{"gene":"MYCN","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2009,"finding":"Aurora A (AURKA) physically interacts with N-Myc and stabilizes it by counteracting SCF(Fbxw7)-mediated ubiquitination. Degradation of N-Myc requires sequential phosphorylation by cyclin B/Cdk1 and GSK3; Aurora A uncouples N-Myc stability from PI3-kinase/growth factor signals by binding both N-Myc and the SCF(Fbxw7) ubiquitin ligase.","method":"shRNA screen, co-immunoprecipitation, protein stability assays, phosphorylation site mutagenesis, ubiquitination assays","journal":"Cancer Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, phospho-mutagenesis, genetic KD), independently replicated by structural study (PMID 27837025)","pmids":["19111882"],"is_preprint":false},{"year":2016,"finding":"Crystal structure (1.72 Å) of Aurora A catalytic domain in complex with a region of N-Myc flanking Myc Box I reveals direct binding; this Aurora-A-binding site also overlaps with the SCF(Fbxw7) docking site, suggesting that Aurora A stabilizes N-Myc by competing with SCF(Fbxw7) and disfavoring Lys48-linked polyubiquitin chain formation. Inhibitors such as alisertib and CD532 induce an Aurora A conformation incompatible with N-Myc binding.","method":"X-ray crystallography, in vitro binding assays, cell-based N-Myc stability assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 1.72 Å plus functional validation, corroborates prior mechanistic findings","pmids":["27837025"],"is_preprint":false},{"year":2016,"finding":"HAUSP/USP7 deubiquitinase physically interacts with N-Myc, deubiquitinates it, and thereby stabilizes N-Myc protein. RNAi-mediated knockdown of USP7 or genetic ablation of Usp7 destabilizes N-Myc and inhibits N-Myc function in neuroblastoma.","method":"Co-immunoprecipitation, RNAi knockdown, in vivo Usp7 genetic ablation, ubiquitination assay, xenograft mouse model with USP7 inhibitors","journal":"Nature Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined phenotype, in vivo pharmacologic validation, multiple orthogonal methods","pmids":["27618649"],"is_preprint":false},{"year":1985,"finding":"N-Myc can cooperate with activated Ha-ras to transform normal primary rat embryo fibroblasts, demonstrating oncogenic/transforming activity comparable to c-Myc.","method":"Gene co-transfection transformation assay, soft-agar colony formation, syngeneic rat tumorigenicity assay","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro transformation assay with multiple readouts, replicated by independent labs","pmids":["3860871"],"is_preprint":false},{"year":1987,"finding":"N-Myc can act alone (without ras) to elicit neoplastic transformation of Rat-1 fibroblasts, causing morphological transformation, anchorage-independent growth, and tumorigenicity; both N-myc and c-myc produce similar phenotypes from the same vectors.","method":"Gene transfection, soft-agar colony formation, tumorigenicity assay in vivo","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gain-of-function assay with multiple readouts, single lab","pmids":["3299052"],"is_preprint":false},{"year":1986,"finding":"Overexpression of N-myc in rat neuroblastoma cells via gene transfer causes down-modulation of MHC class I histocompatibility antigen expression in a cell-type-specific manner, and increases in vivo growth rate and metastatic ability; interferon treatment reverses MHC class I down-modulation without affecting N-myc mRNA.","method":"Gene transfer, FACS for MHC class I, in vivo metastasis assay, interferon treatment","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gene transfer with functional readout, single lab, multiple phenotypic assays","pmids":["3096575"],"is_preprint":false},{"year":1991,"finding":"N-myc transfection in neuroblastoma cells suppresses PKC-delta isoform expression and induces PKC-zeta, blocking phorbol ester-mediated activation of c-fos mRNA and NF-κB; reintroduction of a PKC expression vector restores this inducibility, placing N-myc upstream of PKC-mediated signal transduction.","method":"Gene transfection, Northern blotting, reporter assay for NF-κB and c-fos, PKC rescue experiment","journal":"The EMBO Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by rescue experiment, single lab, multiple signaling readouts","pmids":["1902412"],"is_preprint":false},{"year":2000,"finding":"N-Myc is directly recruited to the promoters of telomerase and prothymosin target genes in living neuroblastoma cells and competes with other Max partners for binding, as demonstrated by chromatin immunoprecipitation showing that Max occupancy is high before and after N-Myc induction but N-Myc occupancy increases dramatically with overexpression.","method":"Formaldehyde cross-linking chromatin immunoprecipitation (ChIP), differential expression screens, neuroblastoma cell culture","journal":"Molecular Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP in living cells, two target genes tested, single lab","pmids":["11074604"],"is_preprint":false},{"year":2007,"finding":"N-MYC directly binds to the FAK promoter and transcriptionally activates FAK expression in neuroblastoma; two N-MYC binding sites in the FAK promoter were identified, and loss of FAK in N-MYC-expressing cells decreases viability and increases apoptosis.","method":"Electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, siRNA knockdown, dominant-negative FAK","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA + ChIP + reporter assay, multiple orthogonal methods in single lab","pmids":["17327229"],"is_preprint":false},{"year":2005,"finding":"N-Myc sensitizes neuroblastoma cells to TRAIL-induced apoptosis by transcriptionally up-regulating TRAIL receptor-2 (DR5) and Bid via two non-canonical E-boxes in the DR5 promoter; N-Myc-induced apoptosis requires Smac/DIABLO but not cytochrome c-mediated caspase-9 activation.","method":"N-Myc overexpression, TRAIL apoptosis assay, DR5 promoter reporter with E-box mutagenesis, Western blotting for apoptotic intermediates","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis with functional apoptosis readout, single lab, multiple orthogonal methods","pmids":["15632181"],"is_preprint":false},{"year":2000,"finding":"N-Myc can functionally replace c-Myc in murine development: mice in which N-myc coding sequences replace endogenous c-myc survive to adulthood and reproduce, demonstrating that N-Myc and c-Myc share core transcriptional and proliferative functions when expressed from the same locus.","method":"Knock-in mouse genetics (homologous recombination