-catenin/TCF4 complex from ICAT inhibition.","method":"Co-IP, GSK3 kinase assays, ubiquitination assays, site-directed mutagenesis (S474), luciferase reporter, ChIP","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution of phosphorylation-ubiquitination cascade, mutagenesis, multiple interaction assays in single rigorous study","pmids":["26912724"],"is_preprint":false},{"year":2015,"finding":"FOXM1 directly binds the SNAIL promoter via two specific binding sites and constitutively transactivates it, driving EMT-dependent migration and invasion of lung adenocarcinoma cells.","method":"ChIP, luciferase reporter, siRNA knockdown, in vitro migration/invasion assays, in vivo xenograft","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP and reporter assay with functional rescue, single lab","pmids":["25561901"],"is_preprint":false},{"year":2015,"finding":"FOXM1 directly binds the promoters of antiapoptotic genes XIAP and Survivin and transcriptionally upregulates their expression; FOXM1 knockdown reduced XIAP/Survivin expression and promoter binding, conferring apoptosis sensitization in breast cancer cells.","method":"ChIP on XIAP and Survivin promoters, FOXM1 knockdown/overexpression, apoptosis assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP combined with expression knockdown and phenotypic assay, single lab","pmids":["26404623"],"is_preprint":false},{"year":2016,"finding":"FOXM1 acts as a transcriptional repressor and, through association with DNMT3b in an Rb-dependent manner, promotes methylation of the GATA-3 promoter, suppressing luminal differentiation and expanding luminal progenitor pools in the mammary gland.","method":"Mammary gland reconstitution assays, FOXM1 knockdown/overexpression, DNMT3b co-IP/association, bisulfite sequencing of GATA-3 promoter","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — repressor function identified with mechanistic co-IP/methylation assay and in vivo regeneration model, single lab","pmids":["22813746"],"is_preprint":false},{"year":2016,"finding":"FOXM1 acetylation by p300/CBP at lysines K63, K422, K440, K603, and K614 increases its DNA-binding affinity, protein stability, and phosphorylation sensitivity; SIRT1 physically binds to and deacetylates FOXM1, attenuating its transcriptional activity and decreasing protein stability; acetylation-deficient FOXM1 mutants showed significantly weaker tumorigenic activity.","method":"In vivo acetylation assays, site-directed mutagenesis of lysine residues, co-IP with p300/CBP and SIRT1, DNA-binding assays, tumor growth assays","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site mutagenesis combined with in vivo acetylation, co-IP with writer/eraser, and functional tumor growth assay in single study","pmids":["27542221"],"is_preprint":false},{"year":2012,"finding":"FOXM1 directly regulates CDC25A gene transcription via direct promoter binding and indirect activation of E2F-dependent pathways; CDC25A in turn synergistically enhances FOXM1 transcriptional activity through CDK1-dependent phosphorylation of FOXM1 at T600, T611, and T620; a novel protein-protein interaction between FOXM1 and CDC25A is dependent on CDC25A phosphatase activity and is enhanced by T600/T611 phosphorylation.","method":"ChIP, luciferase reporter, mutagenesis of FOXM1 phosphorylation sites, co-IP, co-expression experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus mutagenesis plus co-IP, single lab with multiple orthogonal methods","pmids":["23240008"],"is_preprint":false},{"year":2015,"finding":"FOXM1 directly transcribes STAT3 through binding to the STAT3 promoter (demonstrated by ChIP and luciferase assay) and this is required for human endometrial stromal cell differentiation/decidualization; FOXM1 inhibition also downregulates cyclin B1 and delays G2/M transition in these cells.","method":"ChIP, luciferase reporter assay, siRNA knockdown in HESC, G2/M cell cycle analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP and reporter assay with functional differentiation phenotype, single lab","pmids":["26334131"],"is_preprint":false},{"year":2017,"finding":"FOXM1 directly binds to the UHRF1 gene promoter at FKH motifs and transcriptionally activates UHRF1 expression in an E2F-independent manner, thereby regulating cancer stem cell self-renewal and taxane resistance.","method":"ChIP on UHRF1 promoter, luciferase reporter, FOXM1 knockdown/overexpression, promoter mutagenesis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and reporter with mutagenesis, single lab","pmids":["29752436"],"is_preprint":false},{"year":2018,"finding":"Honokiol directly binds to FOXM1 protein and inhibits FOXM1-mediated transcription and protein expression; binding specificity requires both substitution and dimerization of allylphenols.","method":"Direct binding assay (physical interaction of honokiol with FOXM1), FOXM1 transcriptional activity assay, compound structure-activity studies","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct physical binding demonstrated, SAR study confirms structural requirements, single lab","pmids":["29367668"],"is_preprint":false},{"year":2017,"finding":"USP5 deubiquitinates and stabilizes FoxM1 protein through direct interaction; co-IP confirmed endogenous USP5-FoxM1 interaction; USP5 overexpression extended FoxM1 half-life and knockdown decreased FoxM1 protein levels in a proteasome-dependent manner.","method":"Reciprocal co-IP of endogenous proteins, protein half-life (cycloheximide chase), proteasome inhibitor rescue (MG-132), USP5 knockdown/overexpression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP of endogenous proteins plus half-life measurements, single lab","pmids":["28807830"],"is_preprint":false},{"year":2022,"finding":"USP39 deubiquitinates and stabilizes FOXM1 protein through direct interaction; USP39 overexpression reduces FOXM1 ubiquitination, enhances FOXM1 transcriptional activity, and promotes downstream Cdc25b and Plk1 expression; USP39 and FOXM1 are positively correlated in breast cancer.","method":"Co-IP, in vitro deubiquitination assay, FOXM1 ubiquitination levels, gene expression of downstream targets","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus in vitro deubiquitination assay, single lab","pmids":["36119839"],"is_preprint":false},{"year":2019,"finding":"FOXM1c (the most highly expressed isoform) directly binds the KIF4A promoter and transcriptionally regulates KIF4A expression; FOXM1-induced HCC cell proliferation is dependent on KIF4A, as KIF4A knockdown abolishes FOXM1-induced proliferation.","method":"ChIP, luciferase reporter, isoform-specific knockdown/overexpression, in vitro proliferation assays, xenograft mouse model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay identifying isoform-specific target, epistasis by rescue, confirmed in vivo, single lab","pmids":["31072351"],"is_preprint":false},{"year":2019,"finding":"FOXM1 transcriptionally regulates TYMS, TK-1, and TYMP (5-FU metabolic targets) as demonstrated by ChIP and ChIP-seq; FOXM1 knockdown reduces TYMS expression while overexpression increases it; FOXM1-TYMS axis mediates 5-FU resistance in colorectal cancer.","method":"ChIP, global ChIP-seq, FOXM1 knockdown/overexpression, 5-FU resistance functional assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq genome-wide plus individual ChIP, expression modulation experiments, single lab","pmids":["30728402"],"is_preprint":false},{"year":2016,"finding":"FOXM1 directly interacts with phosphorylated STAT3 under radiation treatment in glioblastoma cells, as demonstrated by co-IP and co-localization; radiation-induced FOXM1 expression is dependent on STAT3 activation.","method":"Co-immunoprecipitation, co-localization assay, STAT3 inhibition experiments, RPPA","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and co-localization with upstream functional dependency, single lab","pmids":["27764801"],"is_preprint":false},{"year":2019,"finding":"Phosphorylated STAT1 (pSTAT1) directly binds the FOXM1 promoter to downregulate its transcription; IFNγ-promoted pSTAT1 suppresses FOXM1 expression and sensitizes pancreatic cancer cells to gemcitabine; demonstrated by dual-luciferase reporter and ChIP assays.","method":"Dual-luciferase