{"gene":"MYC","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1998,"finding":"c-MYC is a transcriptional target of the APC/beta-catenin/Tcf-4 signaling pathway; wild-type APC represses c-MYC expression while beta-catenin activates it through Tcf-4 binding sites in the c-MYC promoter.","method":"Reporter assay with Tcf-4 binding site mutations, expression manipulation of APC and beta-catenin","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter reporter assays with defined binding site mutations, reciprocal gain/loss-of-function, widely replicated finding","pmids":["9727977"],"is_preprint":false},{"year":2005,"finding":"c-Myc directly binds and activates transcription of the miR-17-92 miRNA cluster on human chromosome 13 (confirmed by ChIP); two members of this cluster, miR-17-5p and miR-20a, negatively regulate translation of E2F1, revealing a feed-forward loop in which c-Myc simultaneously activates E2F1 transcription and limits its translation.","method":"Chromatin immunoprecipitation (ChIP), reporter assay, miRNA functional assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct ChIP binding evidence combined with functional miRNA assays, widely cited and replicated","pmids":["15944709"],"is_preprint":false},{"year":2012,"finding":"In tumor cells with elevated c-Myc, the protein accumulates at promoters of already-active genes and causes transcriptional amplification (increased output of the existing gene expression program) rather than activating a new set of target genes.","method":"ChIP-seq, global transcriptome profiling, comparison of high vs. normal c-Myc expressing tumor cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with transcriptome readout, multiple cell lines, rigorous quantitative analysis","pmids":["23021215"],"is_preprint":false},{"year":2010,"finding":"c-Myc promotes gene expression primarily by stimulating release of promoter-proximally paused RNA polymerase II (Pol II) rather than by recruiting Pol II to promoters.","method":"ChIP-seq for Pol II pausing, GRO-seq, genetic manipulation of c-Myc levels","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genome-wide orthogonal methods (ChIP-seq, GRO-seq) in the same study","pmids":["20434984"],"is_preprint":false},{"year":2007,"finding":"c-Myc has a direct, non-transcriptional role in DNA replication: it interacts with the pre-replicative complex, localizes to early replication sites, and is required for replication initiation in mammalian cells and Xenopus cell-free extracts. Overexpression increases origin firing, causing DNA damage and checkpoint activation.","method":"Co-immunoprecipitation with pre-RC components, localization to replication sites, siRNA depletion in mammalian cells and Xenopus cell-free extract (devoid of RNA transcription)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — cell-free transcription-independent system plus mammalian depletion and overexpression, multiple orthogonal methods","pmids":["17597761"],"is_preprint":false},{"year":2005,"finding":"c-Myc and Max interact in nucleoli, associate with ribosomal DNA, and c-Myc recruits TRRAP cofactor, enhances histone acetylation at rDNA, and activates RNA polymerase I transcription in response to mitogenic signals; this activity is separable from Pol II-dependent transcription.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, MycER system with Pol II inhibition, in situ proximity ligation","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including ChIP, siRNA, pharmacological separation of Pol I from Pol II activity, in situ interaction assays","pmids":["15723053"],"is_preprint":false},{"year":1994,"finding":"c-Myc-induced apoptosis is mediated by p53: activation of c-Myc in quiescent wild-type p53 fibroblasts induces apoptosis and stabilizes p53, whereas p53-null fibroblasts undergo cell cycle re-entry but not apoptosis upon c-Myc activation.","method":"Conditional c-Myc activation (estrogen receptor fusion), p53-null vs. wild-type fibroblast comparison, apoptosis and cell cycle assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using isogenic p53-null vs. wild-type cells with conditional c-Myc activation, clean phenotypic readout","pmids":["8091232"],"is_preprint":false},{"year":2003,"finding":"c-Myc binds preferentially to E-box elements (CACGTG) located within CpG islands at promoters in live human cells; these high-affinity sites correlate with an open, pre-acetylated chromatin state and Myc further enhances histone acetylation at these loci.","method":"Quantitative ChIP with bioinformatics selection of E-box-containing promoters; histone acetylation ChIP","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — large-scale quantitative ChIP in live cells with orthogonal chromatin acetylation analysis","pmids":["12695333"],"is_preprint":false},{"year":2007,"finding":"Ribosomal protein L11 (a c-Myc transcriptional target) binds to Myc box II (MBII) of c-Myc, competes with the coactivator TRRAP for this site, reduces histone H4 acetylation at c-Myc target gene promoters, and thereby inhibits c-Myc transcriptional activity and cell proliferation in a negative feedback loop.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, overexpression, cell proliferation assays","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding studies, ChIP with histone modification readout, siRNA knockdown and overexpression, multiple orthogonal methods in one study","pmids":["17599065"],"is_preprint":false},{"year":1990,"finding":"c-Myc protein negatively autoregulates its own transcription: introduction of activated c-myc suppresses endogenous c-myc expression at the level of transcriptional initiation in a concentration-dependent manner requiring additional trans-acting factors.","method":"Transfection of activated c-myc constructs, nuclear run-on transcription assays, dose-response analysis","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — nuclear run-on assays establishing transcriptional level of regulation, dose-response, additional trans-factor requirement demonstrated","pmids":["2182320"],"is_preprint":false},{"year":2016,"finding":"CRY2, acting as a component of an FBXL3-containing E3 ubiquitin ligase complex, recruits T58-phosphorylated c-MYC for ubiquitylation and degradation; CRY1 cannot substitute for CRY2 in this function.","method":"Co-immunoprecipitation, ubiquitylation assays, CRY1/CRY2 genetic and biochemical comparison, phospho-T58 dependency experiments","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution of ubiquitylation, defined phosphodegron requirement, paralog specificity established","pmids":["27840026"],"is_preprint":false},{"year":2008,"finding":"Pim-1 and Pim-2 kinases stabilize c-Myc by phosphorylating it at Ser329 (Pim-2 more directly) and by promoting decreased T58 phosphorylation with increased S62 phosphorylation (Pim-1), thereby inhibiting proteasomal degradation and enhancing c-Myc transcriptional activity.","method":"In vivo phosphorylation assays, site-directed mutagenesis (Ser329, Thr58, Ser62), pulse-chase protein stability, siRNA knockdown, transcriptional reporter assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-directed mutagenesis combined with in vivo phosphorylation assays and stability measurements","pmids":["18438430"],"is_preprint":false},{"year":2001,"finding":"C/EBPα negatively regulates c-Myc expression through an E2F binding site in the c-myc promoter; stable expression of c-Myc from an exogenous promoter not responsive to C/EBPα blocks myeloid differentiation, establishing that C/EBPα-mediated repression of c-Myc is required for granulocytic differentiation.","method":"Promoter mapping, representational difference analysis, oligonucleotide microarray, inducible C/EBPα cell system, stable c-Myc overexpression from exogenous promoter","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (exogenous c-Myc rescue), promoter mapping, two independent screens for target identification","pmids":["11340171"],"is_preprint":false},{"year":2001,"finding":"TGF-β signaling represses c-myc transcription via Smad3 and E2F-4 binding to a composite TIE/E2F element in the c-myc promoter; TGF-β reduces p300 co-immunoprecipitating with E2F-4 without displacing E2F-4 from DNA.","method":"Promoter reporter assays with TIE/E2F site mutations, EMSA, co-immunoprecipitation of Smad3, E2F-4, and p300","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — EMSA, co-IP, promoter mutagenesis, and kinetic binding assays in one study","pmids":["11689553"],"is_preprint":false},{"year":1991,"finding":"c-Myc suppresses MyoD-initiated and myogenin-initiated skeletal muscle differentiation independently of the negative regulator Id, establishing c-Myc and Id as two independent negative regulators of myogenesis.","method":"Transient and stable cotransfection in NIH 3T3 cells; conditional c-Myc induction system; epistasis with MyoD, myogenin, and Id","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — stable conditional system plus epistasis with multiple myogenic factors, clean differentiation phenotype","pmids":["1850105"],"is_preprint":false},{"year":2018,"finding":"SENP1 is a c-Myc deSUMOylating enzyme: it interacts with and deSUMOylates c-Myc in cells and in vitro; catalytically inactive SENP1 (C603S) fails to stabilize c-Myc. SUMOylation of c-Myc promotes its polyubiquitination and proteasomal degradation, while SENP1-mediated deSUMOylation stabilizes c-Myc and promotes its S62 phosphorylation.","method":"In vitro deSUMOylation assay, co-immunoprecipitation, SENP1 catalytic mutant (C603S), ubiquitination assay, siRNA knockdown","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro biochemical assay plus active-site mutagenesis plus cellular ubiquitination assays, multiple orthogonal methods","pmids":["30305424"],"is_preprint":false},{"year":2014,"finding":"USP37 directly binds and deubiquitinates c-Myc in a DUB activity-dependent manner to stabilize it; USP37 overexpression increases c-Myc levels while USP37 depletion promotes c-Myc degradation.