replacing c-myc with N-myc coding sequences), developmental and cellular phenotype analysis","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic knock-in with in vivo functional complementation, rigorous developmental analysis","pmids":["10837031"],"is_preprint":false},{"year":2006,"finding":"N-Myc acts downstream of Sonic hedgehog (Shh) signaling in cerebellar granule neuron progenitors; degradation of N-Myc triggered by GSK-3β-mediated phosphorylation (primed by Cdk1) is required for progenitor cell-cycle exit. IGF signaling keeps GSK-3β in check to maintain N-Myc levels.","method":"Conditional N-myc knockout in cerebellum, phosphorylation assays, cell-cycle exit analysis","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in conditional KO model, supported by biochemical phosphorylation data, single lab","pmids":["16322694"],"is_preprint":false},{"year":2006,"finding":"Genetic disruption of cyclin-dependent kinase inhibitors p18Ink4c and p27Kip1 in N-Myc-null cerebella partially rescues granule neuron progenitor proliferation and cerebellar foliation, establishing that N-Myc promotes proliferation by suppressing these CDK inhibitors.","method":"Compound conditional knockout genetics, cell proliferation assays, cerebellar morphology analysis","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double-mutant rescue, definitive causal pathway placement","pmids":["16864777"],"is_preprint":false},{"year":2010,"finding":"Wnt/β-catenin signaling promotes basal progenitor production in the developing neocortex via N-myc; expression of stabilized β-catenin or N-myc increases basal progenitor numbers, while conditional deletion of N-myc reduces basal progenitors and cortical neuron number, placing N-myc downstream of Wnt signaling.","method":"In utero electroporation, conditional N-myc knockout, β-catenin gain-of-function mouse, BrdU labeling, neural progenitor quantification","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with loss and gain of function, in vivo confirmation, multiple orthogonal approaches","pmids":["20215343"],"is_preprint":false},{"year":2002,"finding":"In postmitotic sympathetic neurons, N-myc expression at neuroblastoma-like levels induces S-phase re-entry (measured by BrdU incorporation and cell cycle protein expression) while protecting neurons from apoptosis caused by NGF withdrawal; cell cycle re-entry but not survival is blocked by constitutively hypophosphorylated Rb, indicating that N-myc uses separate pathways for cell cycle and survival.","method":"Adenoviral gene delivery to postmitotic neurons, BrdU incorporation, Rb dominant-negative epistasis, apoptosis assay","journal":"Journal of Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with Rb, direct cell cycle assay, single lab","pmids":["11826111"],"is_preprint":false},{"year":2013,"finding":"HDAC5 and N-Myc form a protein complex that co-represses a subset of genes in neuroblastoma; N-Myc upregulates HDAC5 expression, and HDAC5 in turn increases Aurora A expression and decreases NEDD4 ligase expression, thereby further stabilizing N-Myc protein. HDAC5 knockdown reduces proliferation and promotes differentiation.","method":"Co-immunoprecipitation, genome-wide gene expression analysis, siRNA knockdown, neuroblastoma differentiation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus genome-wide expression, single lab","pmids":["23812427"],"is_preprint":false},{"year":2009,"finding":"N-Myc directly binds the LIF promoter and represses LIF transcription in a manner independent of Myc/Max interaction, requiring instead a contiguous N-terminal N-Myc domain, as shown by promoter reporter assays using N-Myc deletion mutants.","method":"Promoter-reporter assay with N-Myc deletion mutants, Northern blotting, adenoviral STAT3 phosphorylation-deficient mutant rescue","journal":"European Journal of Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping mutagenesis in reporter assay, single lab, mechanistic follow-up","pmids":["12153570"],"is_preprint":false},{"year":2004,"finding":"N-myc binds a conserved site in the parkin promoter and represses parkin transcription, as shown by ChIP and promoter-reporter assays; parkin expression is inversely correlated with N-myc levels in developing brain, neuroblastoma cell lines, and an inducible N-myc cell line.","method":"ChIP, promoter-reporter assay, inducible N-myc cell line, expression correlation in brain development and neuroblastoma","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP plus reporter assay, single lab","pmids":["15078880"],"is_preprint":false},{"year":2009,"finding":"N-Myc directly binds the LIF promoter (ChIP assay) and regulates expression of pluripotency genes (lif, klf2, klf4, lin28b) in neuroblastoma and neural stem cells; N-Myc also regulates histone H3 lysine 4 trimethylation at the lif promoter, linking N-Myc transcriptional activity to active chromatin marks.","method":"ChIP-chip, direct ChIP, microarray expression profiling, Tet-regulatable N-myc system, nestin-cre N-myc knockout neural stem cells","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-chip plus direct ChIP plus two orthogonal cell systems, single lab","pmids":["19495417"],"is_preprint":false},{"year":2016,"finding":"N-Myc overexpression drives neuroendocrine prostate cancer (NEPC) in a genetically engineered mouse model and induces Polycomb Repressive Complex 2 (EZH2) signaling with abrogation of androgen receptor signaling.","method":"Genetically engineered mouse model (MYCN overexpression), transcriptome analysis, integration with human NEPC data","journal":"Cancer Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with molecular pathway analysis, single lab","pmids":["27728805"],"is_preprint":false},{"year":2016,"finding":"N-Myc and activated AKT1 together are sufficient to transform human prostate epithelial cells into prostate adenocarcinoma and NEPC; N-Myc is required for tumor maintenance, and Aurora A kinase inhibition destabilizes N-Myc and reduces tumor burden.","method":"Lentiviral transduction of human prostate epithelial cells, xenograft mouse model, Aurora A inhibitor treatment","journal":"Cancer Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transformation assay with human cells plus in vivo validation, single lab","pmids":["27050099"],"is_preprint":false},{"year":2014,"finding":"ATF4 cooperates with N-Myc to directly activate ASCT2 (SLC1A5) glutamine transporter expression in MYCN-amplified neuroblastoma cells; ASCT2 depletion inhibits glutaminolysis and reduces cell proliferation