reporter, ChIP on FOXM1 promoter, IFNγ treatment, in vitro and in vivo apoptosis/proliferation assays","journal":"Clinical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter occupancy by ChIP plus reporter and functional drug sensitivity assay, single lab","pmids":["30782607"],"is_preprint":false},{"year":2009,"finding":"p53 negatively regulates FOXM1 expression: partial deletion or inactivation of p53 leads to upregulation of FOXM1 mRNA and protein, while p53 induction by DNA damage leads to FOXM1 downregulation.","method":"p53 knockdown in human fibroblasts and cancer cell lines, DNA damage induction, mRNA and protein level analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockdown plus gain-of-function DNA damage system, multiple cell line contexts, single lab","pmids":["19806025"],"is_preprint":false},{"year":2017,"finding":"FOXM1 transcriptionally regulates integrin β1 (ITGB1) gene expression by directly binding to its promoter, and this drives FAK activation in triple-negative breast cancer cells.","method":"ChIP, luciferase reporter assay, siRNA knockdown, Western blot for FAK activation","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay with downstream signaling readout, single lab","pmids":["28361350"],"is_preprint":false},{"year":2017,"finding":"FOXM1 transcriptionally activates RFC5 (replication factor C5) by binding to the RFC5 promoter, and this promotes temozolomide resistance in glioma cells independently of MGMT; knockdown of FOXM1 or RFC5 re-sensitizes glioma cells to TMZ.","method":"ChIP on RFC5 promoter, FOXM1/RFC5 knockdown, drug sensitivity assays, correlation in human glioma cells","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP with functional epistasis, single lab","pmids":["28185110"],"is_preprint":false},{"year":2020,"finding":"FOXM1 protein translocates into mitochondria and inhibits oxidative phosphorylation by directly binding to and increasing PTCD1 (a mitochondrial leucine-specific tRNA binding protein that inhibits leucine-rich ETC complexes); this mitochondrial function is independent of nuclear transcription and does not affect cellular proliferation.","method":"Site-directed mutagenesis to generate compartment-specific localization mutants, mitochondrial fractionation, direct binding assay with PTCD1, mitochondrial respiration measurements, membrane potential assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis uncoupling nuclear and mitochondrial functions, direct binding demonstrated, multiple orthogonal mitochondrial function readouts in one study","pmids":["32348194"],"is_preprint":false},{"year":2021,"finding":"FOXM1 directly binds the DKK1 gene 5'-UTR and transcriptionally activates DKK1 expression; DKK1 in turn signals via CKAP4-AKT and ERK pathways to maintain FOXM1 expression, forming a positive feedback loop that promotes tumor growth; FOXM1 induces DKK1 independently of Wnt signaling.","method":"FOXM1 binding site identification in DKK1 5'-UTR, DKK1/FOXM1 knockdown, pathway inhibitor epistasis, RNA-seq","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding site identified with knockdown epistasis and pathway inhibitor studies, single lab","pmids":["34117362"],"is_preprint":false},{"year":2021,"finding":"MMB-FOXM1 complex (comprising FOXM1, LIN54, and MYBL2/B-MYB) is required for CHK1 inhibitor-induced premature mitosis in late S phase; knockout of FOXM1 or LIN54 reduces CHK1i-induced DNA replication stress markers and premature mitosis; a feedback loop between the MMB-FOXM1 complex and CDK1 drives this premature mitosis.","method":"Genome-wide CRISPR-Cas9 screens, FOXM1/LIN54 knockout, DNA damage marker assays, cell cycle analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide unbiased CRISPR screen with targeted validation, multiple knockouts identifying same complex, mechanistic cell cycle phenotype","pmids":["33657372"],"is_preprint":false},{"year":2021,"finding":"LIN9 is the direct binding partner of FOXM1 in the MMB complex; FOXM1 and its target gene network are co-upregulated in oesophageal adenocarcinoma; ChIP-seq defines the FOXM1 target gene network in OAC cells.","method":"ChIP-seq, Nanostring gene expression assay, LIN9-FOXM1 binding assay, OAC tissue analysis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq genome-wide target identification and direct binding partner identification, single lab","pmids":["25889361"],"is_preprint":false},{"year":2020,"finding":"FOXM1 directly binds DVL2 and enhances nuclear translocation of DVL2, promoting DVL2-mediated Wnt/β-catenin transcriptional activity to induce Snail expression, metastasis, and chemoresistance in colorectal cancer.","method":"Co-IP (FOXM1-DVL2 interaction), nuclear fractionation, TCF/LEF reporter assay for β-catenin transcriptional activity, knockdown of DVL2/Snail/FOXM1","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating physical interaction with functional nuclear translocation and transcriptional activity assay, single lab","pmids":["33291076"],"is_preprint":false},{"year":2020,"finding":"E3 ubiquitin ligase Cdh1 (Fzr1) is required for FoxM1 ubiquitylation and subsequent degradation; loss of Cdh1 promotes quiescent satellite cells into the cell cycle and depletes the satellite cell pool; haploinsufficiency of FoxM1 ameliorates the muscle regeneration defect of Cdh1 knockout mice. FoxM1 also functions as a direct transcriptional activator of Apc (adenomatous polyposis coli) to prevent hyperactivation of Wnt/β-catenin signaling during muscle regeneration.","method":"Conditional FoxM1 knockout in satellite cells, Cdh1 knockout mice, genetic rescue (FoxM1 haploinsufficiency in Cdh1 KO), ChIP/promoter assay for Apc, ubiquitination assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis (double mutant rescue), direct ubiquitination, and transcriptional target assay with multiple readouts","pmids":["32152291"],"is_preprint":false},{"year":2022,"finding":"FOXM1 binds RB1 and recruits DNMT3B to repress FOXO1 expression; reduced FOXO1 leads to decreased CDK-inhibitor levels, enabling RB1 phosphorylation and inactivation; inhibition of FOXM1 restores FOXO1 and activates RB1, inducing senescence of HCC cells in vitro and in vivo.","method":"Co-IP (FOXM1-RB1-DNMT3B complex), FOXO1/RB1 expression analysis upon FOXM1 manipulation, repression-deficient FOXM1 mutants, in vivo tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional mutagenesis and in vivo validation, single lab","pmids":["35761036"],"is_preprint":false},{"year":2014,"finding":"FoxM1 directly binds and transcriptionally activates the SIRT1 promoter at a minimal FoxM1 binding site in glioma cells; FoxM1 overexpression promotes and knockdown inhibits Sirt1 expression.","method":"ChIP, luciferase reporter, siRNA knockdown, RT-PCR and Western blot","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and reporter assay but single low-impact journal, single lab, limited orthogonal validation","pmids":["24488909"],"is_preprint":false},{"year":2025,"finding":"FOXM1 undergoes liquid-liquid phase separation (LLPS) with FKH consensus DNA elements, compartmentalizing the transcription apparatus in the nucleus to sustain chromatin accessibility and super-enhancer landscapes; AMPK phosphorylates FOXM1 at a specific IDR1 site, causing electrostatic repulsion that abolishes FOXM1 LLPS; a peptide targeting IDR1 disrupts FOXM1 condensates and inhibits tumor malignancy while activating innate immune responses.","method":"Phase separation screening, genetic code-expansion orthogonal system demonstrating phosphoryl moiety at IDR1, AMPK phosphorylation assays, chromatin accessibility assays (ATAC-seq), super-enhancer profiling, peptide functional assays in vivo","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted LLPS, genetic code expansion for site-specific phosphorylation validation, multiple orthogonal genomic and functional methods","pmids":["39814884"],"is_preprint":false},{"year":2019,"finding":"FOXM1 isoforms FOXM1b and FOXM1c are transcriptionally active while FOXM1a is not, as demonstrated in a CRISPR FOXM1 knockout model; FOXM1c shows highest expression in normal and tumor tissues.","method":"CRISPR knockout, isoform-specific re-expression, transcriptional activity