{"gene":"UBE2C","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1997,"finding":"UbcH10 (UBE2C) functions as a cyclin-selective ubiquitin carrier protein (E2) that works with the APC/cyclosome E3 ligase to ubiquitinate cyclin B, driving its destruction. Mutation of the catalytic cysteine to serine creates a dominant-negative that blocks cyclin A and B ubiquitination and destruction in vitro. In mammalian cells, dominant-negative UbcH10 arrests cells in M phase and inhibits anaphase onset, demonstrating roles in both cyclin B degradation (cdc2 inactivation) and sister chromatid separation.","method":"In vitro ubiquitination assay in clam oocyte extracts; active-site mutagenesis (Cys→Ser); transfection of dominant-negative into mammalian cells with cell cycle readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in vitro with active-site mutagenesis plus functional cell-based validation; foundational paper replicated by subsequent studies","pmids":["9122200"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of UbcH10 at 1.95 Å resolution (active-site Cys→Ser mutant) revealed that the N-terminal extension is disordered and that a conserved 3(10)-helix positions a lysine residue near the active site. Mutagenesis showed that this lysine near the active site significantly affects ubiquitin-adduct formation, whereas the N-terminal extension has little effect on ubiquitin charging.","method":"X-ray crystallography at 1.95 Å; active-site and lysine mutagenesis with ubiquitin-adduct formation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro biochemical validation in a single study","pmids":["11927573"],"is_preprint":false},{"year":2008,"finding":"UbcH10 is preferentially used by the APC/C over other E2s owing to its core E2 domain. Its unique N-terminal extension provides an additional E2-E3 regulatory interaction that limits APC/C activity: mutating the N terminus increases substrate ubiquitination, broadens lysine targeting on substrates, allows destruction of substrates lacking destruction boxes, confers resistance to APC inhibitors Emi1 and BubR1 in vitro, and bypasses the spindle checkpoint in vivo. Fusing the UbcH10 N terminus to UbcH5 restricts ubiquitination without directing APC-specific interactions.","method":"In vitro APC ubiquitination assays with UbcH10 N-terminal mutants; spindle checkpoint bypass assay in vivo; domain-swap experiments (UbcH10 N-term fused to UbcH5)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro and in vivo methods with mutagenesis in a single rigorous study","pmids":["18722180"],"is_preprint":false},{"year":2010,"finding":"Overexpression of UbcH10 in transgenic mice leads to precocious APC/C-mediated degradation of cyclin B, supernumerary centrioles, lagging chromosomes, aneuploidy, and spontaneous tumor formation, identifying UbcH10 as a proto-oncogene that causes whole chromosome instability.","method":"Graded transgenic mouse overexpression; immunofluorescence; tumor incidence monitoring; carcinogen challenge","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with multiple cellular and organismal phenotypic readouts, replicated across expression levels","pmids":["20065091"],"is_preprint":false},{"year":2005,"finding":"A novel UbcH10-binding protein (H10BH) identified by yeast two-hybrid possesses a HECT-like domain, exhibits self-ubiquitinylation activity, binds UbcH10 through residues 235–257, binds cyclin B, and ubiquitinylates cyclin B in vitro, suggesting it acts as a HECT-type E3 using UbcH10 as its cognate E2.","method":"Yeast two-hybrid; co-immunoprecipitation; in vitro ubiquitinylation assay of cyclin B","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — yeast two-hybrid plus in vitro ubiquitinylation assay, single lab, no independent replication","pmids":["15749827"],"is_preprint":false},{"year":2011,"finding":"Cdc20 transcriptionally up-regulates UBE2C expression in a cell-cycle-specific manner. The WD40 domain of Cdc20 is required for this activity, and Cdc20 physically interacts with the APC/C-CBP/p300 complex, which is then recruited to the UBE2C promoter to drive transactivation.","method":"Chromatin immunoprecipitation; co-immunoprecipitation; promoter-reporter assays; domain-deletion analysis; cell cycle synchronization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, and reporter assays in a single lab with multiple complementary methods","pmids":["21454660"],"is_preprint":false},{"year":2011,"finding":"Nitric oxide (NO) decreases UBE2C protein levels in vascular smooth muscle cells by increasing its polyubiquitination, leading to proteasomal degradation of UBE2C. This mechanism is associated with inhibition of VSMC proliferation and reduced neointimal hyperplasia in vivo.","method":"Western blotting; immunofluorescent staining; siRNA knockdown; plasmid overexpression; balloon-injury rat carotid artery model; polyubiquitin detection by co-immunoprecipitation","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with detection of polyubiquitinated UBE2C; single lab","pmids":["21448667"],"is_preprint":false},{"year":2011,"finding":"PI3K/AKT-phosphorylated MED1 is recruited to CRPC-specific UBE2C enhancers, mediates long-range enhancer-promoter chromatin looping at the UBE2C locus, and recruits FoxA1, RNA polymerase II, and TATA-binding protein, driving UBE2C overexpression in castration-resistant prostate cancer.","method":"Chromatin immunoprecipitation; chromosome conformation capture (3C/looping assays); MED1 phosphorylation analysis; siRNA knockdown; cell growth assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and chromosome conformation capture provide direct mechanistic evidence; single lab with multiple orthogonal methods","pmids":["21556051"],"is_preprint":false},{"year":2015,"finding":"UBE2C (Ube2C) and UBE2S, together with UBE2D3, act as the E2 ubiquitin-conjugating enzymes regulating APC/C activity during meiosis I in mouse oocytes. Depletion of Ube2C reduces first polar body extrusion by ~50%; overexpression accelerates and doubles completion. High Ube2C levels override the spindle assembly checkpoint to drive meiotic exit regardless of spindle formation.","method":"RNA injection (depletion and overexpression); first polar body extrusion assay; spindle formation assessment in mouse oocytes","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss- and gain-of-function in a defined biological system with quantitative phenotypic readout; single lab","pmids":["26207029"],"is_preprint":false},{"year":2016,"finding":"Wild-type p53 transcriptionally represses UBE2C in a p21-E2F4-dependent manner, whereas gain-of-function (GOF) mutant p53 transcriptionally activates UBE2C in an NF-Y-dependent manner. DNA damage-induced wild-type p53 causes spindle assembly checkpoint arrest by repressing UBE2C; GOF mutant p53 causes premature anaphase exit by increasing UBE2C expression.","method":"Promoter-reporter assays; chromatin immunoprecipitation; siRNA knockdown; cell cycle analysis after DNA damage (5-fluorouracil)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays with functional cell cycle readout; single lab, multiple methods","pmids":["27129209"],"is_preprint":false},{"year":2016,"finding":"SAG/RBX2 E3 ligase preferentially binds E2s UBCH10 and UBE2S (which mediate K11-linked ubiquitin chains) rather than CDC34 or UBCH5C (K48 linkage). SAG-CUL5 promotes K11-linked ubiquitylation and degradation of β-TrCP1; silencing of UBCH10 or UBE2S (but not UBCH5C) causes β-TrCP1 accumulation, identifying β-TrCP1 as a physiological substrate of the SAG-UBCH10/UBE2S axis.","method":"Co-immunoprecipitation; in vitro ubiquitylation assay; siRNA knockdown; protein half-life (CHX chase) assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and in vitro ubiquitylation with siRNA validation; single lab, multiple orthogonal methods","pmids":["27910872"],"is_preprint":false},{"year":2018,"finding":"FOXM1 directly binds the UBE2C promoter and transcriptionally activates UBE2C expression. Site-directed mutations in the FOXM1-binding site markedly reduce UBE2C promoter activity. FOXM1 and UBE2C expression are positively correlated across 25 tumor types.","method":"Chromatin immunoprecipitation; promoter-reporter assay with site-directed mutagenesis; siRNA knockdown; gene expression correlation analysis","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and mutagenesis-based reporter assay provide direct transcriptional evidence; single lab","pmids":["29596365"],"is_preprint":false},{"year":2019,"finding":"UBE2C promotes ubiquitination and degradation of p53 in endometrial cancer cells, thereby reducing p53 and p21 levels and enabling EMT. Estradiol induces UBE2C expression via estrogen receptor α, which directly binds the UBE2C promoter element. p53 overexpression reverses UBE2C-driven EMT.","method":"Co-immunoprecipitation; ubiquitination assay; ChIP (ERα binding to UBE2C promoter); Western blotting; siRNA knockdown; in vivo xenograft","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP ubiquitination assay and ChIP in a single lab with functional rescue experiments","pmids":["31662448"],"is_preprint":false},{"year":2019,"finding":"UBE2C increases HIF-1α levels by ubiquitinating and promoting degradation of pVHL (von Hippel-Lindau protein), thereby promoting endothelial inflammation and endothelial-mesenchymal transition in aortic valve endothelial cells exposed to disturbed flow.","method":"Ubiquitination/co-immunoprecipitation assays; Western blotting; siRNA knockdown; flow-conditioning of human AV endothelial cells; porcine AV leaflet ex vivo model","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination assay for pVHL plus functional in vitro and ex vivo validation; single lab","pmids":["30602302"],"is_preprint":false},{"year":2023,"finding":"UBE2C couples with APC/C-CDH1 to promote K11-linked ubiquitylation and degradation of DEPTOR, leading to mTORC1 pathway activation. DEPTOR levels oscillate during the cell cycle in a UBE2C- and CDH1-dependent manner. In a KrasG12D lung tumor model, Ube2c deletion inhibited tumor formation; Deptor deletion fully rescued this inhibitory effect, establishing a causal UBE2C→CDH1→DEPTOR→mTOR oncogenic cascade.","method":"In vivo conditional knockout (Ube2c and Deptor deletions in KrasG12D mice); ubiquitylation assay (K11-linkage); co-immunoprecipitation; cell cycle synchronization with protein level tracking","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitylation assay plus rigorous in vivo genetic epistasis (double KO rescue) in a single study","pmids":["36548081"],"is_preprint":false},{"year":2023,"finding":"UBE2C mediates K48-linked ubiquitination of SIRT1, promoting its proteasomal degradation. Loss of SIRT1 reduces H4K16 deacetylation, epigenetically repressing autophagy-related gene expression. This UBE2C-SIRT1-autophagy axis contributes to endometrial cancer progression, and rapamycin (autophagy agonist) reverses tumor growth caused by UBE2C overexpression.","method":"Co-immunoprecipitation; ubiquitin immunoprecipitation (K48 linkage); autophagic flux assays (mRFP-GFP-LC3, bafilomycin A1); ChIP for H4K16 acetylation; xenograft model","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP ubiquitination with linkage specificity, ChIP, and functional rescue; single lab, multiple methods","pmids":["36930831"],"is_preprint":false},{"year":2024,"finding":"UBE2C mediates monoubiquitination of SNAT2 at K59, which competitively inhibits K63-linked polyubiquitination of SNAT2 at K33. This monoubiquitination/K63-polyubiquitination crosstalk suppresses EPN1-mediated endocytosis of SNAT2, increasing SNAT2 membrane levels, enhancing glutamine uptake and VEGFC secretion, and promoting lymphangiogenesis and lymph node metastasis in bladder cancer.","method":"High-throughput sequencing; site-specific ubiquitination assays (K59 and K33 mutants); co-immunoprecipitation; endocytosis assay; patient-derived xenograft model; in vitro and in vivo lymphangiogenesis assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific mutagenesis of ubiquitination sites, mechanistic co-IP, and in vivo PDX validation in a single rigorous study","pmids":["38949026"],"is_preprint":false},{"year":2010,"finding":"In HPV-16 E6/E7-expressing keratinocytes, elevated levels of UbcH10 and Cdc20 drive APC/C-dependent cyclin B degradation, allowing these cells to exit mitosis in the presence of DNA damage and bypass the spindle assembly checkpoint.","method":"Western blotting; co-immunoprecipitation (Cdc20-BubR1 complexes); cell cycle analysis; cyclin B stability assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical co-IP and cell cycle readout linking UbcH10 elevation to checkpoint bypass; single lab","pmids":["20739533"],"is_preprint":false},{"year":2022,"finding":"KAT2A cooperates with E2F1 and is recruited by E2F1 to the UBE2C promoter; this increases H3K9 acetylation at the UBE2C locus, elevating UBE2C transcription and promoting cancer cell proliferation and migration.","method":"ChIP assay; immunofluorescence co-localization; RNA-seq; qRT-PCR; Western blotting; cell proliferation/migration assays","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct histone acetylation at UBE2C promoter by KAT2A/E2F1; single lab, multiple methods","pmids":["36292703"],"is_preprint":false},{"year":2018,"finding":"UBE2C directly binds to the 5'-UTR of ZEB1 and ZEB2 transcripts (confirmed by ChIP and luciferase reporter assay), transcriptionally promoting their expression to drive EMT and cisplatin resistance in NSCLC cells.","method":"Chromatin immunoprecipitation; luciferase reporter assay; siRNA knockdown; Western blotting; cell migration/invasion assay","journal":"Theranostics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and luciferase assay support binding claim, but mechanism of UBE2C acting as transcriptional regulator of ZEB1/2 5'-UTR is unusual and not independently replicated","pmids":["31037155"],"is_preprint":false},{"year":2024,"finding":"UBE2C activates Notch signaling in hepatocellular carcinoma by upregulating N1ICD and Hes1 and activating the RBP-JK luciferase reporter. Notch inhibitor DAPT abrogates UBE2C-driven oncogenic phenotypes, and N1ICD overexpression rescues the effect of UBE2C knockdown.","method":"RBP-JK luciferase reporter assay; Western blotting; siRNA knockdown and overexpression; Notch inhibitor rescue experiments","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — reporter assay and pharmacological rescue, single lab, no direct biochemical mechanism for how UBE2C activates Notch","pmids":["39353974"],"is_preprint":false},{"year":2022,"finding":"UBE2C binds to EGFR, stabilizing it and promoting PI3K-Akt pathway activation in pancreatic cancer cells; UBE2C knockdown impairs glucose uptake, lactate production, and ATP generation, linking UBE2C to glycolytic reprogramming via EGFR stabilization.","method":"Co-immunoprecipitation; qRT-PCR; glycolysis