and tumourigenesis.","method":"Glutamine influx analysis, siRNA knockdown, luciferase reporter assay showing ATF4/N-Myc co-activation of ASCT2 promoter, xenograft assay","journal":"Journal of Pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus functional KD plus in vivo xenograft, single lab","pmids":["25142020"],"is_preprint":false},{"year":1992,"finding":"IL-7 induces rapid N-myc and c-myc expression in normal pre-B cells at the transcriptional level; for N-myc, induction is largely mediated by release of a transcriptional attenuation block between exons 1 and 2. More mature B-lineage cells respond to mitogens with c-myc but not N-myc induction, indicating developmental stage-specificity.","method":"Nuclear run-on transcription assay, Northern blotting, IL-7 stimulation of pre-B cells","journal":"Genes & Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear run-on assay identifies transcriptional attenuation mechanism, single lab","pmids":["1730410"],"is_preprint":false},{"year":1990,"finding":"N-myc mRNA forms an RNA-RNA duplex in vivo with endogenous antisense transcripts originating from intron 1; most cytoplasmic nonpolyadenylated antisense RNA exists as a duplex with ~5% of sense N-myc mRNA, and duplex formation involves a subset of N-myc mRNA species retaining intron 1, suggesting a role in modulating RNA processing.","method":"Nuclear run-off transcription, RNase protection assay for in vivo duplexes, cDNA cloning of both strands","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical detection of in vivo RNA duplex, single lab, well-controlled assay","pmids":["1695323"],"is_preprint":false},{"year":2019,"finding":"N-Myc differentially regulates the miR-421/ATM pathway in a cell-context-dependent manner: in LNCaP cells, N-Myc overexpression upregulates miR-421 to suppress ATM, relieving ADT-induced senescence; in C4-2 cells, N-Myc upregulates ATM, promoting migration and Enzalutamide resistance. ATM knockout or inhibition re-sensitizes N-Myc-overexpressing cells to Enzalutamide.","method":"Stable N-Myc overexpression cell lines, CRISPR-Cas9 ATM knockout, SA-β-gal senescence assay, MTS viability assay, xenograft model","journal":"Molecular Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knockout epistasis with defined phenotypic readout, multiple cell lines, single lab","pmids":["30657058"],"is_preprint":false},{"year":2012,"finding":"GCN5/KAT2A histone acetyltransferase functions as an N-Myc transcriptional cofactor in neural stem cells; approximately one-sixth of genes regulated by N-Myc loss are co-regulated by GCN5 loss, and GCN5 is required for maintenance of histone acetylation at N-Myc target gene promoters. Conditional knockout of GCN5 in NSC phenocopies N-Myc loss (microcephaly, reduced proliferation).","method":"Conditional knockout (nestin-cre), gene expression profiling, histone acetylation ChIP, phenotypic analysis","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with functional and chromatin-level evidence, single lab","pmids":["22745758"],"is_preprint":false},{"year":1986,"finding":"Human N-myc and c-myc share a similar three-exon intron/exon structure with coding sequences in exons 2 and 3, long 5' untranslated regions, and significant protein sequence homology, indicating structural and functional kinship.","method":"Nucleotide sequencing, exon-intron structure analysis, protein sequence deduction","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct sequencing of human N-myc, single lab, foundational structural characterization","pmids":["3510398"],"is_preprint":false},{"year":1986,"finding":"The N-myc protein is 62-64 kDa as identified by immunoprecipitation from neuroblastoma cells using antisera raised against bacterially expressed N-myc fragments; it shares biochemical features with the c-myc protein family.","method":"Bacterial expression of N-myc antigen fragments, immunization, immunoprecipitation from neuroblastoma cell lysates","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical identification of protein size and family membership, single lab","pmids":["3008339"],"is_preprint":false},{"year":2021,"finding":"Coactivation of ALK (F1174C-activating mutation) and N-Myc is sufficient to transform mouse prostate basal stem cells into aggressive NEPC via Wnt/β-catenin pathway activation; ALK inhibition suppresses Wnt/β-catenin signaling and cooperates with Wnt inhibition to suppress tumor growth and metastasis.","method":"Tissue recombination mouse model, genetic coactivation, pharmacologic ALK/Wnt inhibition in vitro and in vivo","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo tissue recombination model plus pharmacologic pathway validation, single lab","pmids":["33637566"],"is_preprint":false}],"current_model":"MYCN encodes N-Myc, a bHLH-Zip transcription factor that heterodimerizes with Max to bind E-boxes and directly activate or repress target genes (including DR5, FAK, parkin, LIF, ASCT2, and pluripotency factors); its protein stability is tightly controlled by sequential CDK1/GSK3 phosphorylation triggering SCF(Fbxw7) ubiquitination and proteasomal degradation, which is counteracted by Aurora A kinase (which directly binds N-Myc's Myc Box I region as shown by crystal structure) and by the deubiquitinase HAUSP/USP7; N-Myc drives proliferation in neural progenitors partly by suppressing CDK inhibitors p18Ink4c and p27Kip1 downstream of Shh and Wnt/β-catenin signaling, promotes survival and cell-cycle re-entry through pathways separable from its pro-apoptotic sensitization (via DR5/Bid upregulation), and collaborates with cofactors including HDAC5 and GCN5 to regulate chromatin and transcription in neural and cancer contexts."