reporter","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR KO rescue with individual isoforms, single lab","pmids":["30795624"],"is_preprint":false},{"year":2022,"finding":"FOXM1 directly binds the METTL3 promoter and represses METTL3 transcription in human scleral fibroblasts; reduced METTL3 decreases m6A methylation of APOA1 mRNA, reducing YTHDF2-mediated degradation and thereby increasing APOA1 stability and expression.","method":"ChIP (FOXM1 enrichment at METTL3 promoter), Me-RIP (m6A levels of APOA1), PAR-CLIP (METTL3-APOA1 binding), loss- and gain-of-function experiments","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP, Me-RIP, and PAR-CLIP provide multiple orthogonal methods in single study, single lab","pmids":["38190128"],"is_preprint":false},{"year":2021,"finding":"FOXM1 nuclear localization is inhibited by the small-molecule compound RCM-1, and RCM-1 decreases the protein-protein interaction between β-catenin and FOXM1 in tumor cells, reducing β-catenin nuclear localization and inhibiting tumor growth.","method":"Confocal imaging of FOXM1 nuclear localization, co-IP (β-catenin/FOXM1 interaction), colony formation assay, in vivo tumor models (rhabdomyosarcoma, melanoma, lung adenocarcinoma)","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-IP of FOXM1-β-catenin interaction with nuclear localization imaging and in vivo validation, single lab","pmids":["31040162"],"is_preprint":false},{"year":2023,"finding":"Foxm1 is required for cardiomyocyte proliferation after cardiac injury in zebrafish through transcriptional regulation of cell cycle genes including cenpf; foxm1 mutant hearts show decreased cardiomyocyte proliferation and cell cycle gene expression; cenpf (a microtubule/kinetochore binding protein) mutants show increased cardiomyocyte binucleation, suggesting a role in completing mitosis.","method":"foxm1 zebrafish mutant, transcriptomic analysis, cenpf mutant characterization, cardiomyocyte proliferation markers","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function in zebrafish with transcriptomic and phenotypic characterization, single lab","pmids":["36846912"],"is_preprint":false},{"year":2022,"finding":"FAM64A physically interacts with FOXM1 in HNSCC cells and promotes FOXM1-dependent transcription; FAM64A also modulates FOXM1 expression via the FOXM1 autoregulatory loop.","method":"Co-IP (FAM64A-FOXM1 interaction), FOXM1 transcriptional activity assay, FAM64A depletion/overexpression, in vitro and in vivo cancer cell assays","journal":"International journal of oral science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP and activity assay, single lab, limited mechanistic depth in abstract","pmids":["35538067"],"is_preprint":false},{"year":2014,"finding":"An N-terminally truncated activated form of FoxM1 (FoxM1ΔNRD) bypasses two post-translational controls: exposure of the forkhead DNA-binding domain and targeted proteasomal degradation; activated FoxM1 protects β-cells from streptozotocin-induced death and alters extracellular matrix and immune cell gene expression profiles.","method":"Inducible transgenic mouse model (RIP-rtTA;TetO-HA-FoxM1ΔNRD), STZ-induced β-cell injury, RNA sequencing, β-cell mass/proliferation/death measurements","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo genetic model with RNA-seq defining FOXM1ΔNRD targets, revealing bypass of post-translational control, single lab","pmids":["25073103"],"is_preprint":false}],"current_model":"FOXM1 is a forkhead-family transcription factor that directly binds forkhead response elements on target gene promoters (including cyclin B1, NBS1, SNAIL, XIAP, Survivin, STAT3, CDC25A, UHRF1, KIF4A, TYMS, integrin β1, RFC5, Sirt1, Apc, and DKK1) to drive cell cycle progression at G1/S and G2/M, DNA damage repair, and invasion; its activity and stability are tightly controlled by multi-layered post-translational modifications including CDK-mediated phosphorylation (activating, at T600/T611/T620 among others), GSK3-mediated phosphorylation at S474 (promoting FBXW7-dependent ubiquitination and degradation), Wnt/USP5-mediated deubiquitination (stabilization), SUMO1 modification (inhibitory, promoting cytoplasmic translocation and APC/Cdh1-mediated degradation), p300/CBP-mediated acetylation (activating DNA binding and stability) reversed by SIRT1, and APC/Cdh1-mediated ubiquitin-proteasomal degradation; FOXM1 is also subject to transcriptional repression by p53 and pSTAT1, interacts physically with partners including β-catenin/TCF4, DVL2, RB1/DNMT3B, phospho-STAT3, PTCD1, and LIN9 (in the MMB complex), undergoes liquid-liquid phase separation at super-enhancers in the nucleus (disrupted by AMPK-mediated IDR1 phosphorylation), and localizes to mitochondria to inhibit oxidative phosphorylation via PTCD1 independent of nuclear transcription."},"narrative":{"mechanistic_narrative":"FOXM1 is a forkhead-family transcription factor that drives proliferation by directly binding forkhead response elements on cell-cycle and genome-maintenance gene promoters, establishing it as a master regulator of G2/M progression and DNA repair [PMID:11682060, PMID:24141789]. It transactivates cyclin B1 to promote mitotic entry [PMID:11682060] and induces NBS1 to elevate MRN/ATM signaling and homologous-recombination repair, with NBS1 being indispensable for its HR function [PMID:24141789]. Its target repertoire, defined in part by ChIP-seq, extends to genes governing invasion, apoptosis resistance, stemness, and drug metabolism, including SNAIL [PMID:25561901], XIAP and Survivin [PMID:26404623], UHRF1 [PMID:29752436], KIF4A [PMID:31072351], and the 5-FU metabolic enzyme TYMS [PMID:30728402], as well as integrin β1 to drive FAK activation [PMID:28361350]. FOXM1 also acts as a transcriptional repressor: through RB1- and DNMT3B-dependent promoter methylation it silences differentiation genes (GATA-3, FOXO1), suppressing senescence and luminal differentiation [PMID:22813746, PMID:35761036]. FOXM1 abundance and activity are governed by layered post-translational control: CDK1/CDC25A-mediated phosphorylation activates it [PMID:23240008], GSK3 phosphorylation at S474 triggers FBXW7-dependent degradation while Wnt signaling and the deubiquitinases USP5 and USP39 stabilize it [PMID:26912724, PMID:28807830, PMID:36119839], APC/Cdh1 directs its ubiquitin-proteasomal turnover [PMID:32152291], SUMO1 modification inhibits it and promotes cytoplasmic translocation [PMID:24362530], and p300/CBP acetylation—reversed by SIRT1—enhances DNA binding and stability [PMID:27542221]. FOXM1 integrates with Wnt signaling by recruiting β-catenin to target promoters and binding DVL2 to potentiate β-catenin transcriptional activity [PMID:26912724, PMID:33291076], and assembles into the MMB complex with LIN9/LIN54 and MYBL2 to control mitotic timing [PMID:33657372, PMID:25889361]. Beyond canonical transcription, FOXM1 forms liquid-liquid phase-separated condensates at super-enhancers to sustain chromatin accessibility, a behavior abolished by AMPK phosphorylation of its IDR1 [PMID:39814884], and a fraction translocates to mitochondria to inhibit oxidative phosphorylation via PTCD1 independently of nuclear transcription [PMID:32348194].","teleology":[{"year":1997,"claim":"Establishing the FOXM1 gene structure and a cell-cycle-regulated promoter framed it as a candidate proliferation-associated transcription factor before its targets were known.","evidence":"cDNA/gene isolation, chromosomal mapping, and promoter analysis in synchronized fibroblasts","pmids":["9441747"],"confidence":"Medium","gaps":["No direct transcriptional targets identified","DNA-binding specificity not functionally mapped"]},{"year":2001,"claim":"Identifying cyclin B1 as a direct target answered how FOXM1 mechanistically promotes mitotic entry rather than merely correlating with proliferation.","evidence":"Inducible cell lines with promoter reporter assays and expression quantification","pmids":["11682060"],"confidence":"High","gaps":["Did not address upstream control of FOXM1 activity","Genome-wide target scope undefined"]},{"year":2009,"claim":"Showing p53 represses FOXM1 connected its activity to tumor-suppressor surveillance and DNA-damage checkpoints.","evidence":"p53 knockdown and DNA-damage