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, DUB activity-dependent rescue experiments, siRNA knockdown, overexpression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay plus DUB activity dependence, single lab study","pmids":["25284584"],"is_preprint":false},{"year":2018,"finding":"Eya3 directly interacts with the PP2A-B55α holoenzyme and redirects its phosphatase activity toward pT58 on c-Myc (dephosphorylating T58 to stabilize c-Myc), in contrast to PP2A-B56α which dephosphorylates pS62 to destabilize c-Myc; this Eya3-PP2A-B55α complex promotes metastasis.","method":"Co-immunoprecipitation, phosphatase assays, xenograft metastasis model, phospho-specific immunoblotting","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical phosphatase activity assay combined with co-IP and in vivo xenograft, mechanism distinguishes two PP2A holoenzymes","pmids":["29535359"],"is_preprint":false},{"year":2015,"finding":"FBXO32 (Atrogin-1) acts as an E3 ubiquitin ligase that targets c-Myc for proteasomal degradation via ubiquitination at lysine 326; this regulation is independent of T58/S62 phosphorylation status. FBXO32 is itself a direct transcriptional target of c-Myc, forming a negative feedback loop.","method":"Ubiquitination assay, K326 mutagenesis, co-immunoprecipitation, reporter assay, siRNA knockdown/overexpression","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-directed mutagenesis of ubiquitin acceptor lysine, in vivo ubiquitination assay, feedback loop established","pmids":["25944903"],"is_preprint":false},{"year":2016,"finding":"ELL functions as a novel E3 ubiquitin ligase targeting c-Myc for proteasomal degradation, using UbcH8 as the ubiquitin-conjugating enzyme; cysteine 595 is the active site (C595A mutation abolishes ubiquitination and degradation of c-Myc).","method":"In vivo ubiquitination assay, active-site mutagenesis (C595A), co-immunoprecipitation, xenograft tumor assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — active-site mutagenesis establishes catalytic requirement, ubiquitination assay, in vivo tumor model","pmids":["27009366"],"is_preprint":false},{"year":2013,"finding":"Ribosomal protein S14 (RPS14) interacts with the MBII and bHLH-LZ domains of c-Myc, inhibits c-Myc transcriptional activity by preventing recruitment of c-Myc and TRRAP to target gene promoters, and promotes c-Myc mRNA degradation through an Ago2/miRNA-dependent pathway.","method":"Co-immunoprecipitation (domain mapping), ChIP, siRNA knockdown, luciferase reporter assay","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping co-IP, ChIP, and mRNA degradation pathway assays, single lab","pmids":["23775087"],"is_preprint":false},{"year":1993,"finding":"c-Myc directly induces expression and enzymatic activity of ornithine decarboxylase (ODC) in a manner not requiring de novo protein synthesis, establishing ODC as a direct transcriptional target mediating c-Myc's cell cycle effects.","method":"Conditional MycER activation, ODC mRNA and enzymatic activity assays, cycloheximide treatment to exclude indirect effects","journal":"Cell Growth & Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional system with protein synthesis inhibitor control; single lab","pmids":["8297793"],"is_preprint":false},{"year":2002,"finding":"CK2 (casein kinase II) regulates c-Myc protein stability: pharmacological inhibition or antisense knockdown of CK2 accelerates proteasome-dependent c-Myc protein turnover, while CK2 overexpression increases c-Myc levels.","method":"CK2 inhibitor treatment, sense/antisense CK2 transfection, proteasome inhibitor epistasis, protein stability assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic manipulation with proteasome inhibitor controls, single lab","pmids":["12149649"],"is_preprint":false},{"year":2001,"finding":"PDGF stimulates c-myc promoter activity and expression through a Src-dependent, Ras/MAPK-independent pathway involving Vav2 activation of Rac GTPase.","method":"c-myc promoter reporter assay, dominant-negative constructs for Ras, MEK, Src, Vav2, and Rac; epistasis analysis","journal":"Nature Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis with multiple dominant negatives, promoter reporter assays, single lab","pmids":["11389443"],"is_preprint":false},{"year":1996,"finding":"Endogenous c-Myc and YY1 associate in vivo; c-Myc inhibits YY1 transcriptional activity not by blocking YY1 DNA binding but by interfering with YY1's ability to contact basal transcription factors TBP and TFIIB.","method":"Co-immunoprecipitation of endogenous proteins, gel shift assays for DNA binding, protein-protein interaction assays with TBP and TFIIB","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous co-IP plus mechanistic dissection of TBP/TFIIB interaction, single lab","pmids":["8855231"],"is_preprint":false},{"year":2009,"finding":"c-Myc overexpression accelerates S-phase progression; WRN helicase is required to prevent replication-associated DNA damage in c-Myc-overexpressing cells, as WRN depletion in this context activates ATR-CHK1-CHK2-p53 replication stress signaling and induces senescence rescued by p53 loss.","method":"BrdU incorporation (S-phase timing), WRN siRNA depletion, DNA damage markers (γH2AX at replication sites), pathway inhibition, p53 knockdown rescue","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — replication site-specific DNA damage assay, genetic epistasis with p53 rescue, single lab","pmids":["19554081"],"is_preprint":false},{"year":2006,"finding":"c-Myc overexpression causes anaplastic histopathology in medulloblastoma xenografts, with increased nuclear size, macronucleoli, and elevated indices of proliferation and apoptosis, establishing a causal link between c-Myc and anaplasia.","method":"Stable c-Myc overexpression in medulloblastoma cell lines, subcutaneous xenograft in nude mice, histopathological analysis, proliferation/apoptosis indices","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined gain-of-function in two cell lines with in vivo xenograft phenotype, single lab","pmids":["16423996"],"is_preprint":false},{"year":2009,"finding":"c-MYC directly induces transcription of the AP4 transcription factor, which then represses p21 (CDKN1A) by binding elements near its promoter, thereby interfering with p21 induction by the DNA damage/p53 and TGFβ/Smad pathways.","method":"ChIP, reporter assay, AP4 overexpression/knockdown, epistasis with p53 and TGFβ pathways","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, reporter assay, epistasis experiments, single lab","pmids":["19270520"],"is_preprint":false},{"year":2021,"finding":"IKKα binds c-Myc and phosphorylates it at serines 67 and 71; this phosphorylation stabilizes c-Myc by reducing T58 phosphorylation (the GSK3β target) and consequent polyubiquitination. Phosphomimetic S67D/S71D c-Myc mutants show slower turnover and increased proliferative activity.","method":"Co-immunoprecipitation, FRET microscopy, in vitro kinase assay, cycloheximide chase, CRISPR/Cas9 IKKα knockout, phosphomimetic and non-phosphorylatable mutants","journal":"Molecular Cancer","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay plus active-site mutagenesis plus CRISPR KO plus optical pulse-chase, multiple orthogonal methods in one study","pmids":["33461590"],"is_preprint":false},{"year":2006,"finding":"c-Myc aberrant stabilization in leukemia cell lines correlates with abnormal phosphorylation at T58 and S62 and decreased affinity for GSK3β (the kinase that phosphorylates T58 to trigger degradation), establishing deregulation of the T58/S62 phosphorylation-dependent degradation pathway as a mechanism of c-Myc overexpression in leukemia.","method":"Protein stability (pulse-chase), phospho-specific immunoblotting, GSK3β binding assay, sequencing for c-myc mutations","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulse-chase stability assays, kinase-binding assays, phospho-site analysis; single lab, no mutagenesis