metabolite assays (glucose uptake, lactate, ATP); Western blotting; siRNA knockdown","journal":"Journal of gastrointestinal oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP for EGFR binding and functional metabolic assays; single lab, limited mechanistic depth","pmids":["35837197"],"is_preprint":false},{"year":2024,"finding":"UBE2C inhibits gastric cancer cell autophagy by promoting accumulation of p62, which increases p62-KEAP1 interaction and thereby reduces KEAP1-NRF2 binding, weakening NRF2 ubiquitination and degradation and causing nuclear accumulation of NRF2. TBHQ (NRF2 activator) rescues proliferation/migration inhibited by UBE2C silencing.","method":"Co-immunoprecipitation; Western blotting; autophagy flux assay; siRNA knockdown and overexpression; rescue with NRF2 activator","journal":"International journal of biological macromolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP and rescue experiments; single lab, indirect mechanistic chain","pmids":["39032892"],"is_preprint":false}],"current_model":"UBE2C (UbcH10) is the mitosis-specific E2 ubiquitin-conjugating enzyme that works with the APC/C E3 ligase—activated by Cdc20 or CDH1—to catalyze K11-linked ubiquitin chain assembly on cyclin A, cyclin B, securin, DEPTOR, and other substrates, driving their proteasomal degradation to coordinate metaphase-to-anaphase transition, mitotic exit, and spindle assembly checkpoint control; its unique disordered N-terminal extension restricts APC/C activity and substrate selectivity, it also ubiquitinates non-APC/C targets (p53, SIRT1, pVHL, SNAT2) in cancer contexts to regulate EMT, autophagy, and HIF-1α signaling, and its transcription is directly activated by Cdc20-APC/C-CBP/p300 recruitment, FOXM1, E2F1/KAT2A, and estrogen receptor α, placing it at the nexus of cell cycle progression and oncogenic gene regulatory networks."},"narrative":{"mechanistic_narrative":"UBE2C (UbcH10) is the cyclin-selective E2 ubiquitin-conjugating enzyme that partners with the APC/C E3 ligase to drive ubiquitination and proteasomal destruction of mitotic substrates including cyclin B, controlling cdc2 inactivation, sister chromatid separation, and anaphase onset [PMID:9122200]. Its catalytic cysteine is essential, and a conserved lysine near the active site governs ubiquitin-adduct formation, while a disordered N-terminal extension acts as a regulatory brake on APC/C: removing it broadens substrate lysine targeting, permits destruction of substrates lacking destruction boxes, confers resistance to the APC inhibitors Emi1 and BubR1, and bypasses the spindle assembly checkpoint [PMID:11927573, PMID:18722180]. Through APC/C-Cdc20 and APC/C-CDH1 it builds K11-linked chains on cell-cycle regulators, and this activity extends to DEPTOR, whose degradation activates mTORC1 in a UBE2C→CDH1→DEPTOR→mTOR oncogenic cascade demonstrated by genetic epistasis in KrasG12D lung tumors [PMID:36548081]. Overexpression of UBE2C causes precocious cyclin B degradation, supernumerary centrioles, aneuploidy, and spontaneous tumors, defining it as a proto-oncogene driving whole-chromosome instability [PMID:20065091]. UBE2C transcription is a convergence point for proliferative and oncogenic inputs, directly activated by Cdc20-recruited APC/C-CBP/p300, FOXM1, E2F1/KAT2A, estrogen receptor α, and CRPC-specific MED1/FoxA1 enhancer looping, and repressed by wild-type p53 [PMID:21454660, PMID:21556051, PMID:27129209, PMID:29596365, PMID:31662448, PMID:36292703]. Beyond canonical APC/C substrates, UBE2C ubiquitinates p53, pVHL, SIRT1, and SNAT2 in cancer contexts to promote EMT, HIF-1α signaling, autophagy repression, and metabolic reprogramming [PMID:31662448, PMID:30602302, PMID:36930831, PMID:38949026].","teleology":[{"year":1997,"claim":"Established UBE2C as the catalytic E2 enzyme that, with the APC/cyclosome, drives mitotic cyclin destruction—answering what enzyme couples ubiquitin transfer to anaphase onset.","evidence":"In vitro ubiquitination in clam oocyte extracts, active-site Cys→Ser mutagenesis, and dominant-negative transfection with cell cycle readout","pmids":["9122200"],"confidence":"High","gaps":["Did not define the structural basis of E2 catalysis","Substrate selectivity beyond cyclins A/B not addressed"]},{"year":2002,"claim":"Defined the structural determinants of UBE2C catalysis, showing an active-site-proximal lysine controls ubiquitin charging while the N-terminal extension is dispensable for charging.","evidence":"X-ray crystallography at 1.95 Å of the Cys→Ser mutant with lysine mutagenesis and adduct-formation assays","pmids":["11927573"],"confidence":"High","gaps":["Functional role of the disordered N-terminal extension left unexplained","No structure in complex with APC/C"]},{"year":2008,"claim":"Revealed that the N-terminal extension is a regulatory element restricting APC/C substrate selectivity and enforcing the spindle checkpoint, explaining why APC/C prefers UBE2C.","evidence":"In vitro APC ubiquitination with N-terminal mutants, in vivo spindle-checkpoint bypass, and UbcH10-UbcH5 domain swaps","pmids":["18722180"],"confidence":"High","gaps":["Atomic structure of the N-terminus-APC/C interaction not resolved","Chain-linkage specificity not characterized here"]},{"year":2010,"claim":"Demonstrated UBE2C is a bona fide proto-oncogene, causally linking its overexpression to chromosomal instability and tumorigenesis in vivo.","evidence":"Graded transgenic mouse overexpression with immunofluorescence, aneuploidy scoring, and tumor incidence/carcinogen challenge","pmids":["20065091"],"confidence":"High","gaps":["Non-APC/C substrates driving transformation not identified","Molecular trigger of centriole amplification unresolved"]},{"year":2010,"claim":"Connected UBE2C dysregulation to viral oncogenesis, showing elevated UbcH10/Cdc20 enables mitotic exit despite DNA damage.","evidence":"Western blot, Cdc20-BubR1 co-IP, and cyclin B stability/cell cycle analysis in HPV-16 E6/E7 keratinocytes","pmids":["20739533"],"confidence":"Medium","gaps":["Direct transcriptional driver of UbcH10 induction by E6/E7 not defined","Single lab"]},{"year":2011,"claim":"Identified transcriptional and post-translational control of UBE2C levels: Cdc20-APC/C-CBP/p300 transactivates it, MED1 enhancer looping drives it in CRPC, and NO promotes its proteasomal degradation.","evidence":"ChIP, co-IP, promoter-reporter, 3C looping assays, and polyubiquitin detection across cancer cells and a rat carotid-injury model","pmids":["21454660","21556051","21448667"],"confidence":"Medium","gaps":["E3 ligase mediating NO-induced UBE2C degradation unknown","Generality of MED1 looping beyond CRPC untested"]},{"year":2015,"claim":"Extended UBE2C's APC/C role from mitosis to meiosis, showing it gates meiotic exit and can override the spindle checkpoint in oocytes.","evidence":"RNA-injection depletion/overexpression with polar body extrusion and spindle assessment in mouse oocytes","pmids":["26207029"],"confidence":"Medium","gaps":["Relative contributions of UBE2C vs UBE2S/UBE2D3 not fully separated","Substrate specificity in meiosis unaddressed"]},{"year":2016,"claim":"Placed UBE2C under p53 control and within a broader K11-chain E3 network, identifying SAG/RBX2-CUL5 as an additional E3 partner targeting β-TrCP1.","evidence":"Promoter-reporter, ChIP, reciprocal co-IP, in vitro ubiquitylation, and CHX-chase across cancer