},"narrative":{"mechanistic_narrative":"MYCN encodes N-Myc, a Myc-family transcription factor that drives proliferation and oncogenic transformation across neural progenitors and multiple cancer lineages [PMID:3860871, PMID:10837031]. N-Myc shares its three-exon gene architecture, long 5'UTR, and protein-family features with c-Myc, and can functionally replace c-Myc at the endogenous locus to support murine development, establishing that the two share core transcriptional and proliferative programs [PMID:10837031, PMID:3510398]. Mechanistically, N-Myc is recruited to target promoters in living cells where it competes with other Max partners for E-box occupancy [PMID:11074604], and it both activates targets (FAK; the TRAIL receptor DR5 and Bid; the ASCT2/SLC1A5 glutamine transporter in cooperation with ATF4) and represses targets (parkin; LIF, the latter through an N-terminal domain independent of Myc/Max), coupling its transcriptional output to adhesion, apoptotic sensitization, glutaminolysis, and pluripotency-gene control [PMID:17327229, PMID:15632181, PMID:25142020, PMID:12153570, PMID:15078880, PMID:19495417]. In neural development N-Myc acts downstream of Sonic hedgehog and Wnt/β-catenin signaling to drive progenitor proliferation, doing so in part by suppressing the CDK inhibitors p18Ink4c and p27Kip1 whose genetic loss rescues proliferation in N-Myc-null cerebella [PMID:16322694, PMID:20215343, PMID:16864777]; it can also force postmitotic neurons into S-phase re-entry through an Rb-dependent pathway separable from its pro-survival activity [PMID:11826111]. N-Myc protein stability is the dominant control point: sequential cyclin B/Cdk1 and GSK-3β phosphorylation primes SCF(Fbxw7)-mediated polyubiquitination and degradation, which is opposed by Aurora A kinase, which binds the Myc Box I-flanking region (resolved by crystallography) at a site overlapping the Fbxw7 docking site, and by the deubiquitinase HAUSP/USP7 [PMID:19111882, PMID:27837025, PMID:27618649, PMID:16322694]. N-Myc cooperates with chromatin cofactors GCN5/KAT2A and HDAC5 to maintain its transcriptional and self-stabilizing programs [PMID:22745758, PMID:23812427], and beyond neuroblastoma it drives neuroendocrine prostate cancer in cooperation with AKT1, ALK, and Wnt/β-catenin signaling [PMID:27728805, PMID:27050099, PMID:33637566].","teleology":[{"year":1986,"claim":"Establishing that N-myc is a c-myc-related gene with a defined protein product framed it as a Myc-family transcription factor rather than an isolated amplicon.","evidence":"Genomic sequencing of human N-myc and immunoprecipitation of the 62-64 kDa protein from neuroblastoma cells","pmids":["3510398","3008339"],"confidence":"Medium","gaps":["Sequence kinship did not establish DNA-binding specificity or partner requirements","No functional transcriptional assay in these studies"]},{"year":1987,"claim":"Demonstrating that N-Myc transforms fibroblasts alone or with Ha-ras assigned it bona fide oncogenic activity equivalent to c-Myc.","evidence":"Co-transfection transformation and soft-agar/tumorigenicity assays in rat fibroblasts","pmids":["3860871","3299052"],"confidence":"High","gaps":["Transformation readout did not define the transcriptional targets responsible","Fibroblast context differs from the neural lineage where N-Myc normally acts"]},{"year":1992,"claim":"Showing IL-7-driven N-myc induction occurs via release of a transcriptional attenuation block clarified how its expression is gated in a developmental-stage-specific manner.","evidence":"Nuclear run-on transcription assays in normal pre-B cells","pmids":["1730410"],"confidence":"Medium","gaps":["Attenuation mechanism characterized in B-lineage, not neural cells","Did not identify the trans-acting factors controlling attenuation"]},{"year":2000,"claim":"Knock-in complementation and ChIP recruitment together showed N-Myc shares c-Myc's core function and physically engages target promoters through Max-competitive binding.","evidence":"c-myc/N-myc coding-sequence knock-in mice and formaldehyde-crosslinking ChIP at telomerase/prothymosin promoters","pmids":["10837031","11074604"],"confidence":"High","gaps":["ChIP limited to two target genes","Did not establish genome-wide occupancy or repression mechanisms"]},{"year":2007,"claim":"Mapping direct activating and repressing targets defined how N-Myc converts promoter binding into specific phenotypes spanning adhesion, apoptosis sensitization, metabolism, and pluripotency.","evidence":"EMSA/ChIP/reporter and promoter-mutagenesis studies on FAK, DR5/Bid, parkin, LIF, ASCT2, and pluripotency genes","pmids":["17327229","15632181","15078880","12153570","19495417","25142020"],"confidence":"Medium","gaps":["Most targets validated in single labs on individual promoters","LIF repression via a Max-independent N-terminal domain was not structurally resolved","Relative contribution of each target to tumor phenotype unquantified"]},{"year":2010,"claim":"Genetic epistasis placed N-Myc as the proliferative effector downstream of Shh and Wnt/β-catenin that drives neural progenitor expansion by suppressing CDK inhibitors.","evidence":"Conditional N-myc knockouts, β-catenin gain-of-function, p18/p27 double-mutant rescue, and Rb-dependent S-phase re-entry assays","pmids":["16322694","16864777","20215343","11826111"],"confidence":"High","gaps":["Whether CDK-inhibitor suppression is direct transcriptional repression not fully resolved","Survival pathway separable from cell-cycle re-entry remains molecularly undefined"]},{"year":2016,"claim":"Identifying the Cdk1/GSK3-Fbxw7 degradation axis and its antagonists Aurora A and USP7 established N-Myc protein abundance as a druggable control point.","evidence":"Co-IP, ubiquitination/phospho-mutagenesis assays, a 1.72 Å Aurora A–N-Myc crystal structure, and in vivo USP7 ablation/inhibitor studies","pmids":["19111882","27837025","27618649"],"confidence":"High","gaps":["Whether Aurora A's stabilizing function is fully kinase-independent versus structural is incompletely separated","NEDD4 and other ligases noted but not mechanistically dissected"]},{"year":2013,"claim":"Linking N-Myc to chromatin cofactors GCN5 and HDAC5 connected its transcriptional output to histone acetylation and a feed-forward loop reinforcing its own stability.","evidence":"Co-IP, conditional GCN5 knockout phenocopy, histone-acetylation ChIP, and HDAC5 knockdown differentiation assays","pmids":["22745758","23812427"],"confidence":"Medium","gaps":["Only a subset of N-Myc target genes shown to be cofactor-dependent","Direct versus indirect effects of HDAC5 on Aurora A/NEDD4 not resolved"]},{"year":2021,"claim":"Extending N-Myc oncogenesis to neuroendocrine prostate cancer showed it cooperates with AKT1, ALK, and Wnt/β-catenin and remains required for tumor maintenance and Aurora A-targetable.","evidence":"Genetically engineered and tissue-recombination mouse models, human prostate epithelial transformation, and Aurora A/ALK/Wnt pharmacologic inhibition","pmids":["27728805","27050099","33637566","30657058"],"confidence":"Medium","gaps":["Cell-context-dependent miR-421/ATM regulation not mechanistically unified","Single-lab models for each cooperating oncogene"]},{"year":null,"claim":"How N-Myc's genome-wide target selection, repressive (Max-independent) activities, and cofactor switching are integrated to specify distinct lineage outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of N-Myc/Max/cofactor complexes on chromatin","Determinants of activation versus repression at individual promoters undefined","Role of the intron-1 antisense RNA duplex in regulating N-myc expression uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,8,9,16,17,18,21]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[8,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,18]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,8,9,16,17,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,11,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,19,20,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":["MAX","AURKA","USP7","FBXW7","HDAC5","GCN5","ATF4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P04198","full_name":"N-myc proto-oncogene protein","aliases":["Class E basic helix-loop-helix protein 37","bHLHe37"],"length_aa":464,"mass_kda":49.6,"function":"Positively regulates the transcription of MYCNOS in neuroblastoma cells","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P04198/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYCN","classification":"Not Classified","n_dependent_lines":44,"n_total_lines":1208,"dependency_fraction":0.03642384105960265},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYCN","total_profiled":1310},"omim":[{"mim_id":"621189","title":"LONG INTERGENIC NONCODING RNA 2525; LINC02525","url":"https://www.omim.org/entry/621189"},{"mim_id":"620748","title":"MEGALENCEPHALY-POLYDACTYLY SYNDROME; MPAPA","url":"https://www.omim.org/entry/620748"},{"mim_id":"620079","title":"LONG INTERGENIC NONCODING RNA 467; LINC00467","url":"https://www.omim.org/entry/620079"},{"mim_id":"618703","title":"ZINC FINGER PROTEIN 281; ZNF281","url":"https://www.omim.org/entry/618703"},{"mim_id":"615968","title":"MYCN UPSTREAM TRANSCRIPT, NONCODING; MYCNUT","url":"https://www.omim.org/entry/615968"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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surgery","url":"https://pubmed.ncbi.nlm.nih.gov/8331499","citation_count":24,"is_preprint":false},{"pmid":"27748806","id":"PMC_27748806","title":"NCYM is upregulated by lncUSMycN and modulates N-Myc expression.","date":"2016","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27748806","citation_count":23,"is_preprint":false},{"pmid":"26177922","id":"PMC_26177922","title":"Nifurtimox reduces N-Myc expression and aerobic glycolysis in neuroblastoma.","date":"2015","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/26177922","citation_count":23,"is_preprint":false},{"pmid":"8454274","id":"PMC_8454274","title":"N-myc gene amplification/expression in localized stroma-rich neuroblastoma (ganglioneuroblastoma).","date":"1993","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8454274","citation_count":23,"is_preprint":false},{"pmid":"26160903","id":"PMC_26160903","title":"Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea.","date":"2015","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26160903","citation_count":23,"is_preprint":false},{"pmid":"26874464","id":"PMC_26874464","title":"Roles of N-Myc and STAT interactor in cancer: From initiation to dissemination.","date":"2016","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26874464","citation_count":22,"is_preprint":false},{"pmid":"34523032","id":"PMC_34523032","title":"N-Myc promotes angiogenesis and therapeutic resistance of prostate cancer by TEM8.","date":"2021","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34523032","citation_count":20,"is_preprint":false},{"pmid":"2004353","id":"PMC_2004353","title":"Transcription of N-myc and proliferation-related genes is linked in human neuroblastoma.","date":"1991","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/2004353","citation_count":20,"is_preprint":false},{"pmid":"15293230","id":"PMC_15293230","title":"N-myc downstream-regulated gene 1 expression in injured sciatic nerves.","date":"2004","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/15293230","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44377,"output_tokens":6692,"usd":0.116755,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15700,"output_tokens":3737,"usd":0.085962,"stage2_stop_reason":"end_turn"},"total_usd":0.202717,"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\": 2009,\n      \"finding\": \"Aurora A (AURKA) physically interacts with N-Myc and stabilizes it by counteracting SCF(Fbxw7)-mediated ubiquitination. Degradation of N-Myc requires sequential phosphorylation by cyclin B/Cdk1 and GSK3; Aurora A uncouples N-Myc stability from PI3-kinase/growth factor signals by binding both N-Myc and the SCF(Fbxw7) ubiquitin ligase.\",\n      \"method\": \"shRNA screen, co-immunoprecipitation, protein stability assays, phosphorylation site mutagenesis, ubiquitination assays\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, phospho-mutagenesis, genetic KD), independently replicated by structural study (PMID 27837025)\",\n      \"pmids\": [\"19111882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure (1.72 Å) of Aurora A catalytic domain in complex with a region of N-Myc flanking Myc Box I reveals direct binding; this Aurora-A-binding site also overlaps with the SCF(Fbxw7) docking site, suggesting that Aurora A stabilizes N-Myc by competing with SCF(Fbxw7) and disfavoring Lys48-linked polyubiquitin chain formation. Inhibitors such as alisertib and CD532 induce an Aurora A conformation incompatible with N-Myc binding.\",\n      \"method\": \"X-ray crystallography, in vitro binding assays, cell-based N-Myc stability assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 1.72 Å plus functional validation, corroborates prior mechanistic findings\",\n      \"pmids\": [\"27837025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HAUSP/USP7 deubiquitinase physically interacts with N-Myc, deubiquitinates it, and thereby stabilizes N-Myc protein. RNAi-mediated knockdown of USP7 or genetic ablation of Usp7 destabilizes N-Myc and inhibits N-Myc function in neuroblastoma.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, in vivo Usp7 genetic ablation, ubiquitination assay, xenograft mouse model with USP7 inhibitors\",\n      \"journal\": \"Nature Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined phenotype, in vivo pharmacologic validation, multiple orthogonal methods\",\n      \"pmids\": [\"27618649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"N-Myc can cooperate with activated Ha-ras to transform normal primary rat embryo fibroblasts, demonstrating oncogenic/transforming activity comparable to c-Myc.