rescue","pmids":["16855632"],"is_preprint":false},{"year":2009,"finding":"Nickel compounds and hypoxia degrade c-Myc protein via the 26S proteasome through two mechanisms: (1) increased T58 phosphorylation leading to Fbw7-mediated ubiquitination, and (2) decreased levels of the deubiquitinase USP28 (via transcriptional repression through H3K9 dimethylation and protein degradation), both increasing net c-Myc ubiquitination.","method":"Proteasome inhibitor epistasis, phospho-T58 immunoblotting, USP28 siRNA knockdown, chromatin modification ChIP at USP28 promoter, HIF knockdown epistasis","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway epistasis with siRNA and inhibitors, chromatin modification at USP28 promoter, single lab","pmids":["20046830"],"is_preprint":false},{"year":2014,"finding":"PP2A dephosphorylates c-MYC at serine 62 (S62) to destabilize it; endogenous PP2A inhibitors SET and CIP2A maintain S62 phosphorylation and c-MYC activity in breast cancer; SET antagonist OP449 decreases S62-pMYC and reduces tumorigenic potential.","method":"siRNA knockdown of SET/CIP2A, pharmacological PP2A activation (OP449), phospho-S62 immunoblotting, in vitro and in vivo tumor assays","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-site specific readout with genetic and pharmacological PP2A manipulation, in vivo validation; single lab","pmids":["24927563"],"is_preprint":false},{"year":2014,"finding":"TAZ is a direct transcriptional target of c-MYC; TAZ is required to prevent c-Myc-induced hepatocyte apoptosis during tumor initiation; conditional Taz knockout (but not Yap knockout) completely prevents c-Myc-driven hepatocarcinogenesis and causes tumor regression.","method":"Conditional knockout mice (Taz, Yap, Yap;Taz), ChIP for c-MYC at TAZ promoter, inducible TTR-CreERT2 system, tumor histology","journal":"Journal of Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in conditional knockout mouse models with ChIP confirmation of direct transcriptional target, in vivo tumor regression","pmids":["34464659"],"is_preprint":false},{"year":1995,"finding":"c-Myc protein (complexed with myn/Max) binds to the transcription initiator elements of lambda 5 and TdT promoters and represses their transcriptional activity when c-Myc is overexpressed.","method":"Gel retardation (EMSA), supershift with c-Myc and Max antibodies, cotransfection reporter assay with initiator mutations","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA with supershift plus functional reporter assay, single lab","pmids":["7870572"],"is_preprint":false},{"year":2024,"finding":"USP43 deubiquitinates c-Myc at K148 and K289 in a DUB activity-dependent manner to stabilize it, and also competes with FBXW7 for access to c-Myc; this creates a USP43/c-Myc positive feedback loop promoting glycolysis and bladder cancer progression.","method":"siRNA library screen, co-immunoprecipitation, in vivo ubiquitination assay, site-directed mutagenesis (K148, K289), FBXW7 competition assay","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination site mutagenesis, competition assay with FBXW7, single lab","pmids":["38218970"],"is_preprint":false}],"current_model":"c-Myc is a nuclear bHLH-LZ transcription factor that heterodimerizes with Max to bind E-box elements and activate or repress target genes; it stimulates transcription primarily by releasing promoter-proximally paused RNA Pol II and, at high levels, amplifies the entire active gene expression program; it also activates RNA Pol I-dependent rDNA transcription in the nucleolus and directly engages the pre-replicative complex to promote DNA replication initiation independent of transcription; its protein stability is tightly controlled by sequential phosphorylation at S62 (stabilizing, by Ras/ERK, Pim, IKKα) and T58 (destabilizing, by GSK3β), followed by FBXW7/SCF-mediated ubiquitination and proteasomal degradation, with multiple deubiquitinases (USP28, USP37, USP36, USP43) and the CRY2-FBXL3 E3 ligase also regulating its turnover; additional PTMs including SUMOylation (promoting degradation, reversed by SENP1) and CK2 phosphorylation further modulate stability; upstream, c-MYC expression is transcriptionally activated by the Wnt/β-catenin/Tcf-4, PDGF/Src/Vav2/Rac, and Pim pathways and repressed by APC, TGF-β/Smad3, C/EBPα, and by its own negative autoregulation; c-Myc co-ordinates cell proliferation, ribosome biogenesis, DNA replication, and apoptosis (the latter largely through p53 stabilization), and is subject to negative feedback from ribosomal proteins L11 and S14 that bind MBII and displace the TRRAP coactivator."},"narrative":{"mechanistic_narrative":"c-MYC is a sequence-specific transcription factor that, in complex with Max, binds E-box (CACGTG) elements located within open, pre-acetylated CpG-island promoters and further enhances local histone acetylation, coordinating cell proliferation, ribosome biogenesis, DNA replication, and apoptosis [PMID:12695333, PMID:15723053]. Rather than recruiting RNA Pol II de novo, c-Myc principally stimulates release of promoter-proximally paused Pol II, and when overexpressed in tumor cells it accumulates at already-active promoters to amplify the existing transcriptional program rather than activate new targets [PMID:20434984, PMID:23021215]. Its biosynthetic output extends beyond Pol II: c-Myc and Max localize to nucleoli, associate with rDNA, recruit the TRRAP coactivator, and drive RNA Pol I transcription in a Pol II-independent manner [PMID:15723053], and c-Myc additionally has a transcription-independent role at the pre-replicative complex, localizing to early replication sites and promoting origin firing, with overexpression causing replication-associated DNA damage [PMID:17597761]. Through defined targets, c-Myc activates the miR-17-92 cluster (creating a feed-forward loop with E2F1), ornithine decarboxylase, AP4 (which represses p21), and TAZ, the last being required to suppress c-Myc-induced apoptosis during hepatocarcinogenesis [PMID:15944709, PMID:8297793, PMID:19270520, PMID:34464659]; c-Myc-induced apoptosis itself is mediated through p53 stabilization [PMID:8091232]. c-Myc protein abundance is governed by a phosphorylation-dependent degron in which S62 phosphorylation stabilizes and T58 phosphorylation destabilizes the protein, controlling FBXW7-type ubiquitination; this is tuned by Pim and IKKα kinases that favor S62 over T58 phosphorylation, by PP2A holoenzymes that dephosphorylate either site, by SUMOylation (reversed by SENP1), and by multiple deubiquitinases and alternative E3 ligases [PMID:18438430, PMID:33461590, PMID:29535359, PMID:24927563, PMID:30305424, PMID:38218970, PMID:27009366, PMID:25944903]. Upstream, c-MYC transcription is activated by Wnt/β-catenin/Tcf-4 and PDGF/Src/Vav2/Rac signaling and repressed by TGF-β/Smad3, C/EBPα, and its own negative autoregulation, integrating c-Myc levels into differentiation decisions [PMID:9727977, PMID:11389443, PMID:11689553, PMID:11340171, PMID:2182320].","teleology":[{"year":1990,"claim":"Established that c-Myc controls its own abundance at the transcriptional level, defining negative autoregulation as a homeostatic constraint on Myc dosage.","evidence":"Transfection of activated c-myc with nuclear run-on transcription assays and dose-response analysis","pmids":["2182320"],"confidence":"High","gaps":["Identity of the additional trans-acting factors required was not defined","Did not establish direct DNA binding by Myc at its own promoter"]},{"year":1994,"claim":"Resolved how c-Myc couples proliferation to apoptosis by showing the death output requires p53, separating Myc's cell-cycle and apoptotic functions.","evidence":"Conditional MycER activation in isogenic p53-null vs. wild-type fibroblasts with apoptosis and cell-cycle readouts","pmids":["8091232"],"confidence":"High","gaps":["Molecular route from Myc to p53 stabilization not defined","Did not address which Myc target genes mediate the apoptotic signal"]},{"year":1998,"claim":"Connected c-MYC to a major oncogenic signaling axis by identifying it as a Wnt/β-catenin/Tcf-4 transcriptional target repressed by APC.","evidence":"Promoter reporter assays with Tcf-4 site mutations and reciprocal APC/β-catenin manipulation","pmids":["9727977"],"confidence":"High","gaps":["Did not address cofactor requirements at the c-MYC promoter","Cell-type dependence of this regulation not mapped"]},{"year":2003,"claim":"Defined the genomic logic of Myc binding by showing it prefers E-boxes in CpG islands already in an open, acetylated chromatin state and further increases acetylation there.","evidence":"Quantitative ChIP in live human cells with bioinformatic E-box selection and histone acetylation ChIP","pmids":["12695333"],"confidence":"High","gaps":["Did not establish how chromatin state is read to select sites","Functional consequence of binding for transcription not directly measured here"]},{"year":2005,"claim":"Extended Myc function beyond Pol II by demonstrating direct activation