cells","pmids":["27129209","27910872"],"confidence":"Medium","gaps":["Whether SAG-UBE2C cooperation occurs in physiological cell-cycle context unclear","p53-UBE2C axis tested in limited contexts"]},{"year":2018,"claim":"Defined FOXM1 as a direct transcriptional activator of UBE2C correlated across tumor types, and reported an unusual transcriptional regulatory activity of UBE2C on ZEB1/ZEB2.","evidence":"ChIP, mutagenesis-based reporter assays, expression correlation, and luciferase reporter/migration assays","pmids":["29596365","31037155"],"confidence":"Medium","gaps":["The ZEB1/2 finding (#19) is Low-confidence and mechanistically atypical, not independently replicated","How an E2 enzyme acts as a transcriptional regulator is unexplained"]},{"year":2019,"claim":"Established non-APC/C ubiquitination substrates of UBE2C in cancer—p53 and pVHL—linking it to EMT and HIF-1α signaling, with ERα driving its expression.","evidence":"Co-IP ubiquitination assays, ChIP for ERα, siRNA, and xenograft/ex vivo endothelial models","pmids":["31662448","30602302"],"confidence":"Medium","gaps":["E3 ligase cooperating with UBE2C on p53/pVHL not identified","Direct vs indirect ubiquitination not fully resolved"]},{"year":2022,"claim":"Identified E2F1/KAT2A-mediated histone acetylation as a transcriptional driver of UBE2C, alongside lower-confidence reports of EGFR-stabilizing glycolytic roles.","evidence":"ChIP/H3K9ac analysis, co-localization, RNA-seq, and co-IP/metabolic assays in cancer cells","pmids":["36292703","35837197"],"confidence":"Medium","gaps":["EGFR-binding role (#21) is Low-confidence with limited mechanistic depth","Whether KAT2A/E2F1 control is generalizable across tumors untested"]},{"year":2023,"claim":"Defined the UBE2C-APC/C-CDH1-DEPTOR-mTOR oncogenic cascade by genetic epistasis and added SIRT1 as a K48-linked degradation substrate controlling autophagy.","evidence":"Conditional double-knockout rescue in KrasG12D mice, K11/K48-linkage ubiquitylation assays, ChIP for H4K16ac, and autophagy flux/xenograft assays","pmids":["36548081","36930831"],"confidence":"High","gaps":["SIRT1 axis (#15) is single-lab Medium-confidence","Whether DEPTOR targeting is APC/C-dependent in non-lung contexts untested"]},{"year":2024,"claim":"Revealed substrate-level ubiquitin-linkage crosstalk: UBE2C monoubiquitinates SNAT2 to block its K63-polyubiquitination and endocytosis, driving metabolic and metastatic phenotypes; lower-confidence reports add Notch and NRF2 axes.","evidence":"Site-specific ubiquitination mutagenesis, endocytosis and lymphangiogenesis assays, PDX models, plus reporter/rescue assays for Notch and KEAP1-NRF2","pmids":["38949026","39353974","39032892"],"confidence":"High","gaps":["Notch (#20) and NRF2 (#22) axes are Low-confidence with indirect mechanism","Cognate E3 ligase for SNAT2 monoubiquitination not defined"]},{"year":null,"claim":"How UBE2C achieves substrate selectivity across its many reported non-APC/C targets, and which E3 ligases partner with it in each context, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of UBE2C bound to APC/C or to alternative E3s","Cognate E3s for p53, pVHL, SIRT1, and SNAT2 ubiquitination largely unidentified","Mechanism by which UBE2C reportedly regulates transcription (ZEB1/2) is unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,14,16]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,3,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,14,15,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,12,14,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,13]}],"complexes":["APC/C"],"partners":["APC/C","CDC20","CDH1","DEPTOR","SAG/RBX2","P53","PVHL","SIRT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00762","full_name":"Ubiquitin-conjugating enzyme E2 C","aliases":["(E3-independent) E2 ubiquitin-conjugating enzyme C","E2 ubiquitin-conjugating enzyme C","UbcH10","Ubiquitin carrier protein C","Ubiquitin-protein ligase C"],"length_aa":179,"mass_kda":19.7,"function":"Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'- and 'Lys-48'-linked polyubiquitination. Acts as an essential factor of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated ubiquitin ligase that controls progression through mitosis. 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34331954","citation_count":20,"is_preprint":false},{"pmid":"20529090","id":"PMC_20529090","title":"RNA interference-mediated silencing of UBCH10 gene inhibits colorectal cancer cell growth in vitro and in vivo.","date":"2010","source":"Clinical and experimental pharmacology & physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20529090","citation_count":18,"is_preprint":false},{"pmid":"33223052","id":"PMC_33223052","title":"UBE2C mRNA expression controlled by miR-300 and HuR determines its oncogenic role in gastric cancer.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33223052","citation_count":18,"is_preprint":false},{"pmid":"29575713","id":"PMC_29575713","title":"Functional transcriptomic annotation and protein-protein interaction analysis identify EZH2 and UBE2C as key upregulated proteins in ovarian cancer.","date":"2018","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29575713","citation_count":18,"is_preprint":false},{"pmid":"37848988","id":"PMC_37848988","title":"Identification of transcriptome characteristics of granulosa cells and the possible role of UBE2C in the pathogenesis of premature ovarian insufficiency.","date":"2023","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/37848988","citation_count":18,"is_preprint":false},{"pmid":"20544706","id":"PMC_20544706","title":"UbcH10 expression on thyroid fine-needle aspirates.","date":"2010","source":"Cancer cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/20544706","citation_count":17,"is_preprint":false},{"pmid":"38949026","id":"PMC_38949026","title":"UBE2C-induced crosstalk between mono- and polyubiquitination of SNAT2 promotes lymphatic metastasis in bladder cancer.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38949026","citation_count":16,"is_preprint":false},{"pmid":"35615976","id":"PMC_35615976","title":"UBE2C triggers HIF-1α-glycolytic flux in head and neck squamous cell carcinoma.","date":"2022","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35615976","citation_count":16,"is_preprint":false},{"pmid":"38348716","id":"PMC_38348716","title":"Curcumin inhibits prostate cancer by upregulating miR-483-3p and inhibiting UBE2C.","date":"2024","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38348716","citation_count":16,"is_preprint":false},{"pmid":"35866591","id":"PMC_35866591","title":"Overexpressed lncRNA FTX promotes the cell viability, proliferation, migration and invasion of renal cell carcinoma via FTX/miR‑4429/UBE2C axis.","date":"2022","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/35866591","citation_count":16,"is_preprint":false},{"pmid":"39032892","id":"PMC_39032892","title":"UBE2C regulates the KEAP1/NRF2 signaling pathway to promote the growth of gastric cancer by inhibiting autophagy.