\",\n      \"method\": \"Gene co-transfection transformation assay, soft-agar colony formation, syngeneic rat tumorigenicity assay\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro transformation assay with multiple readouts, replicated by independent labs\",\n      \"pmids\": [\"3860871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"N-Myc can act alone (without ras) to elicit neoplastic transformation of Rat-1 fibroblasts, causing morphological transformation, anchorage-independent growth, and tumorigenicity; both N-myc and c-myc produce similar phenotypes from the same vectors.\",\n      \"method\": \"Gene transfection, soft-agar colony formation, tumorigenicity assay in vivo\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain-of-function assay with multiple readouts, single lab\",\n      \"pmids\": [\"3299052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Overexpression of N-myc in rat neuroblastoma cells via gene transfer causes down-modulation of MHC class I histocompatibility antigen expression in a cell-type-specific manner, and increases in vivo growth rate and metastatic ability; interferon treatment reverses MHC class I down-modulation without affecting N-myc mRNA.\",\n      \"method\": \"Gene transfer, FACS for MHC class I, in vivo metastasis assay, interferon treatment\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gene transfer with functional readout, single lab, multiple phenotypic assays\",\n      \"pmids\": [\"3096575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"N-myc transfection in neuroblastoma cells suppresses PKC-delta isoform expression and induces PKC-zeta, blocking phorbol ester-mediated activation of c-fos mRNA and NF-κB; reintroduction of a PKC expression vector restores this inducibility, placing N-myc upstream of PKC-mediated signal transduction.\",\n      \"method\": \"Gene transfection, Northern blotting, reporter assay for NF-κB and c-fos, PKC rescue experiment\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by rescue experiment, single lab, multiple signaling readouts\",\n      \"pmids\": [\"1902412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"N-Myc is directly recruited to the promoters of telomerase and prothymosin target genes in living neuroblastoma cells and competes with other Max partners for binding, as demonstrated by chromatin immunoprecipitation showing that Max occupancy is high before and after N-Myc induction but N-Myc occupancy increases dramatically with overexpression.\",\n      \"method\": \"Formaldehyde cross-linking chromatin immunoprecipitation (ChIP), differential expression screens, neuroblastoma cell culture\",\n      \"journal\": \"Molecular Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP in living cells, two target genes tested, single lab\",\n      \"pmids\": [\"11074604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"N-MYC directly binds to the FAK promoter and transcriptionally activates FAK expression in neuroblastoma; two N-MYC binding sites in the FAK promoter were identified, and loss of FAK in N-MYC-expressing cells decreases viability and increases apoptosis.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, siRNA knockdown, dominant-negative FAK\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA + ChIP + reporter assay, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"17327229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"N-Myc sensitizes neuroblastoma cells to TRAIL-induced apoptosis by transcriptionally up-regulating TRAIL receptor-2 (DR5) and Bid via two non-canonical E-boxes in the DR5 promoter; N-Myc-induced apoptosis requires Smac/DIABLO but not cytochrome c-mediated caspase-9 activation.\",\n      \"method\": \"N-Myc overexpression, TRAIL apoptosis assay, DR5 promoter reporter with E-box mutagenesis, Western blotting for apoptotic intermediates\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis with functional apoptosis readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15632181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"N-Myc can functionally replace c-Myc in murine development: mice in which N-myc coding sequences replace endogenous c-myc survive to adulthood and reproduce, demonstrating that N-Myc and c-Myc share core transcriptional and proliferative functions when expressed from the same locus.\",\n      \"method\": \"Knock-in mouse genetics (homologous recombination replacing c-myc with N-myc coding sequences), developmental and cellular phenotype analysis\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic knock-in with in vivo functional complementation, rigorous developmental analysis\",\n      \"pmids\": [\"10837031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"N-Myc acts downstream of Sonic hedgehog (Shh) signaling in cerebellar granule neuron progenitors; degradation of N-Myc triggered by GSK-3β-mediated phosphorylation (primed by Cdk1) is required for progenitor cell-cycle exit. IGF signaling keeps GSK-3β in check to maintain N-Myc levels.\",\n      \"method\": \"Conditional N-myc knockout in cerebellum, phosphorylation assays, cell-cycle exit analysis\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in conditional KO model, supported by biochemical phosphorylation data, single lab\",\n      \"pmids\": [\"16322694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Genetic disruption of cyclin-dependent kinase inhibitors p18Ink4c and p27Kip1 in N-Myc-null cerebella partially rescues granule neuron progenitor proliferation and cerebellar foliation, establishing that N-Myc promotes proliferation by suppressing these CDK inhibitors.\",\n      \"method\": \"Compound conditional knockout genetics, cell proliferation assays, cerebellar morphology analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double-mutant rescue, definitive causal pathway placement\",\n      \"pmids\": [\"16864777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Wnt/β-catenin signaling promotes basal progenitor production in the developing neocortex via N-myc; expression of stabilized β-catenin or N-myc increases basal progenitor numbers, while conditional deletion of N-myc reduces basal progenitors and cortical neuron number, placing N-myc downstream of Wnt signaling.