of Pol I-dependent rDNA transcription in nucleoli, linking Myc to ribosome biogenesis.","evidence":"Co-IP, ChIP at rDNA, siRNA, MycER with Pol II inhibition, and in situ proximity ligation","pmids":["15723053"],"confidence":"High","gaps":["Mechanism of Myc recruitment to rDNA not defined","Relative contribution of Pol I vs Pol II activity to growth not quantified"]},{"year":2005,"claim":"Revealed a non-coding-RNA arm of Myc regulation by showing direct activation of the miR-17-92 cluster, which dampens E2F1 translation in a feed-forward loop.","evidence":"ChIP, reporter assays, and miRNA functional assays","pmids":["15944709"],"confidence":"High","gaps":["Did not map the full target set of the cluster in this context","Physiological balance of E2F1 activation vs repression not quantified"]},{"year":2007,"claim":"Uncovered a transcription-independent function: c-Myc engages the pre-replicative complex and drives replication initiation, explaining replication stress upon overexpression.","evidence":"Co-IP with pre-RC components, replication-site localization, and siRNA depletion in mammalian cells and Xenopus cell-free extracts lacking transcription","pmids":["17597761"],"confidence":"High","gaps":["Direct binding partner within the pre-RC not pinned down","Whether this function is genetically separable from transcription in vivo not established"]},{"year":2007,"claim":"Identified a ribosome-to-Myc feedback circuit by showing ribosomal protein L11 binds MBII, displaces TRRAP, and restrains Myc activity.","evidence":"Reciprocal co-IP, ChIP with histone acetylation readout, siRNA and overexpression with proliferation assays","pmids":["17599065"],"confidence":"High","gaps":["Stoichiometry of L11 vs TRRAP competition in vivo not defined","Scope of target genes affected not genome-wide mapped"]},{"year":2010,"claim":"Clarified the core transcriptional mechanism by showing Myc acts mainly through pause release of Pol II rather than Pol II recruitment.","evidence":"Pol II ChIP-seq, GRO-seq, and genetic manipulation of Myc levels","pmids":["20434984"],"confidence":"High","gaps":["Direct pause-release effector recruited by Myc not identified here","Did not address gene-selectivity of the pause-release effect"]},{"year":2012,"claim":"Reframed oncogenic Myc action by showing that at high levels it amplifies the existing active program genome-wide rather than activating a distinct target set.","evidence":"ChIP-seq and global transcriptome profiling in high vs normal Myc tumor cells","pmids":["23021215"],"confidence":"High","gaps":["Did not reconcile amplification model with selective target activation at physiologic levels","Determinants of which active genes are amplified not fully defined"]},{"year":2016,"claim":"Defined the canonical degron logic and a circadian E3 input by showing CRY2-FBXL3 recognizes T58-phosphorylated Myc, with CRY1 unable to substitute.","evidence":"Co-IP, ubiquitylation assays, phospho-T58 dependency, and CRY1/CRY2 paralog comparison","pmids":["27840026"],"confidence":"High","gaps":["In vivo contribution relative to FBXW7 not quantified","Circadian dynamics of Myc turnover not directly measured"]},{"year":2018,"claim":"Showed that SUMOylation status feeds into Myc stability, with SENP1 deSUMOylating Myc to stabilize it and promote S62 phosphorylation.","evidence":"In vitro deSUMOylation, co-IP, SENP1 catalytic mutant (C603S), and ubiquitination assays","pmids":["30305424"],"confidence":"High","gaps":["SUMO acceptor lysines on Myc not defined in this entry","Crosstalk ordering between SUMO and phospho-degron not resolved"]},{"year":2018,"claim":"Demonstrated phosphatase-level control of the degron by showing Eya3 redirects PP2A-B55α to dephosphorylate pT58 (stabilizing), opposite to PP2A-B56α at pS62.","evidence":"Co-IP, phosphatase activity assays, phospho-specific immunoblotting, and xenograft metastasis model","pmids":["29535359"],"confidence":"High","gaps":["Determinants of holoenzyme site-selectivity not fully defined","Generality across tissues beyond the metastasis model not established"]},{"year":2021,"claim":"Added a kinase that biases the degron toward stability by showing IKKα phosphorylates S67/S71 to reduce T58 phosphorylation and slow turnover.","evidence":"In vitro kinase assay, FRET, CRISPR IKKα knockout, cycloheximide chase, and phosphomimetic/non-phosphorylatable mutants","pmids":["33461590"],"confidence":"High","gaps":["Upstream signals activating IKKα toward Myc not defined here","Interplay with GSK3β at T58 not kinetically resolved"]},{"year":null,"claim":"How the many opposing stability inputs (phosphorylation, 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Degradation and Inhibits c-Myc Activity.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25944903","citation_count":64,"is_preprint":false},{"pmid":"16620029","id":"PMC_16620029","title":"c-Myc, genome instability, and tumorigenesis: the devil is in the details.","date":"2006","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16620029","citation_count":62,"is_preprint":false},{"pmid":"18032916","id":"PMC_18032916","title":"Feedback regulation of c-Myc by ribosomal protein L11.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18032916","citation_count":58,"is_preprint":false},{"pmid":"2133113","id":"PMC_2133113","title":"C-MYC: evidence for multiple regulatory functions.","date":"1990","source":"Seminars in cancer biology","url":"https://pubmed.ncbi.nlm.nih.gov/2133113","citation_count":58,"is_preprint":false},{"pmid":"15082916","id":"PMC_15082916","title":"Of mice and Myc: c-Myc and mammary tumorigenesis.","date":"2004","source":"Journal of mammary gland biology and neoplasia","url":"https://pubmed.ncbi.nlm.nih.gov/15082916","citation_count":52,"is_preprint":false},{"pmid":"26096932","id":"PMC_26096932","title":"Integrin α1β1 expression is controlled by c-MYC in colorectal cancer cells.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/26096932","citation_count":51,"is_preprint":false},{"pmid":"34464659","id":"PMC_34464659","title":"TAZ is indispensable for c-MYC-induced hepatocarcinogenesis.","date":"2021","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/34464659","citation_count":50,"is_preprint":false},{"pmid":"9482408","id":"PMC_9482408","title":"Expression of the c-Myc protein in childhood medulloblastoma.","date":"1998","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/9482408","citation_count":50,"is_preprint":false},{"pmid":"1384028","id":"PMC_1384028","title":"Antisense c-myc oligodeoxyribonucleotide cellular uptake.","date":"1992","source":"Pharmaceutical research","url":"https://pubmed.ncbi.nlm.nih.gov/1384028","citation_count":49,"is_preprint":false},{"pmid":"20046830","id":"PMC_20046830","title":"Mechanisms of c-myc degradation by nickel compounds and hypoxia.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20046830","citation_count":48,"is_preprint":false},{"pmid":"18648001","id":"PMC_18648001","title":"How the c-myc promoter works and why it sometimes does not.","date":"2008","source":"Journal of the National Cancer Institute. Monographs","url":"https://pubmed.ncbi.nlm.nih.gov/18648001","citation_count":45,"is_preprint":false},{"pmid":"3475758","id":"PMC_3475758","title":"Effect of 4-hydroxynonenal on c-myc expression.","date":"1987","source":"Toxicologic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/3475758","citation_count":45,"is_preprint":false},{"pmid":"14529093","id":"PMC_14529093","title":"c-Myc-induced genomic instability.","date":"2003","source":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/14529093","citation_count":44,"is_preprint":false},{"pmid":"25284017","id":"PMC_25284017","title":"Aurora kinase A mediates c-Myc's oncogenic effects in hepatocellular carcinoma.","date":"2014","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25284017","citation_count":43,"is_preprint":false},{"pmid":"23601184","id":"PMC_23601184","title":"Sp1 and c-Myc regulate transcription of BMI1 in nasopharyngeal carcinoma.","date":"2013","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/23601184","citation_count":42,"is_preprint":false},{"pmid":"32817420","id":"PMC_32817420","title":"Circadian regulation of c-MYC in mice.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32817420","citation_count":41,"is_preprint":false},{"pmid":"7870572","id":"PMC_7870572","title":"The c-myc protein represses the lambda 5 and TdT initiators.","date":"1995","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/7870572","citation_count":41,"is_preprint":false},{"pmid":"16410134","id":"PMC_16410134","title":"c-Myc inhibition negatively impacts lymphoma growth.","date":"2006","source":"Journal of pediatric surgery","url":"https://pubmed.ncbi.nlm.nih.gov/16410134","citation_count":40,"is_preprint":false},{"pmid":"27009366","id":"PMC_27009366","title":"ELL targets c-Myc for proteasomal degradation and suppresses tumour growth.