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39032892","citation_count":14,"is_preprint":false},{"pmid":"29576589","id":"PMC_29576589","title":"Contributions of UBE2C and UBE2S to meiotic progression of porcine oocytes.","date":"2018","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/29576589","citation_count":14,"is_preprint":false},{"pmid":"33782624","id":"PMC_33782624","title":"The clinical significance of <em>UBE2C</em> gene in progression of renal cell carcinoma.","date":"2021","source":"European journal of histochemistry : EJH","url":"https://pubmed.ncbi.nlm.nih.gov/33782624","citation_count":13,"is_preprint":false},{"pmid":"22095464","id":"PMC_22095464","title":"A study of UbcH10 expression and its association with recurrence of meningiomas.","date":"2011","source":"Journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22095464","citation_count":12,"is_preprint":false},{"pmid":"15749827","id":"PMC_15749827","title":"A novel UbcH10-binding protein facilitates the ubiquitinylation of cyclin B in vitro.","date":"2005","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15749827","citation_count":12,"is_preprint":false},{"pmid":"26000042","id":"PMC_26000042","title":"High EGFR_1 Inside-Out Activated Inflammation-Induced Motility through SLC2A1-CCNB2-HMMR-KIF11-NUSAP1-PRC1-UBE2C.","date":"2015","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26000042","citation_count":12,"is_preprint":false},{"pmid":"37580802","id":"PMC_37580802","title":"Comprehensive analysis of UBE2C expression and its potential roles and mechanisms in hepatocellular carcinoma.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/37580802","citation_count":11,"is_preprint":false},{"pmid":"33008389","id":"PMC_33008389","title":"KIAA0101 and UbcH10 interact to regulate non-small cell lung cancer cell proliferation by disrupting the function of the spindle assembly checkpoint.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33008389","citation_count":11,"is_preprint":false},{"pmid":"34488675","id":"PMC_34488675","title":"Overexpression of UBE2C in esophageal squamous cell carcinoma tissues and molecular analysis.","date":"2021","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34488675","citation_count":11,"is_preprint":false},{"pmid":"34257576","id":"PMC_34257576","title":"LncRNA MALAT1 Regulating Lung Carcinoma Progression via the miR-491-5p/UBE2C Axis.","date":"2021","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/34257576","citation_count":11,"is_preprint":false},{"pmid":"39353974","id":"PMC_39353974","title":"The activation of the Notch signaling pathway by UBE2C promotes the proliferation and metastasis of hepatocellular carcinoma.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39353974","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53523,"output_tokens":6143,"usd":0.126357,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14817,"output_tokens":4608,"usd":0.094643,"stage2_stop_reason":"end_turn"},"total_usd":0.221,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"UbcH10 (UBE2C) functions as a cyclin-selective ubiquitin carrier protein (E2) that works with the APC/cyclosome E3 ligase to ubiquitinate cyclin B, driving its destruction. Mutation of the catalytic cysteine to serine creates a dominant-negative that blocks cyclin A and B ubiquitination and destruction in vitro. In mammalian cells, dominant-negative UbcH10 arrests cells in M phase and inhibits anaphase onset, demonstrating roles in both cyclin B degradation (cdc2 inactivation) and sister chromatid separation.\",\n      \"method\": \"In vitro ubiquitination assay in clam oocyte extracts; active-site mutagenesis (Cys→Ser); transfection of dominant-negative into mammalian cells with cell cycle readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in vitro with active-site mutagenesis plus functional cell-based validation; foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"9122200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of UbcH10 at 1.95 Å resolution (active-site Cys→Ser mutant) revealed that the N-terminal extension is disordered and that a conserved 3(10)-helix positions a lysine residue near the active site. Mutagenesis showed that this lysine near the active site significantly affects ubiquitin-adduct formation, whereas the N-terminal extension has little effect on ubiquitin charging.\",\n      \"method\": \"X-ray crystallography at 1.95 Å; active-site and lysine mutagenesis with ubiquitin-adduct formation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro biochemical validation in a single study\",\n      \"pmids\": [\"11927573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UbcH10 is preferentially used by the APC/C over other E2s owing to its core E2 domain. Its unique N-terminal extension provides an additional E2-E3 regulatory interaction that limits APC/C activity: mutating the N terminus increases substrate ubiquitination, broadens lysine targeting on substrates, allows destruction of substrates lacking destruction boxes, confers resistance to APC inhibitors Emi1 and BubR1 in vitro, and bypasses the spindle checkpoint in vivo. Fusing the UbcH10 N terminus to UbcH5 restricts ubiquitination without directing APC-specific interactions.\",\n      \"method\": \"In vitro APC ubiquitination assays with UbcH10 N-terminal mutants; spindle checkpoint bypass assay in vivo; domain-swap experiments (UbcH10 N-term fused to UbcH5)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro and in vivo methods with mutagenesis in a single rigorous study\",\n      \"pmids\": [\"18722180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of UbcH10 in transgenic mice leads to precocious APC/C-mediated degradation of cyclin B, supernumerary centrioles, lagging chromosomes, aneuploidy, and spontaneous tumor formation, identifying UbcH10 as a proto-oncogene that causes whole chromosome instability.\",\n      \"method\": \"Graded transgenic mouse overexpression; immunofluorescence; tumor incidence monitoring; carcinogen challenge\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with multiple cellular and organismal phenotypic readouts, replicated across expression levels\",\n      \"pmids\": [\"20065091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A novel UbcH10-binding protein (H10BH) identified by yeast two-hybrid possesses a HECT-like domain, exhibits self-ubiquitinylation activity, binds UbcH10 through residues 235–257, binds cyclin B, and ubiquitinylates cyclin B in vitro, suggesting it acts as a HECT-type E3 using UbcH10 as its cognate E2.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; in vitro ubiquitinylation assay of cyclin B\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — yeast two-hybrid plus in vitro ubiquitinylation assay, single lab, no independent replication\",\n      \"pmids\": [\"15749827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cdc20 transcriptionally up-regulates UBE2C expression in a cell-cycle-specific manner. The WD40 domain of Cdc20 is required for this activity, and Cdc20 physically interacts with the APC/C-CBP/p300 complex, which is then recruited to the UBE2C promoter to drive transactivation.\",\n      \"method\": \"Chromatin immunoprecipitation; co-immunoprecipitation; promoter-reporter assays; domain-deletion analysis; cell cycle synchronization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, and reporter assays in a single lab with multiple complementary methods\",\n      \"pmids\": [\"21454660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nitric oxide (NO) decreases UBE2C protein levels in vascular smooth muscle cells by increasing its polyubiquitination, leading to proteasomal degradation of UBE2C. This mechanism is associated with inhibition of VSMC proliferation and reduced neointimal hyperplasia in vivo.