induction with mRNA/protein readouts across cell lines","pmids":["19806025"],"confidence":"Medium","gaps":["Direct vs indirect repression mechanism not resolved","No promoter occupancy data"]},{"year":2013,"claim":"Defining the FOXM1-NBS1 axis and SUMO1 control extended FOXM1 beyond cell-cycle gene activation into DNA repair and revealed an inhibitory PTM that relocalizes and degrades it.","evidence":"ChIP, rescue/epistasis HR assays (NBS1) and SUMOylation-site mutagenesis with Ubc9-fusion (SUMO1)","pmids":["24141789","24362530"],"confidence":"High","gaps":["SUMO ligase and deSUMOylase not identified","Coupling between SUMOylation and APC/Cdh1 recognition mechanistically incomplete"]},{"year":2012,"claim":"The reciprocal FOXM1-CDC25A circuit explained how FOXM1 activity is amplified during the cell cycle via CDK1-dependent phosphorylation at T600/T611/T620.","evidence":"ChIP, phosphosite mutagenesis, and co-IP showing phosphatase-dependent interaction","pmids":["23240008"],"confidence":"Medium","gaps":["Structural basis of the phospho-enhanced interaction unknown","Quantitative contribution of each phosphosite undefined"]},{"year":2016,"claim":"Acetylation/deacetylation and the GSK3-FBXW7/Wnt-USP5 axis established that FOXM1 stability and DNA-binding affinity are set by competing PTM writers and erasers.","evidence":"Site-directed lysine/serine mutagenesis, co-IP with p300/CBP, SIRT1, USP5, kinase and ubiquitination assays","pmids":["27542221","26912724","28807830"],"confidence":"High","gaps":["Crosstalk hierarchy among acetylation, phosphorylation, and ubiquitination unresolved","USP5 catalytic mechanism on FOXM1 not reconstituted in vitro"]},{"year":2016,"claim":"Demonstrating repressor activity via RB-dependent DNMT3B recruitment broadened FOXM1's mechanism from activator to context-dependent silencer of differentiation programs.","evidence":"Mammary reconstitution, DNMT3B co-IP, and bisulfite sequencing of GATA-3 promoter","pmids":["22813746"],"confidence":"Medium","gaps":["How FOXM1 switches between activation and repression unknown","Generality across tissues untested in this study"]},{"year":2015,"claim":"A wave of ChIP-based target studies mapped FOXM1 onto invasion, apoptosis-resistance, stemness, and drug-resistance programs, defining its breadth as an oncogenic effector.","evidence":"ChIP/luciferase and ChIP-seq with knockdown phenotypes (SNAIL, XIAP/Survivin, STAT3, UHRF1, KIF4A, TYMS, ITGB1, RFC5, LIN9 network)","pmids":["25561901","26404623","26334131","29752436","31072351","30728402","28361350","28185110","25889361"],"confidence":"Medium","gaps":["Direct vs E2F-cooperative binding not always distinguished","Single-lab, single-cancer contexts limit generality"]},{"year":2020,"claim":"Uncoupling FOXM1's nuclear and mitochondrial pools revealed a transcription-independent role in suppressing oxidative phosphorylation through PTCD1.","evidence":"Compartment-specific localization mutants, mitochondrial fractionation, PTCD1 binding, and respiration measurements","pmids":["32348194"],"confidence":"High","gaps":["Mechanism of FOXM1 mitochondrial import unknown","Physiological contribution relative to nuclear function unquantified"]},{"year":2021,"claim":"Genetic identification of the MMB-FOXM1 complex and in vivo Cdh1 epistasis tied FOXM1 to mitotic-timing control and degradation-dependent quiescence in physiological settings.","evidence":"Genome-wide CRISPR screens with FOXM1/LIN54 knockouts; conditional knockouts and double-mutant rescue in mouse satellite cells","pmids":["33657372","32152291"],"confidence":"High","gaps":["Stoichiometry and assembly order of the MMB-FOXM1 complex undefined","Direct CDK1 feedback target sites on the complex not mapped"]},{"year":2025,"claim":"Discovery of FOXM1 liquid-liquid phase separation at super-enhancers, switched off by AMPK phosphorylation of IDR1, reframed its transcriptional function as condensate-driven and revealed a druggable disordered region.","evidence":"Reconstituted LLPS, genetic code-expansion site-specific phosphorylation, ATAC-seq, super-enhancer profiling, and IDR1 peptide in vivo","pmids":["39814884"],"confidence":"High","gaps":["Composition of FOXM1 condensates incompletely defined","Relationship between LLPS and PTM-controlled stability unexplored"]},{"year":null,"claim":"How the many PTMs, the MMB complex, condensate formation, and the mitochondrial pool are integrated into a single coherent regulatory logic across cell-cycle phases remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking PTM state to LLPS vs degradation vs mitochondrial localization","Structural basis of forkhead-element recognition within condensates undefined","Determinants of activator vs repressor mode unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,6,7,16,17,26,32]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,9,31]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[23]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,31,34]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,10,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,6,7,16,17,26]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,27]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,5,9,14,28]}],"complexes":["MMB complex (FOXM1-LIN9/LIN54-MYBL2)"],"partners":["CDC25A","USP5","USP39","RB1","DNMT3B","DVL2","PTCD1","LIN9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q08050","full_name":"Forkhead box protein M1","aliases":["Forkhead-related protein FKHL16","Hepatocyte nuclear factor 3 forkhead homolog 11","HFH-11","HNF-3/fork-head homolog 11","M-phase phosphoprotein 2","MPM-2 reactive phosphoprotein 2","Transcription factor Trident","Winged-helix factor from INS-1 cells"],"length_aa":763,"mass_kda":84.3,"function":"Transcription factor regulating the expression of cell cycle genes essential for DNA replication and mitosis (PubMed:19160488, PubMed:20360045). Plays a role in the control of cell proliferation (PubMed:19160488). Also plays a role in DNA break repair, participating in the DNA damage checkpoint response (PubMed:17101782). 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NONCODING RNA; PRANCR","url":"https://www.omim.org/entry/619085"},{"mim_id":"618217","title":"EGFR LONG NONCODING DOWNSTREAM RNA; ELDR","url":"https://www.omim.org/entry/618217"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoli rim","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":23.6},{"tissue":"lymphoid 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luciferase reporter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (protein/mRNA quantification + promoter reporter), replicated in multiple stable cell lines\",\n      \"pmids\": [\"11682060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The human FOXM1 gene (then FKHL16/TRIDENT) is located on chromosome 12p13, consists of 10 exons with the winged-helix DNA-binding domain encoded on three exons, and a 300-base promoter fragment drives cell cycle-specific expression in synchronized fibroblasts.\",\n      \"method\": \"cDNA/gene isolation, chromosomal mapping, promoter analysis in synchronized Rat-1 fibroblasts\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter mapping and chromosomal localization with functional promoter characterization in synchronized cells, single lab\",\n      \"pmids\": [\"9441747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FOXM1 directly transcribes the tubulin-destabilizing protein Stathmin, and FOXM1 overexpression alters microtubule dynamics to protect breast tumor cells from paclitaxel-induced apoptosis; siRNA knockdown of FOXM1 reversed resistance.\",\n      \"method\": \"siRNA knockdown, ARF-derived peptide inhibitor, transcriptional target assay, cell viability assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic knockdown with defined phenotype, direct transcriptional target identification, single lab\",\n      \"pmids\": [\"20530690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FOXM1 regulates NBS1 expression at the transcriptional level through a forkhead response element on the NBS1 promoter; FOXM1 increases NBS1/MRN complex levels and ATM phosphorylation to promote homologous recombination DNA repair; NBS1 is indispensable for the HR function of FOXM1 (FOXM1 overexpression failed to augment HR in NBS1-depleted cells).