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27009366","citation_count":38,"is_preprint":false},{"pmid":"37537342","id":"PMC_37537342","title":"The DUBA-SLC7A11-c-Myc axis is critical for stemness and ferroptosis.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/37537342","citation_count":36,"is_preprint":false},{"pmid":"33461590","id":"PMC_33461590","title":"The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity.","date":"2021","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33461590","citation_count":36,"is_preprint":false},{"pmid":"1707594","id":"PMC_1707594","title":"c-myc protooncogene polypeptide expression in endometriosis.","date":"1991","source":"American journal of obstetrics and gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/1707594","citation_count":35,"is_preprint":false},{"pmid":"26697836","id":"PMC_26697836","title":"Deubiquitinating c-Myc: USP36 steps up in the nucleolus.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/26697836","citation_count":35,"is_preprint":false},{"pmid":"24657971","id":"PMC_24657971","title":"Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/24657971","citation_count":34,"is_preprint":false},{"pmid":"35039060","id":"PMC_35039060","title":"SLCO4A1-AS1 promotes colorectal tumourigenesis by regulating Cdk2/c-Myc signalling.","date":"2022","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/35039060","citation_count":34,"is_preprint":false},{"pmid":"29795406","id":"PMC_29795406","title":"Artemisitene suppresses tumorigenesis by inducing DNA damage through deregulating c-Myc-topoisomerase pathway.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29795406","citation_count":34,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41395,"output_tokens":8285,"usd":0.12423,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17720,"output_tokens":4557,"usd":0.101263,"stage2_stop_reason":"end_turn"},"total_usd":0.225493,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"c-MYC is a transcriptional target of the APC/beta-catenin/Tcf-4 signaling pathway; wild-type APC represses c-MYC expression while beta-catenin activates it through Tcf-4 binding sites in the c-MYC promoter.\",\n      \"method\": \"Reporter assay with Tcf-4 binding site mutations, expression manipulation of APC and beta-catenin\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter reporter assays with defined binding site mutations, reciprocal gain/loss-of-function, widely replicated finding\",\n      \"pmids\": [\"9727977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Myc directly binds and activates transcription of the miR-17-92 miRNA cluster on human chromosome 13 (confirmed by ChIP); two members of this cluster, miR-17-5p and miR-20a, negatively regulate translation of E2F1, revealing a feed-forward loop in which c-Myc simultaneously activates E2F1 transcription and limits its translation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), reporter assay, miRNA functional assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct ChIP binding evidence combined with functional miRNA assays, widely cited and replicated\",\n      \"pmids\": [\"15944709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In tumor cells with elevated c-Myc, the protein accumulates at promoters of already-active genes and causes transcriptional amplification (increased output of the existing gene expression program) rather than activating a new set of target genes.\",\n      \"method\": \"ChIP-seq, global transcriptome profiling, comparison of high vs. normal c-Myc expressing tumor cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with transcriptome readout, multiple cell lines, rigorous quantitative analysis\",\n      \"pmids\": [\"23021215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Myc promotes gene expression primarily by stimulating release of promoter-proximally paused RNA polymerase II (Pol II) rather than by recruiting Pol II to promoters.\",\n      \"method\": \"ChIP-seq for Pol II pausing, GRO-seq, genetic manipulation of c-Myc levels\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genome-wide orthogonal methods (ChIP-seq, GRO-seq) in the same study\",\n      \"pmids\": [\"20434984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"c-Myc has a direct, non-transcriptional role in DNA replication: it interacts with the pre-replicative complex, localizes to early replication sites, and is required for replication initiation in mammalian cells and Xenopus cell-free extracts. Overexpression increases origin firing, causing DNA damage and checkpoint activation.\",\n      \"method\": \"Co-immunoprecipitation with pre-RC components, localization to replication sites, siRNA depletion in mammalian cells and Xenopus cell-free extract (devoid of RNA transcription)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — cell-free transcription-independent system plus mammalian depletion and overexpression, multiple orthogonal methods\",\n      \"pmids\": [\"17597761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"c-Myc and Max interact in nucleoli, associate with ribosomal DNA, and c-Myc recruits TRRAP cofactor, enhances histone acetylation at rDNA, and activates RNA polymerase I transcription in response to mitogenic signals; this activity is separable from Pol II-dependent transcription.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, MycER system with Pol II inhibition, in situ proximity ligation\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including ChIP, siRNA, pharmacological separation of Pol I from Pol II activity, in situ interaction assays\",\n      \"pmids\": [\"15723053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"c-Myc-induced apoptosis is mediated by p53: activation of c-Myc in quiescent wild-type p53 fibroblasts induces apoptosis and stabilizes p53, whereas p53-null fibroblasts undergo cell cycle re-entry but not apoptosis upon c-Myc activation.\",\n      \"method\": \"Conditional c-Myc activation (estrogen receptor fusion), p53-null vs. wild-type fibroblast comparison, apoptosis and cell cycle assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using isogenic p53-null vs. wild-type cells with conditional c-Myc activation, clean phenotypic readout\",\n      \"pmids\": [\"8091232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"c-Myc binds preferentially to E-box elements (CACGTG) located within CpG islands at promoters in live human cells; these high-affinity sites correlate with an open, pre-acetylated chromatin state and Myc further enhances histone acetylation at these loci.\",\n      \"method\": \"Quantitative ChIP with bioinformatics selection of E-box-containing promoters; histone acetylation ChIP\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large-scale quantitative ChIP in live cells with orthogonal chromatin acetylation analysis\",\n      \"pmids\": [\"12695333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ribosomal protein L11 (a c-Myc transcriptional target) binds to Myc box II (MBII) of c-Myc, competes with the coactivator TRRAP for this site, reduces histone H4 acetylation at c-Myc target gene promoters, and thereby inhibits c-Myc transcriptional activity and cell proliferation in a negative feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, overexpression, cell proliferation assays\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding studies, ChIP with histone modification readout, siRNA knockdown and overexpression, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17599065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"c-Myc protein negatively autoregulates its own transcription: introduction of activated c-myc suppresses endogenous c-myc expression at the level of transcriptional initiation in a concentration-dependent manner requiring additional trans-acting factors.\",\n      \"method\": \"Transfection of activated c-myc constructs, nuclear run-on transcription assays, dose-response analysis\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — nuclear run-on assays establishing transcriptional level of regulation, dose-response, additional trans-factor requirement demonstrated\",\n      \"pmids\": [\"2182320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CRY2, acting as a component of an FBXL3-containing E3 ubiquitin ligase complex, recruits T58-phosphorylated c-MYC for ubiquitylation and degradation; CRY1 cannot substitute for CRY2 in this function.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, CRY1/CRY2 genetic and biochemical comparison, phospho-T58 dependency experiments\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution of ubiquitylation, defined phosphodegron requirement, paralog specificity established\",\n      \"pmids\": [\"27840026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pim-1 and Pim-2 kinases stabilize c-Myc by phosphorylating it at Ser329 (Pim-2 more directly) and by promoting decreased T58 phosphorylation with increased S62 phosphorylation (Pim-1), thereby inhibiting proteasomal degradation and enhancing c-Myc transcriptional activity.