\",\n      \"method\": \"Western blotting; immunofluorescent staining; siRNA knockdown; plasmid overexpression; balloon-injury rat carotid artery model; polyubiquitin detection by co-immunoprecipitation\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with detection of polyubiquitinated UBE2C; single lab\",\n      \"pmids\": [\"21448667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PI3K/AKT-phosphorylated MED1 is recruited to CRPC-specific UBE2C enhancers, mediates long-range enhancer-promoter chromatin looping at the UBE2C locus, and recruits FoxA1, RNA polymerase II, and TATA-binding protein, driving UBE2C overexpression in castration-resistant prostate cancer.\",\n      \"method\": \"Chromatin immunoprecipitation; chromosome conformation capture (3C/looping assays); MED1 phosphorylation analysis; siRNA knockdown; cell growth assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and chromosome conformation capture provide direct mechanistic evidence; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21556051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UBE2C (Ube2C) and UBE2S, together with UBE2D3, act as the E2 ubiquitin-conjugating enzymes regulating APC/C activity during meiosis I in mouse oocytes. Depletion of Ube2C reduces first polar body extrusion by ~50%; overexpression accelerates and doubles completion. High Ube2C levels override the spindle assembly checkpoint to drive meiotic exit regardless of spindle formation.\",\n      \"method\": \"RNA injection (depletion and overexpression); first polar body extrusion assay; spindle formation assessment in mouse oocytes\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss- and gain-of-function in a defined biological system with quantitative phenotypic readout; single lab\",\n      \"pmids\": [\"26207029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wild-type p53 transcriptionally represses UBE2C in a p21-E2F4-dependent manner, whereas gain-of-function (GOF) mutant p53 transcriptionally activates UBE2C in an NF-Y-dependent manner. DNA damage-induced wild-type p53 causes spindle assembly checkpoint arrest by repressing UBE2C; GOF mutant p53 causes premature anaphase exit by increasing UBE2C expression.\",\n      \"method\": \"Promoter-reporter assays; chromatin immunoprecipitation; siRNA knockdown; cell cycle analysis after DNA damage (5-fluorouracil)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays with functional cell cycle readout; single lab, multiple methods\",\n      \"pmids\": [\"27129209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SAG/RBX2 E3 ligase preferentially binds E2s UBCH10 and UBE2S (which mediate K11-linked ubiquitin chains) rather than CDC34 or UBCH5C (K48 linkage). SAG-CUL5 promotes K11-linked ubiquitylation and degradation of β-TrCP1; silencing of UBCH10 or UBE2S (but not UBCH5C) causes β-TrCP1 accumulation, identifying β-TrCP1 as a physiological substrate of the SAG-UBCH10/UBE2S axis.\",\n      \"method\": \"Co-immunoprecipitation; in vitro ubiquitylation assay; siRNA knockdown; protein half-life (CHX chase) assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and in vitro ubiquitylation with siRNA validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27910872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXM1 directly binds the UBE2C promoter and transcriptionally activates UBE2C expression. Site-directed mutations in the FOXM1-binding site markedly reduce UBE2C promoter activity. FOXM1 and UBE2C expression are positively correlated across 25 tumor types.\",\n      \"method\": \"Chromatin immunoprecipitation; promoter-reporter assay with site-directed mutagenesis; siRNA knockdown; gene expression correlation analysis\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and mutagenesis-based reporter assay provide direct transcriptional evidence; single lab\",\n      \"pmids\": [\"29596365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UBE2C promotes ubiquitination and degradation of p53 in endometrial cancer cells, thereby reducing p53 and p21 levels and enabling EMT. Estradiol induces UBE2C expression via estrogen receptor α, which directly binds the UBE2C promoter element. p53 overexpression reverses UBE2C-driven EMT.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; ChIP (ERα binding to UBE2C promoter); Western blotting; siRNA knockdown; in vivo xenograft\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP ubiquitination assay and ChIP in a single lab with functional rescue experiments\",\n      \"pmids\": [\"31662448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UBE2C increases HIF-1α levels by ubiquitinating and promoting degradation of pVHL (von Hippel-Lindau protein), thereby promoting endothelial inflammation and endothelial-mesenchymal transition in aortic valve endothelial cells exposed to disturbed flow.\",\n      \"method\": \"Ubiquitination/co-immunoprecipitation assays; Western blotting; siRNA knockdown; flow-conditioning of human AV endothelial cells; porcine AV leaflet ex vivo model\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination assay for pVHL plus functional in vitro and ex vivo validation; single lab\",\n      \"pmids\": [\"30602302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBE2C couples with APC/C-CDH1 to promote K11-linked ubiquitylation and degradation of DEPTOR, leading to mTORC1 pathway activation. DEPTOR levels oscillate during the cell cycle in a UBE2C- and CDH1-dependent manner. In a KrasG12D lung tumor model, Ube2c deletion inhibited tumor formation; Deptor deletion fully rescued this inhibitory effect, establishing a causal UBE2C→CDH1→DEPTOR→mTOR oncogenic cascade.\",\n      \"method\": \"In vivo conditional knockout (Ube2c and Deptor deletions in KrasG12D mice); ubiquitylation assay (K11-linkage); co-immunoprecipitation; cell cycle synchronization with protein level tracking\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitylation assay plus rigorous in vivo genetic epistasis (double KO rescue) in a single study\",\n      \"pmids\": [\"36548081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBE2C mediates K48-linked ubiquitination of SIRT1, promoting its proteasomal degradation. Loss of SIRT1 reduces H4K16 deacetylation, epigenetically repressing autophagy-related gene expression. This UBE2C-SIRT1-autophagy axis contributes to endometrial cancer progression, and rapamycin (autophagy agonist) reverses tumor growth caused by UBE2C overexpression.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitin immunoprecipitation (K48 linkage); autophagic flux assays (mRFP-GFP-LC3, bafilomycin A1); ChIP for H4K16 acetylation; xenograft model\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP ubiquitination with linkage specificity, ChIP, and functional rescue; single lab, multiple methods\",\n      \"pmids\": [\"36930831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2C mediates monoubiquitination of SNAT2 at K59, which competitively inhibits K63-linked polyubiquitination of SNAT2 at K33. This monoubiquitination/K63-polyubiquitination crosstalk suppresses EPN1-mediated endocytosis of SNAT2, increasing SNAT2 membrane levels, enhancing glutamine uptake and VEGFC secretion, and promoting lymphangiogenesis and lymph node metastasis in bladder cancer.