\",\n      \"method\": \"ChIP on NBS1 promoter, luciferase reporter, siRNA knockdown/rescue, HR assay, γH2AX foci, senescence assays in breast cancer cells and MEFs\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct promoter binding demonstrated by ChIP, functional epistasis by rescue experiments, multiple orthogonal readouts\",\n      \"pmids\": [\"24141789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FOXM1 is dynamically modified by SUMO1 (but not SUMO2/3) at multiple consensus conjugation sites; SUMOylation inhibits FOXM1 transcriptional activity, promotes cytoplasmic translocation, and enhances APC/Cdh1-mediated ubiquitination and degradation; a SUMOylation-deficient mutant showed enhanced proliferation while an auto-SUMOylating (FOXM1-Ubc9) fusion caused persistent cyclin B1 expression and mitotic delay.\",\n      \"method\": \"Mutagenesis of SUMOylation sites, Ubc9 fusion protein (auto-SUMOylating mutant), cell cycle analysis, ubiquitination assays, localization studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis plus gain-of-function mutant with multiple orthogonal functional readouts in single rigorous study\",\n      \"pmids\": [\"24362530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GSK3 phosphorylates FOXM1 at serine 474, inducing FBXW7-mediated ubiquitination and degradation; Wnt signaling activation inhibits GSK3-Axin-mediated FoxM1 phosphorylation, leading to USP5-mediated deubiquitination and FoxM1 stabilization; stabilized nuclear FoxM1 then recruits β-catenin to Wnt target-gene promoters and protects the β-catenin/TCF4 complex from ICAT inhibition.\",\n      \"method\": \"Co-IP, GSK3 kinase assays, ubiquitination assays, site-directed mutagenesis (S474), luciferase reporter, ChIP\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution of phosphorylation-ubiquitination cascade, mutagenesis, multiple interaction assays in single rigorous study\",\n      \"pmids\": [\"26912724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOXM1 directly binds the SNAIL promoter via two specific binding sites and constitutively transactivates it, driving EMT-dependent migration and invasion of lung adenocarcinoma cells.\",\n      \"method\": \"ChIP, luciferase reporter, siRNA knockdown, in vitro migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP and reporter assay with functional rescue, single lab\",\n      \"pmids\": [\"25561901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOXM1 directly binds the promoters of antiapoptotic genes XIAP and Survivin and transcriptionally upregulates their expression; FOXM1 knockdown reduced XIAP/Survivin expression and promoter binding, conferring apoptosis sensitization in breast cancer cells.\",\n      \"method\": \"ChIP on XIAP and Survivin promoters, FOXM1 knockdown/overexpression, apoptosis assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP combined with expression knockdown and phenotypic assay, single lab\",\n      \"pmids\": [\"26404623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXM1 acts as a transcriptional repressor and, through association with DNMT3b in an Rb-dependent manner, promotes methylation of the GATA-3 promoter, suppressing luminal differentiation and expanding luminal progenitor pools in the mammary gland.\",\n      \"method\": \"Mammary gland reconstitution assays, FOXM1 knockdown/overexpression, DNMT3b co-IP/association, bisulfite sequencing of GATA-3 promoter\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — repressor function identified with mechanistic co-IP/methylation assay and in vivo regeneration model, single lab\",\n      \"pmids\": [\"22813746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXM1 acetylation by p300/CBP at lysines K63, K422, K440, K603, and K614 increases its DNA-binding affinity, protein stability, and phosphorylation sensitivity; SIRT1 physically binds to and deacetylates FOXM1, attenuating its transcriptional activity and decreasing protein stability; acetylation-deficient FOXM1 mutants showed significantly weaker tumorigenic activity.\",\n      \"method\": \"In vivo acetylation assays, site-directed mutagenesis of lysine residues, co-IP with p300/CBP and SIRT1, DNA-binding assays, tumor growth assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site mutagenesis combined with in vivo acetylation, co-IP with writer/eraser, and functional tumor growth assay in single study\",\n      \"pmids\": [\"27542221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FOXM1 directly regulates CDC25A gene transcription via direct promoter binding and indirect activation of E2F-dependent pathways; CDC25A in turn synergistically enhances FOXM1 transcriptional activity through CDK1-dependent phosphorylation of FOXM1 at T600, T611, and T620; a novel protein-protein interaction between FOXM1 and CDC25A is dependent on CDC25A phosphatase activity and is enhanced by T600/T611 phosphorylation.\",\n      \"method\": \"ChIP, luciferase reporter, mutagenesis of FOXM1 phosphorylation sites, co-IP, co-expression experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus mutagenesis plus co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23240008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOXM1 directly transcribes STAT3 through binding to the STAT3 promoter (demonstrated by ChIP and luciferase assay) and this is required for human endometrial stromal cell differentiation/decidualization; FOXM1 inhibition also downregulates cyclin B1 and delays G2/M transition in these cells.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown in HESC, G2/M cell cycle analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP and reporter assay with functional differentiation phenotype, single lab\",\n      \"pmids\": [\"26334131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXM1 directly binds to the UHRF1 gene promoter at FKH motifs and transcriptionally activates UHRF1 expression in an E2F-independent manner, thereby regulating cancer stem cell self-renewal and taxane resistance.\",\n      \"method\": \"ChIP on UHRF1 promoter, luciferase reporter, FOXM1 knockdown/overexpression, promoter mutagenesis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and reporter with mutagenesis, single lab\",\n      \"pmids\": [\"29752436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Honokiol directly binds to FOXM1 protein and inhibits FOXM1-mediated transcription and protein expression; binding specificity requires both substitution and dimerization of allylphenols.\",\n      \"method\": \"Direct binding assay (physical interaction of honokiol with FOXM1), FOXM1 transcriptional activity assay, compound structure-activity studies\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct physical binding demonstrated, SAR study confirms structural requirements, single lab\",\n      \"pmids\": [\"29367668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP5 deubiquitinates and stabilizes FoxM1 protein through direct interaction; co-IP confirmed endogenous USP5-FoxM1 interaction; USP5 overexpression extended FoxM1 half-life and knockdown decreased FoxM1 protein levels in a proteasome-dependent manner.\",\n      \"method\": \"Reciprocal co-IP of endogenous proteins, protein half-life (cycloheximide chase), proteasome inhibitor rescue (MG-132), USP5 knockdown/overexpression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP of endogenous proteins plus half-life measurements, single lab\",\n      \"pmids\": [\"28807830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP39 deubiquitinates and stabilizes FOXM1 protein through direct interaction; USP39 overexpression reduces FOXM1 ubiquitination, enhances FOXM1 transcriptional activity, and promotes downstream Cdc25b and Plk1 expression; USP39 and FOXM1 are positively correlated in breast cancer.\",\n      \"method\": \"Co-IP, in vitro deubiquitination assay, FOXM1 ubiquitination levels, gene expression of downstream targets\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus in vitro deubiquitination assay, single lab\",\n      \"pmids\": [\"36119839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXM1c (the most highly expressed isoform) directly binds the KIF4A promoter and transcriptionally regulates KIF4A expression; FOXM1-induced HCC cell proliferation is dependent on KIF4A, as KIF4A knockdown abolishes FOXM1-induced proliferation.