\",\n      \"method\": \"In vivo phosphorylation assays, site-directed mutagenesis (Ser329, Thr58, Ser62), pulse-chase protein stability, siRNA knockdown, transcriptional reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-directed mutagenesis combined with in vivo phosphorylation assays and stability measurements\",\n      \"pmids\": [\"18438430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"C/EBPα negatively regulates c-Myc expression through an E2F binding site in the c-myc promoter; stable expression of c-Myc from an exogenous promoter not responsive to C/EBPα blocks myeloid differentiation, establishing that C/EBPα-mediated repression of c-Myc is required for granulocytic differentiation.\",\n      \"method\": \"Promoter mapping, representational difference analysis, oligonucleotide microarray, inducible C/EBPα cell system, stable c-Myc overexpression from exogenous promoter\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (exogenous c-Myc rescue), promoter mapping, two independent screens for target identification\",\n      \"pmids\": [\"11340171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TGF-β signaling represses c-myc transcription via Smad3 and E2F-4 binding to a composite TIE/E2F element in the c-myc promoter; TGF-β reduces p300 co-immunoprecipitating with E2F-4 without displacing E2F-4 from DNA.\",\n      \"method\": \"Promoter reporter assays with TIE/E2F site mutations, EMSA, co-immunoprecipitation of Smad3, E2F-4, and p300\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EMSA, co-IP, promoter mutagenesis, and kinetic binding assays in one study\",\n      \"pmids\": [\"11689553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"c-Myc suppresses MyoD-initiated and myogenin-initiated skeletal muscle differentiation independently of the negative regulator Id, establishing c-Myc and Id as two independent negative regulators of myogenesis.\",\n      \"method\": \"Transient and stable cotransfection in NIH 3T3 cells; conditional c-Myc induction system; epistasis with MyoD, myogenin, and Id\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — stable conditional system plus epistasis with multiple myogenic factors, clean differentiation phenotype\",\n      \"pmids\": [\"1850105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SENP1 is a c-Myc deSUMOylating enzyme: it interacts with and deSUMOylates c-Myc in cells and in vitro; catalytically inactive SENP1 (C603S) fails to stabilize c-Myc. SUMOylation of c-Myc promotes its polyubiquitination and proteasomal degradation, while SENP1-mediated deSUMOylation stabilizes c-Myc and promotes its S62 phosphorylation.\",\n      \"method\": \"In vitro deSUMOylation assay, co-immunoprecipitation, SENP1 catalytic mutant (C603S), ubiquitination assay, siRNA knockdown\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro biochemical assay plus active-site mutagenesis plus cellular ubiquitination assays, multiple orthogonal methods\",\n      \"pmids\": [\"30305424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP37 directly binds and deubiquitinates c-Myc in a DUB activity-dependent manner to stabilize it; USP37 overexpression increases c-Myc levels while USP37 depletion promotes c-Myc degradation.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, DUB activity-dependent rescue experiments, siRNA knockdown, overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay plus DUB activity dependence, single lab study\",\n      \"pmids\": [\"25284584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Eya3 directly interacts with the PP2A-B55α holoenzyme and redirects its phosphatase activity toward pT58 on c-Myc (dephosphorylating T58 to stabilize c-Myc), in contrast to PP2A-B56α which dephosphorylates pS62 to destabilize c-Myc; this Eya3-PP2A-B55α complex promotes metastasis.\",\n      \"method\": \"Co-immunoprecipitation, phosphatase assays, xenograft metastasis model, phospho-specific immunoblotting\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical phosphatase activity assay combined with co-IP and in vivo xenograft, mechanism distinguishes two PP2A holoenzymes\",\n      \"pmids\": [\"29535359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXO32 (Atrogin-1) acts as an E3 ubiquitin ligase that targets c-Myc for proteasomal degradation via ubiquitination at lysine 326; this regulation is independent of T58/S62 phosphorylation status. FBXO32 is itself a direct transcriptional target of c-Myc, forming a negative feedback loop.\",\n      \"method\": \"Ubiquitination assay, K326 mutagenesis, co-immunoprecipitation, reporter assay, siRNA knockdown/overexpression\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-directed mutagenesis of ubiquitin acceptor lysine, in vivo ubiquitination assay, feedback loop established\",\n      \"pmids\": [\"25944903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ELL functions as a novel E3 ubiquitin ligase targeting c-Myc for proteasomal degradation, using UbcH8 as the ubiquitin-conjugating enzyme; cysteine 595 is the active site (C595A mutation abolishes ubiquitination and degradation of c-Myc).\",\n      \"method\": \"In vivo ubiquitination assay, active-site mutagenesis (C595A), co-immunoprecipitation, xenograft tumor assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — active-site mutagenesis establishes catalytic requirement, ubiquitination assay, in vivo tumor model\",\n      \"pmids\": [\"27009366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ribosomal protein S14 (RPS14) interacts with the MBII and bHLH-LZ domains of c-Myc, inhibits c-Myc transcriptional activity by preventing recruitment of c-Myc and TRRAP to target gene promoters, and promotes c-Myc mRNA degradation through an Ago2/miRNA-dependent pathway.\",\n      \"method\": \"Co-immunoprecipitation (domain mapping), ChIP, siRNA knockdown, luciferase reporter assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping co-IP, ChIP, and mRNA degradation pathway assays, single lab\",\n      \"pmids\": [\"23775087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"c-Myc directly induces expression and enzymatic activity of ornithine decarboxylase (ODC) in a manner not requiring de novo protein synthesis, establishing ODC as a direct transcriptional target mediating c-Myc's cell cycle effects.\",\n      \"method\": \"Conditional MycER activation, ODC mRNA and enzymatic activity assays, cycloheximide treatment to exclude indirect effects\",\n      \"journal\": \"Cell Growth & Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional system with protein synthesis inhibitor control; single lab\",\n      \"pmids\": [\"8297793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CK2 (casein kinase II) regulates c-Myc protein stability: pharmacological inhibition or antisense knockdown of CK2 accelerates proteasome-dependent c-Myc protein turnover, while CK2 overexpression increases c-Myc levels.\",\n      \"method\": \"CK2 inhibitor treatment, sense/antisense CK2 transfection, proteasome inhibitor epistasis, protein stability assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic manipulation with proteasome inhibitor controls, single lab\",\n      \"pmids\": [\"12149649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PDGF stimulates c-myc promoter activity and expression through a Src-dependent, Ras/MAPK-independent pathway involving Vav2 activation of Rac GTPase.\",\n      \"method\": \"c-myc promoter reporter assay, dominant-negative constructs for Ras, MEK, Src, Vav2, and Rac; epistasis analysis\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis with multiple dominant negatives, promoter reporter assays, single lab\",\n      \"pmids\": [\"11389443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Endogenous c-Myc and YY1 associate in vivo; c-Myc inhibits YY1 transcriptional activity not by blocking YY1 DNA binding but by interfering with YY1's ability to contact basal transcription factors TBP and TFIIB.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, gel shift assays for DNA binding, protein-protein interaction assays with TBP and TFIIB\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous co-IP plus mechanistic dissection of TBP/TFIIB interaction, single lab\",\n      \"pmids\": [\"8855231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"c-Myc overexpression accelerates S-phase progression; WRN helicase is required to prevent replication-associated DNA damage in c-Myc-overexpressing cells, as WRN depletion in this context activates ATR-CHK1-CHK2-p53 replication stress signaling and induces senescence rescued by p53 loss.\",\n      \"method\": \"BrdU incorporation (S-phase timing), WRN siRNA depletion, DNA damage markers (γH2AX at replication sites), pathway inhibition, p53 knockdown rescue\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — replication site-specific DNA damage assay, genetic epistasis with p53 rescue, single lab\",\n      \"pmids\": [\"19554081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Myc overexpression causes anaplastic histopathology in medulloblastoma xenografts, with increased nuclear size, macronucleoli, and elevated indices of proliferation and apoptosis, establishing a causal link between c-Myc and anaplasia.