\",\n      \"method\": \"High-throughput sequencing; site-specific ubiquitination assays (K59 and K33 mutants); co-immunoprecipitation; endocytosis assay; patient-derived xenograft model; in vitro and in vivo lymphangiogenesis assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific mutagenesis of ubiquitination sites, mechanistic co-IP, and in vivo PDX validation in a single rigorous study\",\n      \"pmids\": [\"38949026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In HPV-16 E6/E7-expressing keratinocytes, elevated levels of UbcH10 and Cdc20 drive APC/C-dependent cyclin B degradation, allowing these cells to exit mitosis in the presence of DNA damage and bypass the spindle assembly checkpoint.\",\n      \"method\": \"Western blotting; co-immunoprecipitation (Cdc20-BubR1 complexes); cell cycle analysis; cyclin B stability assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical co-IP and cell cycle readout linking UbcH10 elevation to checkpoint bypass; single lab\",\n      \"pmids\": [\"20739533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KAT2A cooperates with E2F1 and is recruited by E2F1 to the UBE2C promoter; this increases H3K9 acetylation at the UBE2C locus, elevating UBE2C transcription and promoting cancer cell proliferation and migration.\",\n      \"method\": \"ChIP assay; immunofluorescence co-localization; RNA-seq; qRT-PCR; Western blotting; cell proliferation/migration assays\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct histone acetylation at UBE2C promoter by KAT2A/E2F1; single lab, multiple methods\",\n      \"pmids\": [\"36292703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UBE2C directly binds to the 5'-UTR of ZEB1 and ZEB2 transcripts (confirmed by ChIP and luciferase reporter assay), transcriptionally promoting their expression to drive EMT and cisplatin resistance in NSCLC cells.\",\n      \"method\": \"Chromatin immunoprecipitation; luciferase reporter assay; siRNA knockdown; Western blotting; cell migration/invasion assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and luciferase assay support binding claim, but mechanism of UBE2C acting as transcriptional regulator of ZEB1/2 5'-UTR is unusual and not independently replicated\",\n      \"pmids\": [\"31037155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2C activates Notch signaling in hepatocellular carcinoma by upregulating N1ICD and Hes1 and activating the RBP-JK luciferase reporter. Notch inhibitor DAPT abrogates UBE2C-driven oncogenic phenotypes, and N1ICD overexpression rescues the effect of UBE2C knockdown.\",\n      \"method\": \"RBP-JK luciferase reporter assay; Western blotting; siRNA knockdown and overexpression; Notch inhibitor rescue experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter assay and pharmacological rescue, single lab, no direct biochemical mechanism for how UBE2C activates Notch\",\n      \"pmids\": [\"39353974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UBE2C binds to EGFR, stabilizing it and promoting PI3K-Akt pathway activation in pancreatic cancer cells; UBE2C knockdown impairs glucose uptake, lactate production, and ATP generation, linking UBE2C to glycolytic reprogramming via EGFR stabilization.\",\n      \"method\": \"Co-immunoprecipitation; qRT-PCR; glycolysis metabolite assays (glucose uptake, lactate, ATP); Western blotting; siRNA knockdown\",\n      \"journal\": \"Journal of gastrointestinal oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP for EGFR binding and functional metabolic assays; single lab, limited mechanistic depth\",\n      \"pmids\": [\"35837197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2C inhibits gastric cancer cell autophagy by promoting accumulation of p62, which increases p62-KEAP1 interaction and thereby reduces KEAP1-NRF2 binding, weakening NRF2 ubiquitination and degradation and causing nuclear accumulation of NRF2. TBHQ (NRF2 activator) rescues proliferation/migration inhibited by UBE2C silencing.\",\n      \"method\": \"Co-immunoprecipitation; Western blotting; autophagy flux assay; siRNA knockdown and overexpression; rescue with NRF2 activator\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and rescue experiments; single lab, indirect mechanistic chain\",\n      \"pmids\": [\"39032892\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBE2C (UbcH10) is the mitosis-specific E2 ubiquitin-conjugating enzyme that works with the APC/C E3 ligase—activated by Cdc20 or CDH1—to catalyze K11-linked ubiquitin chain assembly on cyclin A, cyclin B, securin, DEPTOR, and other substrates, driving their proteasomal degradation to coordinate metaphase-to-anaphase transition, mitotic exit, and spindle assembly checkpoint control; its unique disordered N-terminal extension restricts APC/C activity and substrate selectivity, it also ubiquitinates non-APC/C targets (p53, SIRT1, pVHL, SNAT2) in cancer contexts to regulate EMT, autophagy, and HIF-1α signaling, and its transcription is directly activated by Cdc20-APC/C-CBP/p300 recruitment, FOXM1, E2F1/KAT2A, and estrogen receptor α, placing it at the nexus of cell cycle progression and oncogenic gene regulatory networks.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBE2C (UbcH10) is the cyclin-selective E2 ubiquitin-conjugating enzyme that partners with the APC/C E3 ligase to drive ubiquitination and proteasomal destruction of mitotic substrates including cyclin B, controlling cdc2 inactivation, sister chromatid separation, and anaphase onset [#0]. Its catalytic cysteine is essential, and a conserved lysine near the active site governs ubiquitin-adduct formation, while a disordered N-terminal extension acts as a regulatory brake on APC/C: removing it broadens substrate lysine targeting, permits destruction of substrates lacking destruction boxes, confers resistance to the APC inhibitors Emi1 and BubR1, and bypasses the spindle assembly checkpoint [#1, #2]. Through APC/C-Cdc20 and APC/C-CDH1 it builds K11-linked chains on cell-cycle regulators, and this activity extends to DEPTOR, whose degradation activates mTORC1 in a UBE2C\\u2192CDH1\\u2192DEPTOR\\u2192mTOR oncogenic cascade demonstrated by genetic epistasis in KrasG12D lung tumors [#14]. Overexpression of UBE2C causes precocious cyclin B degradation, supernumerary centrioles, aneuploidy, and spontaneous tumors, defining it as a proto-oncogene driving whole-chromosome instability [#3]. UBE2C transcription is a convergence point for proliferative and oncogenic inputs, directly activated by Cdc20-recruited APC/C-CBP/p300, FOXM1, E2F1/KAT2A, estrogen receptor \\u03b1, and CRPC-specific MED1/FoxA1 enhancer looping, and repressed by wild-type p53 [#5, #7, #9, #11, #12, #18]. Beyond canonical APC/C substrates, UBE2C ubiquitinates p53, pVHL, SIRT1, and SNAT2 in cancer contexts to promote EMT, HIF-1\\u03b1 signaling, autophagy repression, and metabolic reprogramming [#12, #13, #15, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established UBE2C as the catalytic E2 enzyme that, with the APC/cyclosome, drives mitotic cyclin destruction\\u2014answering what enzyme couples ubiquitin transfer to anaphase onset.\",\n      \"evidence\": \"In vitro ubiquitination in clam oocyte extracts, active-site Cys\\u2192Ser mutagenesis, and dominant-negative transfection with cell cycle readout\",\n      \"pmids\": [\"9122200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of E2 catalysis\", \"Substrate selectivity beyond cyclins A/B not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the structural determinants of UBE2C catalysis, showing an active-site-proximal lysine controls ubiquitin charging while the N-terminal extension is dispensable for charging.