\",\n      \"method\": \"In utero electroporation, conditional N-myc knockout, β-catenin gain-of-function mouse, BrdU labeling, neural progenitor quantification\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with loss and gain of function, in vivo confirmation, multiple orthogonal approaches\",\n      \"pmids\": [\"20215343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In postmitotic sympathetic neurons, N-myc expression at neuroblastoma-like levels induces S-phase re-entry (measured by BrdU incorporation and cell cycle protein expression) while protecting neurons from apoptosis caused by NGF withdrawal; cell cycle re-entry but not survival is blocked by constitutively hypophosphorylated Rb, indicating that N-myc uses separate pathways for cell cycle and survival.\",\n      \"method\": \"Adenoviral gene delivery to postmitotic neurons, BrdU incorporation, Rb dominant-negative epistasis, apoptosis assay\",\n      \"journal\": \"Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with Rb, direct cell cycle assay, single lab\",\n      \"pmids\": [\"11826111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HDAC5 and N-Myc form a protein complex that co-represses a subset of genes in neuroblastoma; N-Myc upregulates HDAC5 expression, and HDAC5 in turn increases Aurora A expression and decreases NEDD4 ligase expression, thereby further stabilizing N-Myc protein. HDAC5 knockdown reduces proliferation and promotes differentiation.\",\n      \"method\": \"Co-immunoprecipitation, genome-wide gene expression analysis, siRNA knockdown, neuroblastoma differentiation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus genome-wide expression, single lab\",\n      \"pmids\": [\"23812427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"N-Myc directly binds the LIF promoter and represses LIF transcription in a manner independent of Myc/Max interaction, requiring instead a contiguous N-terminal N-Myc domain, as shown by promoter reporter assays using N-Myc deletion mutants.\",\n      \"method\": \"Promoter-reporter assay with N-Myc deletion mutants, Northern blotting, adenoviral STAT3 phosphorylation-deficient mutant rescue\",\n      \"journal\": \"European Journal of Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping mutagenesis in reporter assay, single lab, mechanistic follow-up\",\n      \"pmids\": [\"12153570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"N-myc binds a conserved site in the parkin promoter and represses parkin transcription, as shown by ChIP and promoter-reporter assays; parkin expression is inversely correlated with N-myc levels in developing brain, neuroblastoma cell lines, and an inducible N-myc cell line.\",\n      \"method\": \"ChIP, promoter-reporter assay, inducible N-myc cell line, expression correlation in brain development and neuroblastoma\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP plus reporter assay, single lab\",\n      \"pmids\": [\"15078880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"N-Myc directly binds the LIF promoter (ChIP assay) and regulates expression of pluripotency genes (lif, klf2, klf4, lin28b) in neuroblastoma and neural stem cells; N-Myc also regulates histone H3 lysine 4 trimethylation at the lif promoter, linking N-Myc transcriptional activity to active chromatin marks.\",\n      \"method\": \"ChIP-chip, direct ChIP, microarray expression profiling, Tet-regulatable N-myc system, nestin-cre N-myc knockout neural stem cells\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-chip plus direct ChIP plus two orthogonal cell systems, single lab\",\n      \"pmids\": [\"19495417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"N-Myc overexpression drives neuroendocrine prostate cancer (NEPC) in a genetically engineered mouse model and induces Polycomb Repressive Complex 2 (EZH2) signaling with abrogation of androgen receptor signaling.\",\n      \"method\": \"Genetically engineered mouse model (MYCN overexpression), transcriptome analysis, integration with human NEPC data\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with molecular pathway analysis, single lab\",\n      \"pmids\": [\"27728805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"N-Myc and activated AKT1 together are sufficient to transform human prostate epithelial cells into prostate adenocarcinoma and NEPC; N-Myc is required for tumor maintenance, and Aurora A kinase inhibition destabilizes N-Myc and reduces tumor burden.\",\n      \"method\": \"Lentiviral transduction of human prostate epithelial cells, xenograft mouse model, Aurora A inhibitor treatment\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transformation assay with human cells plus in vivo validation, single lab\",\n      \"pmids\": [\"27050099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ATF4 cooperates with N-Myc to directly activate ASCT2 (SLC1A5) glutamine transporter expression in MYCN-amplified neuroblastoma cells; ASCT2 depletion inhibits glutaminolysis and reduces cell proliferation and tumourigenesis.\",\n      \"method\": \"Glutamine influx analysis, siRNA knockdown, luciferase reporter assay showing ATF4/N-Myc co-activation of ASCT2 promoter, xenograft assay\",\n      \"journal\": \"Journal of Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus functional KD plus in vivo xenograft, single lab\",\n      \"pmids\": [\"25142020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"IL-7 induces rapid N-myc and c-myc expression in normal pre-B cells at the transcriptional level; for N-myc, induction is largely mediated by release of a transcriptional attenuation block between exons 1 and 2. More mature B-lineage cells respond to mitogens with c-myc but not N-myc induction, indicating developmental stage-specificity.\",\n      \"method\": \"Nuclear run-on transcription assay, Northern blotting, IL-7 stimulation of pre-B cells\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear run-on assay identifies transcriptional attenuation mechanism, single lab\",\n      \"pmids\": [\"1730410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"N-myc mRNA forms an RNA-RNA duplex in vivo with endogenous antisense transcripts originating from intron 1; most cytoplasmic nonpolyadenylated antisense RNA exists as a duplex with ~5% of sense N-myc mRNA, and duplex formation involves a subset of N-myc mRNA species retaining intron 1, suggesting a role in modulating RNA processing.