\",\n      \"method\": \"ChIP, luciferase reporter, isoform-specific knockdown/overexpression, in vitro proliferation assays, xenograft mouse model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay identifying isoform-specific target, epistasis by rescue, confirmed in vivo, single lab\",\n      \"pmids\": [\"31072351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXM1 transcriptionally regulates TYMS, TK-1, and TYMP (5-FU metabolic targets) as demonstrated by ChIP and ChIP-seq; FOXM1 knockdown reduces TYMS expression while overexpression increases it; FOXM1-TYMS axis mediates 5-FU resistance in colorectal cancer.\",\n      \"method\": \"ChIP, global ChIP-seq, FOXM1 knockdown/overexpression, 5-FU resistance functional assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq genome-wide plus individual ChIP, expression modulation experiments, single lab\",\n      \"pmids\": [\"30728402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXM1 directly interacts with phosphorylated STAT3 under radiation treatment in glioblastoma cells, as demonstrated by co-IP and co-localization; radiation-induced FOXM1 expression is dependent on STAT3 activation.\",\n      \"method\": \"Co-immunoprecipitation, co-localization assay, STAT3 inhibition experiments, RPPA\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and co-localization with upstream functional dependency, single lab\",\n      \"pmids\": [\"27764801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phosphorylated STAT1 (pSTAT1) directly binds the FOXM1 promoter to downregulate its transcription; IFNγ-promoted pSTAT1 suppresses FOXM1 expression and sensitizes pancreatic cancer cells to gemcitabine; demonstrated by dual-luciferase reporter and ChIP assays.\",\n      \"method\": \"Dual-luciferase reporter, ChIP on FOXM1 promoter, IFNγ treatment, in vitro and in vivo apoptosis/proliferation assays\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter occupancy by ChIP plus reporter and functional drug sensitivity assay, single lab\",\n      \"pmids\": [\"30782607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"p53 negatively regulates FOXM1 expression: partial deletion or inactivation of p53 leads to upregulation of FOXM1 mRNA and protein, while p53 induction by DNA damage leads to FOXM1 downregulation.\",\n      \"method\": \"p53 knockdown in human fibroblasts and cancer cell lines, DNA damage induction, mRNA and protein level analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockdown plus gain-of-function DNA damage system, multiple cell line contexts, single lab\",\n      \"pmids\": [\"19806025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXM1 transcriptionally regulates integrin β1 (ITGB1) gene expression by directly binding to its promoter, and this drives FAK activation in triple-negative breast cancer cells.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, Western blot for FAK activation\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay with downstream signaling readout, single lab\",\n      \"pmids\": [\"28361350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXM1 transcriptionally activates RFC5 (replication factor C5) by binding to the RFC5 promoter, and this promotes temozolomide resistance in glioma cells independently of MGMT; knockdown of FOXM1 or RFC5 re-sensitizes glioma cells to TMZ.\",\n      \"method\": \"ChIP on RFC5 promoter, FOXM1/RFC5 knockdown, drug sensitivity assays, correlation in human glioma cells\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP with functional epistasis, single lab\",\n      \"pmids\": [\"28185110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXM1 protein translocates into mitochondria and inhibits oxidative phosphorylation by directly binding to and increasing PTCD1 (a mitochondrial leucine-specific tRNA binding protein that inhibits leucine-rich ETC complexes); this mitochondrial function is independent of nuclear transcription and does not affect cellular proliferation.\",\n      \"method\": \"Site-directed mutagenesis to generate compartment-specific localization mutants, mitochondrial fractionation, direct binding assay with PTCD1, mitochondrial respiration measurements, membrane potential assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis uncoupling nuclear and mitochondrial functions, direct binding demonstrated, multiple orthogonal mitochondrial function readouts in one study\",\n      \"pmids\": [\"32348194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXM1 directly binds the DKK1 gene 5'-UTR and transcriptionally activates DKK1 expression; DKK1 in turn signals via CKAP4-AKT and ERK pathways to maintain FOXM1 expression, forming a positive feedback loop that promotes tumor growth; FOXM1 induces DKK1 independently of Wnt signaling.\",\n      \"method\": \"FOXM1 binding site identification in DKK1 5'-UTR, DKK1/FOXM1 knockdown, pathway inhibitor epistasis, RNA-seq\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding site identified with knockdown epistasis and pathway inhibitor studies, single lab\",\n      \"pmids\": [\"34117362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MMB-FOXM1 complex (comprising FOXM1, LIN54, and MYBL2/B-MYB) is required for CHK1 inhibitor-induced premature mitosis in late S phase; knockout of FOXM1 or LIN54 reduces CHK1i-induced DNA replication stress markers and premature mitosis; a feedback loop between the MMB-FOXM1 complex and CDK1 drives this premature mitosis.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screens, FOXM1/LIN54 knockout, DNA damage marker assays, cell cycle analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide unbiased CRISPR screen with targeted validation, multiple knockouts identifying same complex, mechanistic cell cycle phenotype\",\n      \"pmids\": [\"33657372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LIN9 is the direct binding partner of FOXM1 in the MMB complex; FOXM1 and its target gene network are co-upregulated in oesophageal adenocarcinoma; ChIP-seq defines the FOXM1 target gene network in OAC cells.\",\n      \"method\": \"ChIP-seq, Nanostring gene expression assay, LIN9-FOXM1 binding assay, OAC tissue analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq genome-wide target identification and direct binding partner identification, single lab\",\n      \"pmids\": [\"25889361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXM1 directly binds DVL2 and enhances nuclear translocation of DVL2, promoting DVL2-mediated Wnt/β-catenin transcriptional activity to induce Snail expression, metastasis, and chemoresistance in colorectal cancer.\",\n      \"method\": \"Co-IP (FOXM1-DVL2 interaction), nuclear fractionation, TCF/LEF reporter assay for β-catenin transcriptional activity, knockdown of DVL2/Snail/FOXM1\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating physical interaction with functional nuclear translocation and transcriptional activity assay, single lab\",\n      \"pmids\": [\"33291076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"E3 ubiquitin ligase Cdh1 (Fzr1) is required for FoxM1 ubiquitylation and subsequent degradation; loss of Cdh1 promotes quiescent satellite cells into the cell cycle and depletes the satellite cell pool; haploinsufficiency of FoxM1 ameliorates the muscle regeneration defect of Cdh1 knockout mice. FoxM1 also functions as a direct transcriptional activator of Apc (adenomatous polyposis coli) to prevent hyperactivation of Wnt/β-catenin signaling during muscle regeneration.\",\n      \"method\": \"Conditional FoxM1 knockout in satellite cells, Cdh1 knockout mice, genetic rescue (FoxM1 haploinsufficiency in Cdh1 KO), ChIP/promoter assay for Apc, ubiquitination assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis (double mutant rescue), direct ubiquitination, and transcriptional target assay with multiple readouts\",\n      \"pmids\": [\"32152291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXM1 binds RB1 and recruits DNMT3B to repress FOXO1 expression; reduced FOXO1 leads to decreased CDK-inhibitor levels, enabling RB1 phosphorylation and inactivation; inhibition of FOXM1 restores FOXO1 and activates RB1, inducing senescence of HCC cells in vitro and in vivo.