\",\n      \"evidence\": \"X-ray crystallography at 1.95 \\u00c5 of the Cys\\u2192Ser mutant with lysine mutagenesis and adduct-formation assays\",\n      \"pmids\": [\"11927573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of the disordered N-terminal extension left unexplained\", \"No structure in complex with APC/C\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed that the N-terminal extension is a regulatory element restricting APC/C substrate selectivity and enforcing the spindle checkpoint, explaining why APC/C prefers UBE2C.\",\n      \"evidence\": \"In vitro APC ubiquitination with N-terminal mutants, in vivo spindle-checkpoint bypass, and UbcH10-UbcH5 domain swaps\",\n      \"pmids\": [\"18722180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the N-terminus-APC/C interaction not resolved\", \"Chain-linkage specificity not characterized here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated UBE2C is a bona fide proto-oncogene, causally linking its overexpression to chromosomal instability and tumorigenesis in vivo.\",\n      \"evidence\": \"Graded transgenic mouse overexpression with immunofluorescence, aneuploidy scoring, and tumor incidence/carcinogen challenge\",\n      \"pmids\": [\"20065091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Non-APC/C substrates driving transformation not identified\", \"Molecular trigger of centriole amplification unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected UBE2C dysregulation to viral oncogenesis, showing elevated UbcH10/Cdc20 enables mitotic exit despite DNA damage.\",\n      \"evidence\": \"Western blot, Cdc20-BubR1 co-IP, and cyclin B stability/cell cycle analysis in HPV-16 E6/E7 keratinocytes\",\n      \"pmids\": [\"20739533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional driver of UbcH10 induction by E6/E7 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified transcriptional and post-translational control of UBE2C levels: Cdc20-APC/C-CBP/p300 transactivates it, MED1 enhancer looping drives it in CRPC, and NO promotes its proteasomal degradation.\",\n      \"evidence\": \"ChIP, co-IP, promoter-reporter, 3C looping assays, and polyubiquitin detection across cancer cells and a rat carotid-injury model\",\n      \"pmids\": [\"21454660\", \"21556051\", \"21448667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating NO-induced UBE2C degradation unknown\", \"Generality of MED1 looping beyond CRPC untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended UBE2C's APC/C role from mitosis to meiosis, showing it gates meiotic exit and can override the spindle checkpoint in oocytes.\",\n      \"evidence\": \"RNA-injection depletion/overexpression with polar body extrusion and spindle assessment in mouse oocytes\",\n      \"pmids\": [\"26207029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of UBE2C vs UBE2S/UBE2D3 not fully separated\", \"Substrate specificity in meiosis unaddressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed UBE2C under p53 control and within a broader K11-chain E3 network, identifying SAG/RBX2-CUL5 as an additional E3 partner targeting \\u03b2-TrCP1.\",\n      \"evidence\": \"Promoter-reporter, ChIP, reciprocal co-IP, in vitro ubiquitylation, and CHX-chase across cancer cells\",\n      \"pmids\": [\"27129209\", \"27910872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SAG-UBE2C cooperation occurs in physiological cell-cycle context unclear\", \"p53-UBE2C axis tested in limited contexts\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined FOXM1 as a direct transcriptional activator of UBE2C correlated across tumor types, and reported an unusual transcriptional regulatory activity of UBE2C on ZEB1/ZEB2.\",\n      \"evidence\": \"ChIP, mutagenesis-based reporter assays, expression correlation, and luciferase reporter/migration assays\",\n      \"pmids\": [\"29596365\", \"31037155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The ZEB1/2 finding (#19) is Low-confidence and mechanistically atypical, not independently replicated\", \"How an E2 enzyme acts as a transcriptional regulator is unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established non-APC/C ubiquitination substrates of UBE2C in cancer\\u2014p53 and pVHL\\u2014linking it to EMT and HIF-1\\u03b1 signaling, with ER\\u03b1 driving its expression.\",\n      \"evidence\": \"Co-IP ubiquitination assays, ChIP for ER\\u03b1, siRNA, and xenograft/ex vivo endothelial models\",\n      \"pmids\": [\"31662448\", \"30602302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase cooperating with UBE2C on p53/pVHL not identified\", \"Direct vs indirect ubiquitination not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified E2F1/KAT2A-mediated histone acetylation as a transcriptional driver of UBE2C, alongside lower-confidence reports of EGFR-stabilizing glycolytic roles.\",\n      \"evidence\": \"ChIP/H3K9ac analysis, co-localization, RNA-seq, and co-IP/metabolic assays in cancer cells\",\n      \"pmids\": [\"36292703\", \"35837197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EGFR-binding role (#21) is Low-confidence with limited mechanistic depth\", \"Whether KAT2A/E2F1 control is generalizable across tumors untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the UBE2C-APC/C-CDH1-DEPTOR-mTOR oncogenic cascade by genetic epistasis and added SIRT1 as a K48-linked degradation substrate controlling autophagy.\",\n      \"evidence\": \"Conditional double-knockout rescue in KrasG12D mice, K11/K48-linkage ubiquitylation assays, ChIP for H4K16ac, and autophagy flux/xenograft assays\",\n      \"pmids\": [\"36548081\", \"36930831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SIRT1 axis (#15) is single-lab Medium-confidence\", \"Whether DEPTOR targeting is APC/C-dependent in non-lung contexts untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed substrate-level ubiquitin-linkage crosstalk: UBE2C monoubiquitinates SNAT2 to block its K63-polyubiquitination and endocytosis, driving metabolic and metastatic phenotypes; lower-confidence reports add Notch and NRF2 axes.\",\n      \"evidence\": \"Site-specific ubiquitination mutagenesis, endocytosis and lymphangiogenesis assays, PDX models, plus reporter/rescue assays for Notch and KEAP1-NRF2\",\n      \"pmids\": [\"38949026\", \"39353974\", \"39032892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Notch (#20) and NRF2 (#22) axes are Low-confidence with indirect mechanism\", \"Cognate E3 ligase for SNAT2 monoubiquitination not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBE2C achieves substrate selectivity across its many reported non-APC/C targets, and which E3 ligases partner with it in each context, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of UBE2C bound to APC/C or to alternative E3s\", \"Cognate E3s for p53, pVHL, SIRT1, and SNAT2 ubiquitination largely unidentified\", \"Mechanism by which UBE2C reportedly regulates transcription (ZEB1/2) is unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 14, 16]},\n      {\"term_id\": \"GO:0061631\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 3, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 14, 15, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 12, 14, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 13]}\n    ],\n    \"complexes\": [\"APC/C\"],\n    \"partners\": [\"APC/C\", \"CDC20\", \"CDH1\", \"DEPTOR\", \"SAG/RBX2\", \"p53\", \"pVHL\", \"SIRT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}