\",\n      \"method\": \"Stable c-Myc overexpression in medulloblastoma cell lines, subcutaneous xenograft in nude mice, histopathological analysis, proliferation/apoptosis indices\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined gain-of-function in two cell lines with in vivo xenograft phenotype, single lab\",\n      \"pmids\": [\"16423996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"c-MYC directly induces transcription of the AP4 transcription factor, which then represses p21 (CDKN1A) by binding elements near its promoter, thereby interfering with p21 induction by the DNA damage/p53 and TGFβ/Smad pathways.\",\n      \"method\": \"ChIP, reporter assay, AP4 overexpression/knockdown, epistasis with p53 and TGFβ pathways\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, reporter assay, epistasis experiments, single lab\",\n      \"pmids\": [\"19270520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IKKα binds c-Myc and phosphorylates it at serines 67 and 71; this phosphorylation stabilizes c-Myc by reducing T58 phosphorylation (the GSK3β target) and consequent polyubiquitination. Phosphomimetic S67D/S71D c-Myc mutants show slower turnover and increased proliferative activity.\",\n      \"method\": \"Co-immunoprecipitation, FRET microscopy, in vitro kinase assay, cycloheximide chase, CRISPR/Cas9 IKKα knockout, phosphomimetic and non-phosphorylatable mutants\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay plus active-site mutagenesis plus CRISPR KO plus optical pulse-chase, multiple orthogonal methods in one study\",\n      \"pmids\": [\"33461590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Myc aberrant stabilization in leukemia cell lines correlates with abnormal phosphorylation at T58 and S62 and decreased affinity for GSK3β (the kinase that phosphorylates T58 to trigger degradation), establishing deregulation of the T58/S62 phosphorylation-dependent degradation pathway as a mechanism of c-Myc overexpression in leukemia.\",\n      \"method\": \"Protein stability (pulse-chase), phospho-specific immunoblotting, GSK3β binding assay, sequencing for c-myc mutations\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulse-chase stability assays, kinase-binding assays, phospho-site analysis; single lab, no mutagenesis rescue\",\n      \"pmids\": [\"16855632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nickel compounds and hypoxia degrade c-Myc protein via the 26S proteasome through two mechanisms: (1) increased T58 phosphorylation leading to Fbw7-mediated ubiquitination, and (2) decreased levels of the deubiquitinase USP28 (via transcriptional repression through H3K9 dimethylation and protein degradation), both increasing net c-Myc ubiquitination.\",\n      \"method\": \"Proteasome inhibitor epistasis, phospho-T58 immunoblotting, USP28 siRNA knockdown, chromatin modification ChIP at USP28 promoter, HIF knockdown epistasis\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway epistasis with siRNA and inhibitors, chromatin modification at USP28 promoter, single lab\",\n      \"pmids\": [\"20046830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PP2A dephosphorylates c-MYC at serine 62 (S62) to destabilize it; endogenous PP2A inhibitors SET and CIP2A maintain S62 phosphorylation and c-MYC activity in breast cancer; SET antagonist OP449 decreases S62-pMYC and reduces tumorigenic potential.\",\n      \"method\": \"siRNA knockdown of SET/CIP2A, pharmacological PP2A activation (OP449), phospho-S62 immunoblotting, in vitro and in vivo tumor assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-site specific readout with genetic and pharmacological PP2A manipulation, in vivo validation; single lab\",\n      \"pmids\": [\"24927563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TAZ is a direct transcriptional target of c-MYC; TAZ is required to prevent c-Myc-induced hepatocyte apoptosis during tumor initiation; conditional Taz knockout (but not Yap knockout) completely prevents c-Myc-driven hepatocarcinogenesis and causes tumor regression.\",\n      \"method\": \"Conditional knockout mice (Taz, Yap, Yap;Taz), ChIP for c-MYC at TAZ promoter, inducible TTR-CreERT2 system, tumor histology\",\n      \"journal\": \"Journal of Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in conditional knockout mouse models with ChIP confirmation of direct transcriptional target, in vivo tumor regression\",\n      \"pmids\": [\"34464659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-Myc protein (complexed with myn/Max) binds to the transcription initiator elements of lambda 5 and TdT promoters and represses their transcriptional activity when c-Myc is overexpressed.\",\n      \"method\": \"Gel retardation (EMSA), supershift with c-Myc and Max antibodies, cotransfection reporter assay with initiator mutations\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA with supershift plus functional reporter assay, single lab\",\n      \"pmids\": [\"7870572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP43 deubiquitinates c-Myc at K148 and K289 in a DUB activity-dependent manner to stabilize it, and also competes with FBXW7 for access to c-Myc; this creates a USP43/c-Myc positive feedback loop promoting glycolysis and bladder cancer progression.\",\n      \"method\": \"siRNA library screen, co-immunoprecipitation, in vivo ubiquitination assay, site-directed mutagenesis (K148, K289), FBXW7 competition assay\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination site mutagenesis, competition assay with FBXW7, single lab\",\n      \"pmids\": [\"38218970\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"c-Myc is a nuclear bHLH-LZ transcription factor that heterodimerizes with Max to bind E-box elements and activate or repress target genes; it stimulates transcription primarily by releasing promoter-proximally paused RNA Pol II and, at high levels, amplifies the entire active gene expression program; it also activates RNA Pol I-dependent rDNA transcription in the nucleolus and directly engages the pre-replicative complex to promote DNA replication initiation independent of transcription; its protein stability is tightly controlled by sequential phosphorylation at S62 (stabilizing, by Ras/ERK, Pim, IKKα) and T58 (destabilizing, by GSK3β), followed by FBXW7/SCF-mediated ubiquitination and proteasomal degradation, with multiple deubiquitinases (USP28, USP37, USP36, USP43) and the CRY2-FBXL3 E3 ligase also regulating its turnover; additional PTMs including SUMOylation (promoting degradation, reversed by SENP1) and CK2 phosphorylation further modulate stability; upstream, c-MYC expression is transcriptionally activated by the Wnt/β-catenin/Tcf-4, PDGF/Src/Vav2/Rac, and Pim pathways and repressed by APC, TGF-β/Smad3, C/EBPα, and by its own negative autoregulation; c-Myc co-ordinates cell proliferation, ribosome biogenesis, DNA replication, and apoptosis (the latter largely through p53 stabilization), and is subject to negative feedback from ribosomal proteins L11 and S14 that bind MBII and displace the TRRAP coactivator.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"c-MYC is a sequence-specific transcription factor that, in complex with Max, binds E-box (CACGTG) elements located within open, pre-acetylated CpG-island promoters and further enhances local histone acetylation, coordinating cell proliferation, ribosome biogenesis, DNA replication, and apoptosis [#7, #5]. Rather than recruiting RNA Pol II de novo, c-Myc principally stimulates release of promoter-proximally paused Pol II, and when overexpressed in tumor cells it accumulates at already-active promoters to amplify the existing transcriptional program rather than activate new targets [#3, #2]. Its biosynthetic output extends beyond Pol II: c-Myc and Max localize to nucleoli, associate with rDNA, recruit the TRRAP coactivator, and drive RNA Pol I transcription in a Pol II-independent manner [#5], and c-Myc additionally has a transcription-independent role at the pre-replicative complex, localizing to early replication sites and promoting origin firing, with overexpression causing replication-associated DNA damage [#4]. Through defined targets, c-Myc activates the miR-17-92 cluster (creating a feed-forward loop with E2F1), ornithine decarboxylase, AP4 (which represses p21), and TAZ, the last being required to suppress c-Myc-induced apoptosis during hepatocarcinogenesis [#1, #21, #27, #32]; c-Myc-induced apoptosis itself is mediated through p53 stabilization [#6]. c-Myc protein abundance is governed by a phosphorylation-dependent degron in which S62 phosphorylation stabilizes and T58 phosphorylation destabilizes the protein, controlling FBXW7-type ubiquitination; this is tuned by Pim and IKKα kinases that favor S62 over T58 phosphorylation, by PP2A holoenzymes that dephosphorylate either site, by SUMOylation (reversed by SENP1), and by multiple deubiquitinases and alternative E3 ligases [#11, #28, #17, #31, #15, #34, #19, #18]. Upstream, c-MYC transcription is activated by Wnt/β-catenin/Tcf-4 and PDGF/Src/Vav2/Rac signaling and repressed by TGF-β/Smad3, C/EBPα, and its own negative autoregulation, integrating c-Myc levels into differentiation decisions [#0, #23, #13, #12, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that c-Myc controls its own abundance at the transcriptional level, defining negative autoregulation as a homeostatic constraint on Myc dosage.