\",\n      \"method\": \"Co-IP (FOXM1-RB1-DNMT3B complex), FOXO1/RB1 expression analysis upon FOXM1 manipulation, repression-deficient FOXM1 mutants, in vivo tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional mutagenesis and in vivo validation, single lab\",\n      \"pmids\": [\"35761036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FoxM1 directly binds and transcriptionally activates the SIRT1 promoter at a minimal FoxM1 binding site in glioma cells; FoxM1 overexpression promotes and knockdown inhibits Sirt1 expression.\",\n      \"method\": \"ChIP, luciferase reporter, siRNA knockdown, RT-PCR and Western blot\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and reporter assay but single low-impact journal, single lab, limited orthogonal validation\",\n      \"pmids\": [\"24488909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXM1 undergoes liquid-liquid phase separation (LLPS) with FKH consensus DNA elements, compartmentalizing the transcription apparatus in the nucleus to sustain chromatin accessibility and super-enhancer landscapes; AMPK phosphorylates FOXM1 at a specific IDR1 site, causing electrostatic repulsion that abolishes FOXM1 LLPS; a peptide targeting IDR1 disrupts FOXM1 condensates and inhibits tumor malignancy while activating innate immune responses.\",\n      \"method\": \"Phase separation screening, genetic code-expansion orthogonal system demonstrating phosphoryl moiety at IDR1, AMPK phosphorylation assays, chromatin accessibility assays (ATAC-seq), super-enhancer profiling, peptide functional assays in vivo\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted LLPS, genetic code expansion for site-specific phosphorylation validation, multiple orthogonal genomic and functional methods\",\n      \"pmids\": [\"39814884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXM1 isoforms FOXM1b and FOXM1c are transcriptionally active while FOXM1a is not, as demonstrated in a CRISPR FOXM1 knockout model; FOXM1c shows highest expression in normal and tumor tissues.\",\n      \"method\": \"CRISPR knockout, isoform-specific re-expression, transcriptional activity reporter\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR KO rescue with individual isoforms, single lab\",\n      \"pmids\": [\"30795624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXM1 directly binds the METTL3 promoter and represses METTL3 transcription in human scleral fibroblasts; reduced METTL3 decreases m6A methylation of APOA1 mRNA, reducing YTHDF2-mediated degradation and thereby increasing APOA1 stability and expression.\",\n      \"method\": \"ChIP (FOXM1 enrichment at METTL3 promoter), Me-RIP (m6A levels of APOA1), PAR-CLIP (METTL3-APOA1 binding), loss- and gain-of-function experiments\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP, Me-RIP, and PAR-CLIP provide multiple orthogonal methods in single study, single lab\",\n      \"pmids\": [\"38190128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXM1 nuclear localization is inhibited by the small-molecule compound RCM-1, and RCM-1 decreases the protein-protein interaction between β-catenin and FOXM1 in tumor cells, reducing β-catenin nuclear localization and inhibiting tumor growth.\",\n      \"method\": \"Confocal imaging of FOXM1 nuclear localization, co-IP (β-catenin/FOXM1 interaction), colony formation assay, in vivo tumor models (rhabdomyosarcoma, melanoma, lung adenocarcinoma)\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-IP of FOXM1-β-catenin interaction with nuclear localization imaging and in vivo validation, single lab\",\n      \"pmids\": [\"31040162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Foxm1 is required for cardiomyocyte proliferation after cardiac injury in zebrafish through transcriptional regulation of cell cycle genes including cenpf; foxm1 mutant hearts show decreased cardiomyocyte proliferation and cell cycle gene expression; cenpf (a microtubule/kinetochore binding protein) mutants show increased cardiomyocyte binucleation, suggesting a role in completing mitosis.\",\n      \"method\": \"foxm1 zebrafish mutant, transcriptomic analysis, cenpf mutant characterization, cardiomyocyte proliferation markers\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function in zebrafish with transcriptomic and phenotypic characterization, single lab\",\n      \"pmids\": [\"36846912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM64A physically interacts with FOXM1 in HNSCC cells and promotes FOXM1-dependent transcription; FAM64A also modulates FOXM1 expression via the FOXM1 autoregulatory loop.\",\n      \"method\": \"Co-IP (FAM64A-FOXM1 interaction), FOXM1 transcriptional activity assay, FAM64A depletion/overexpression, in vitro and in vivo cancer cell assays\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and activity assay, single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"35538067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"An N-terminally truncated activated form of FoxM1 (FoxM1ΔNRD) bypasses two post-translational controls: exposure of the forkhead DNA-binding domain and targeted proteasomal degradation; activated FoxM1 protects β-cells from streptozotocin-induced death and alters extracellular matrix and immune cell gene expression profiles.\",\n      \"method\": \"Inducible transgenic mouse model (RIP-rtTA;TetO-HA-FoxM1ΔNRD), STZ-induced β-cell injury, RNA sequencing, β-cell mass/proliferation/death measurements\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo genetic model with RNA-seq defining FOXM1ΔNRD targets, revealing bypass of post-translational control, single lab\",\n      \"pmids\": [\"25073103\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOXM1 is a forkhead-family transcription factor that directly binds forkhead response elements on target gene promoters (including cyclin B1, NBS1, SNAIL, XIAP, Survivin, STAT3, CDC25A, UHRF1, KIF4A, TYMS, integrin β1, RFC5, Sirt1, Apc, and DKK1) to drive cell cycle progression at G1/S and G2/M, DNA damage repair, and invasion; its activity and stability are tightly controlled by multi-layered post-translational modifications including CDK-mediated phosphorylation (activating, at T600/T611/T620 among others), GSK3-mediated phosphorylation at S474 (promoting FBXW7-dependent ubiquitination and degradation), Wnt/USP5-mediated deubiquitination (stabilization), SUMO1 modification (inhibitory, promoting cytoplasmic translocation and APC/Cdh1-mediated degradation), p300/CBP-mediated acetylation (activating DNA binding and stability) reversed by SIRT1, and APC/Cdh1-mediated ubiquitin-proteasomal degradation; FOXM1 is also subject to transcriptional repression by p53 and pSTAT1, interacts physically with partners including β-catenin/TCF4, DVL2, RB1/DNMT3B, phospho-STAT3, PTCD1, and LIN9 (in the MMB complex), undergoes liquid-liquid phase separation at super-enhancers in the nucleus (disrupted by AMPK-mediated IDR1 phosphorylation), and localizes to mitochondria to inhibit oxidative phosphorylation via PTCD1 independent of nuclear transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FOXM1 is a forkhead-family transcription factor that drives proliferation by directly binding forkhead response elements on cell-cycle and genome-maintenance gene promoters, establishing it as a master regulator of G2/M progression and DNA repair [#0, #3]. It transactivates cyclin B1 to promote mitotic entry [#0] and induces NBS1 to elevate MRN/ATM signaling and homologous-recombination repair, with NBS1 being indispensable for its HR function [#3]. Its target repertoire, defined in part by ChIP-seq, extends to genes governing invasion, apoptosis resistance, stemness, and drug metabolism, including SNAIL [#6], XIAP and Survivin [#7], UHRF1 [#12], KIF4A [#16], and the 5-FU metabolic enzyme TYMS [#17], as well as integrin \\u03b21 to drive FAK activation [#21]. FOXM1 also acts as a transcriptional repressor: through RB1- and DNMT3B-dependent promoter methylation it silences differentiation genes (GATA-3, FOXO1), suppressing senescence and luminal differentiation [#8, #29]. FOXM1 abundance and activity are governed by layered post-translational control: CDK1/CDC25A-mediated phosphorylation activates it [#10], GSK3 phosphorylation at S474 triggers FBXW7-dependent degradation while Wnt signaling and the deubiquitinases USP5 and USP39 stabilize it [#5, #14, #15], APC/Cdh1 directs its ubiquitin-proteasomal turnover [#28], SUMO1 modification inhibits it and promotes cytoplasmic translocation [#4], and p300/CBP acetylation\\u2014reversed by SIRT1\\u2014enhances DNA binding and stability [#9]. FOXM1 integrates with Wnt signaling by recruiting \\u03b2-catenin to target promoters and binding DVL2 to potentiate \\u03b2-catenin transcriptional activity [#5, #27], and assembles into the MMB complex with LIN9/LIN54 and MYBL2 to control mitotic timing [#25, #26]. Beyond canonical transcription, FOXM1 forms liquid-liquid phase-separated condensates at super-enhancers to sustain chromatin accessibility, a behavior abolished by AMPK phosphorylation of its IDR1 [#31], and a fraction translocates to mitochondria to inhibit oxidative phosphorylation via PTCD1 independently of nuclear transcription [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the FOXM1 gene structure and a cell-cycle-regulated promoter framed it as a candidate proliferation-associated transcription factor before its targets were known.\",\n      \"evidence\": \"cDNA/gene isolation, chromosomal mapping, and promoter analysis in synchronized fibroblasts\",\n      \"pmids\": [\"9441747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct transcriptional targets identified\", \"DNA-binding specificity not functionally mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying cyclin B1 as a direct target answered how FOXM1 mechanistically promotes mitotic entry rather than merely correlating with proliferation.\",\n      \"evidence\": \"Inducible cell lines with promoter reporter assays and expression quantification\",\n      \"pmids\": [\"11682060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address upstream control of FOXM1 activity\", \"Genome-wide target scope undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing p53 represses FOXM1 connected its activity to tumor-suppressor surveillance and DNA-damage checkpoints.\",\n      \"evidence\": \"p53 knockdown and DNA-damage induction with mRNA/protein readouts across cell lines\",\n      \"pmids\": [\"19806025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect repression mechanism not resolved\", \"No promoter occupancy data\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining the FOXM1-NBS1 axis and SUMO1 control extended FOXM1 beyond cell-cycle gene activation into DNA repair and revealed an inhibitory PTM that relocalizes and degrades it.\",\n      \"evidence\": \"ChIP, rescue/epistasis HR assays (NBS1) and SUMOylation-site mutagenesis with Ubc9-fusion (SUMO1)\",\n      \"pmids\": [\"24141789\", \"24362530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO ligase and deSUMOylase not identified\", \"Coupling between SUMOylation and APC/Cdh1 recognition mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The reciprocal FOXM1-CDC25A circuit explained how FOXM1 activity is amplified during the cell cycle via CDK1-dependent phosphorylation at T600/T611/T620.\",\n      \"evidence\": \"ChIP, phosphosite mutagenesis, and co-IP showing phosphatase-dependent interaction\",\n      \"pmids\": [\"23240008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the phospho-enhanced interaction unknown\", \"Quantitative contribution of each phosphosite undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Acetylation/deacetylation and the GSK3-FBXW7/Wnt-USP5 axis established that FOXM1 stability and DNA-binding affinity are set by competing PTM writers and erasers.\",\n      \"evidence\": \"Site-directed lysine/serine mutagenesis, co-IP with p300/CBP, SIRT1, USP5, kinase and ubiquitination assays\",\n      \"pmids\": [\"27542221\", \"26912724\", \"28807830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk hierarchy among acetylation, phosphorylation, and ubiquitination unresolved\", \"USP5 catalytic mechanism on FOXM1 not reconstituted in vitro\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating repressor activity via RB-dependent DNMT3B recruitment broadened FOXM1's mechanism from activator to context-dependent silencer of differentiation programs.\",\n      \"evidence\": \"Mammary reconstitution, DNMT3B co-IP, and bisulfite sequencing of GATA-3 promoter\",\n      \"pmids\": [\"22813746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How FOXM1 switches between activation and repression unknown\", \"Generality across tissues untested in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A wave of ChIP-based target studies mapped FOXM1 onto invasion, apoptosis-resistance, stemness, and drug-resistance programs, defining its breadth as an oncogenic effector.\",\n      \"evidence\": \"ChIP/luciferase and ChIP-seq with knockdown phenotypes (SNAIL, XIAP/Survivin, STAT3, UHRF1, KIF4A, TYMS, ITGB1, RFC5, LIN9 network)\",\n      \"pmids\": [\"25561901\", \"26404623\", \"26334131\", \"29752436\", \"31072351\", \"30728402\", \"28361350\", \"28185110\", \"25889361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs E2F-cooperative binding not always distinguished\", \"Single-lab, single-cancer contexts limit generality\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncoupling FOXM1's nuclear and mitochondrial pools revealed a transcription-independent role in suppressing oxidative phosphorylation through PTCD1.\",\n      \"evidence\": \"Compartment-specific localization mutants, mitochondrial fractionation, PTCD1 binding, and respiration measurements\",\n      \"pmids\": [\"32348194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of FOXM1 mitochondrial import unknown\", \"Physiological contribution relative to nuclear function unquantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic identification of the MMB-FOXM1 complex and in vivo Cdh1 epistasis tied FOXM1 to mitotic-timing control and degradation-dependent quiescence in physiological settings.\",\n      \"evidence\": \"Genome-wide CRISPR screens with FOXM1/LIN54 knockouts; conditional knockouts and double-mutant rescue in mouse satellite cells\",\n      \"pmids\": [\"33657372\", \"32152291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the MMB-FOXM1 complex undefined\", \"Direct CDK1 feedback target sites on the complex not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery of FOXM1 liquid-liquid phase separation at super-enhancers, switched off by AMPK phosphorylation of IDR1, reframed its transcriptional function as condensate-driven and revealed a druggable disordered region.\",\n      \"evidence\": \"Reconstituted LLPS, genetic code-expansion site-specific phosphorylation, ATAC-seq, super-enhancer profiling, and IDR1 peptide in vivo\",\n      \"pmids\": [\"39814884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Composition of FOXM1 condensates incompletely defined\", \"Relationship between LLPS and PTM-controlled stability unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many PTMs, the MMB complex, condensate formation, and the mitochondrial pool are integrated into a single coherent regulatory logic across cell-cycle phases remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking PTM state to LLPS vs degradation vs mitochondrial localization\", \"Structural basis of forkhead-element recognition within condensates undefined\", \"Determinants of activator vs repressor mode unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 6, 7, 16, 17, 26, 32]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 9, 31]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 31, 34]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 10, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 6, 7, 16, 17, 26]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 27]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5, 9, 14, 28]}\n    ],\n    \"complexes\": [\"MMB complex (FOXM1-LIN9/LIN54-MYBL2)\"],\n    \"partners\": [\"CDC25A\", \"USP5\", \"USP39\", \"RB1\", \"DNMT3B\", \"DVL2\", \"PTCD1\", \"LIN9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}