\",\n      \"evidence\": \"Transfection of activated c-myc with nuclear run-on transcription assays and dose-response analysis\",\n      \"pmids\": [\"2182320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the additional trans-acting factors required was not defined\", \"Did not establish direct DNA binding by Myc at its own promoter\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Resolved how c-Myc couples proliferation to apoptosis by showing the death output requires p53, separating Myc's cell-cycle and apoptotic functions.\",\n      \"evidence\": \"Conditional MycER activation in isogenic p53-null vs. wild-type fibroblasts with apoptosis and cell-cycle readouts\",\n      \"pmids\": [\"8091232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular route from Myc to p53 stabilization not defined\", \"Did not address which Myc target genes mediate the apoptotic signal\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Connected c-MYC to a major oncogenic signaling axis by identifying it as a Wnt/β-catenin/Tcf-4 transcriptional target repressed by APC.\",\n      \"evidence\": \"Promoter reporter assays with Tcf-4 site mutations and reciprocal APC/β-catenin manipulation\",\n      \"pmids\": [\"9727977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address cofactor requirements at the c-MYC promoter\", \"Cell-type dependence of this regulation not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the genomic logic of Myc binding by showing it prefers E-boxes in CpG islands already in an open, acetylated chromatin state and further increases acetylation there.\",\n      \"evidence\": \"Quantitative ChIP in live human cells with bioinformatic E-box selection and histone acetylation ChIP\",\n      \"pmids\": [\"12695333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how chromatin state is read to select sites\", \"Functional consequence of binding for transcription not directly measured here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended Myc function beyond Pol II by demonstrating direct activation of Pol I-dependent rDNA transcription in nucleoli, linking Myc to ribosome biogenesis.\",\n      \"evidence\": \"Co-IP, ChIP at rDNA, siRNA, MycER with Pol II inhibition, and in situ proximity ligation\",\n      \"pmids\": [\"15723053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Myc recruitment to rDNA not defined\", \"Relative contribution of Pol I vs Pol II activity to growth not quantified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed a non-coding-RNA arm of Myc regulation by showing direct activation of the miR-17-92 cluster, which dampens E2F1 translation in a feed-forward loop.\",\n      \"evidence\": \"ChIP, reporter assays, and miRNA functional assays\",\n      \"pmids\": [\"15944709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the full target set of the cluster in this context\", \"Physiological balance of E2F1 activation vs repression not quantified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Uncovered a transcription-independent function: c-Myc engages the pre-replicative complex and drives replication initiation, explaining replication stress upon overexpression.\",\n      \"evidence\": \"Co-IP with pre-RC components, replication-site localization, and siRNA depletion in mammalian cells and Xenopus cell-free extracts lacking transcription\",\n      \"pmids\": [\"17597761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner within the pre-RC not pinned down\", \"Whether this function is genetically separable from transcription in vivo not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified a ribosome-to-Myc feedback circuit by showing ribosomal protein L11 binds MBII, displaces TRRAP, and restrains Myc activity.\",\n      \"evidence\": \"Reciprocal co-IP, ChIP with histone acetylation readout, siRNA and overexpression with proliferation assays\",\n      \"pmids\": [\"17599065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of L11 vs TRRAP competition in vivo not defined\", \"Scope of target genes affected not genome-wide mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Clarified the core transcriptional mechanism by showing Myc acts mainly through pause release of Pol II rather than Pol II recruitment.\",\n      \"evidence\": \"Pol II ChIP-seq, GRO-seq, and genetic manipulation of Myc levels\",\n      \"pmids\": [\"20434984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct pause-release effector recruited by Myc not identified here\", \"Did not address gene-selectivity of the pause-release effect\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reframed oncogenic Myc action by showing that at high levels it amplifies the existing active program genome-wide rather than activating a distinct target set.\",\n      \"evidence\": \"ChIP-seq and global transcriptome profiling in high vs normal Myc tumor cells\",\n      \"pmids\": [\"23021215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile amplification model with selective target activation at physiologic levels\", \"Determinants of which active genes are amplified not fully defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the canonical degron logic and a circadian E3 input by showing CRY2-FBXL3 recognizes T58-phosphorylated Myc, with CRY1 unable to substitute.\",\n      \"evidence\": \"Co-IP, ubiquitylation assays, phospho-T58 dependency, and CRY1/CRY2 paralog comparison\",\n      \"pmids\": [\"27840026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution relative to FBXW7 not quantified\", \"Circadian dynamics of Myc turnover not directly measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed that SUMOylation status feeds into Myc stability, with SENP1 deSUMOylating Myc to stabilize it and promote S62 phosphorylation.\",\n      \"evidence\": \"In vitro deSUMOylation, co-IP, SENP1 catalytic mutant (C603S), and ubiquitination assays\",\n      \"pmids\": [\"30305424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO acceptor lysines on Myc not defined in this entry\", \"Crosstalk ordering between SUMO and phospho-degron not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated phosphatase-level control of the degron by showing Eya3 redirects PP2A-B55α to dephosphorylate pT58 (stabilizing), opposite to PP2A-B56α at pS62.\",\n      \"evidence\": \"Co-IP, phosphatase activity assays, phospho-specific immunoblotting, and xenograft metastasis model\",\n      \"pmids\": [\"29535359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of holoenzyme site-selectivity not fully defined\", \"Generality across tissues beyond the metastasis model not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Added a kinase that biases the degron toward stability by showing IKKα phosphorylates S67/S71 to reduce T58 phosphorylation and slow turnover.\",\n      \"evidence\": \"In vitro kinase assay, FRET, CRISPR IKKα knockout, cycloheximide chase, and phosphomimetic/non-phosphorylatable mutants\",\n      \"pmids\": [\"33461590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating IKKα toward Myc not defined here\", \"Interplay with GSK3β at T58 not kinetically resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many opposing stability inputs (phosphorylation, SUMOylation, multiple E3 ligases and DUBs) are integrated in a single cell to set Myc level and target output in a context-specific way remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model integrating degron PTMs with the amplification vs selective-activation transcriptional modes\", \"Tissue-specific dominance of individual regulators not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 3, 2, 5, 33]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 33]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 4, 9]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 3, 2, 5]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [4, 25]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [21, 27, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 28, 17, 31, 15, 19, 18, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 23, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 32]}\n    ],\n    \"complexes\": [\"Myc-Max\", \"pre-replicative complex (association)\"],\n    \"partners\": [\"MAX\", \"TRRAP\", \"FBXW7\", \"CRY2\", \"RPL11\", \"RPS14\", \"YY1\", \"SENP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}