\",\n      \"method\": \"Nuclear run-off transcription, RNase protection assay for in vivo duplexes, cDNA cloning of both strands\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical detection of in vivo RNA duplex, single lab, well-controlled assay\",\n      \"pmids\": [\"1695323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"N-Myc differentially regulates the miR-421/ATM pathway in a cell-context-dependent manner: in LNCaP cells, N-Myc overexpression upregulates miR-421 to suppress ATM, relieving ADT-induced senescence; in C4-2 cells, N-Myc upregulates ATM, promoting migration and Enzalutamide resistance. ATM knockout or inhibition re-sensitizes N-Myc-overexpressing cells to Enzalutamide.\",\n      \"method\": \"Stable N-Myc overexpression cell lines, CRISPR-Cas9 ATM knockout, SA-β-gal senescence assay, MTS viability assay, xenograft model\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knockout epistasis with defined phenotypic readout, multiple cell lines, single lab\",\n      \"pmids\": [\"30657058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GCN5/KAT2A histone acetyltransferase functions as an N-Myc transcriptional cofactor in neural stem cells; approximately one-sixth of genes regulated by N-Myc loss are co-regulated by GCN5 loss, and GCN5 is required for maintenance of histone acetylation at N-Myc target gene promoters. Conditional knockout of GCN5 in NSC phenocopies N-Myc loss (microcephaly, reduced proliferation).\",\n      \"method\": \"Conditional knockout (nestin-cre), gene expression profiling, histone acetylation ChIP, phenotypic analysis\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with functional and chromatin-level evidence, single lab\",\n      \"pmids\": [\"22745758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Human N-myc and c-myc share a similar three-exon intron/exon structure with coding sequences in exons 2 and 3, long 5' untranslated regions, and significant protein sequence homology, indicating structural and functional kinship.\",\n      \"method\": \"Nucleotide sequencing, exon-intron structure analysis, protein sequence deduction\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct sequencing of human N-myc, single lab, foundational structural characterization\",\n      \"pmids\": [\"3510398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"The N-myc protein is 62-64 kDa as identified by immunoprecipitation from neuroblastoma cells using antisera raised against bacterially expressed N-myc fragments; it shares biochemical features with the c-myc protein family.\",\n      \"method\": \"Bacterial expression of N-myc antigen fragments, immunization, immunoprecipitation from neuroblastoma cell lysates\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical identification of protein size and family membership, single lab\",\n      \"pmids\": [\"3008339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Coactivation of ALK (F1174C-activating mutation) and N-Myc is sufficient to transform mouse prostate basal stem cells into aggressive NEPC via Wnt/β-catenin pathway activation; ALK inhibition suppresses Wnt/β-catenin signaling and cooperates with Wnt inhibition to suppress tumor growth and metastasis.\",\n      \"method\": \"Tissue recombination mouse model, genetic coactivation, pharmacologic ALK/Wnt inhibition in vitro and in vivo\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo tissue recombination model plus pharmacologic pathway validation, single lab\",\n      \"pmids\": [\"33637566\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYCN encodes N-Myc, a bHLH-Zip transcription factor that heterodimerizes with Max to bind E-boxes and directly activate or repress target genes (including DR5, FAK, parkin, LIF, ASCT2, and pluripotency factors); its protein stability is tightly controlled by sequential CDK1/GSK3 phosphorylation triggering SCF(Fbxw7) ubiquitination and proteasomal degradation, which is counteracted by Aurora A kinase (which directly binds N-Myc's Myc Box I region as shown by crystal structure) and by the deubiquitinase HAUSP/USP7; N-Myc drives proliferation in neural progenitors partly by suppressing CDK inhibitors p18Ink4c and p27Kip1 downstream of Shh and Wnt/β-catenin signaling, promotes survival and cell-cycle re-entry through pathways separable from its pro-apoptotic sensitization (via DR5/Bid upregulation), and collaborates with cofactors including HDAC5 and GCN5 to regulate chromatin and transcription in neural and cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYCN encodes N-Myc, a Myc-family transcription factor that drives proliferation and oncogenic transformation across neural progenitors and multiple cancer lineages [#3, #10]. N-Myc shares its three-exon gene architecture, long 5'UTR, and protein-family features with c-Myc, and can functionally replace c-Myc at the endogenous locus to support murine development, establishing that the two share core transcriptional and proliferative programs [#10, #26]. Mechanistically, N-Myc is recruited to target promoters in living cells where it competes with other Max partners for E-box occupancy [#7], and it both activates targets (FAK; the TRAIL receptor DR5 and Bid; the ASCT2/SLC1A5 glutamine transporter in cooperation with ATF4) and represses targets (parkin; LIF, the latter through an N-terminal domain independent of Myc/Max), coupling its transcriptional output to adhesion, apoptotic sensitization, glutaminolysis, and pluripotency-gene control [#8, #9, #21, #16, #17, #18]. In neural development N-Myc acts downstream of Sonic hedgehog and Wnt/\\u03b2-catenin signaling to drive progenitor proliferation, doing so in part by suppressing the CDK inhibitors p18Ink4c and p27Kip1 whose genetic loss rescues proliferation in N-Myc-null cerebella [#11, #13, #12]; it can also force postmitotic neurons into S-phase re-entry through an Rb-dependent pathway separable from its pro-survival activity [#14]. N-Myc protein stability is the dominant control point: sequential cyclin B/Cdk1 and GSK-3\\u03b2 phosphorylation primes SCF(Fbxw7)-mediated polyubiquitination and degradation, which is opposed by Aurora A kinase, which binds the Myc Box I-flanking region (resolved by crystallography) at a site overlapping the Fbxw7 docking site, and by the deubiquitinase HAUSP/USP7 [#0, #1, #2, #11]. N-Myc cooperates with chromatin cofactors GCN5/KAT2A and HDAC5 to maintain its transcriptional and self-stabilizing programs [#25, #15], and beyond neuroblastoma it drives neuroendocrine prostate cancer in cooperation with AKT1, ALK, and Wnt/\\u03b2-catenin signaling [#19, #20, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Establishing that N-myc is a c-myc-related gene with a defined protein product framed it as a Myc-family transcription factor rather than an isolated amplicon.\",\n      \"evidence\": \"Genomic sequencing of human N-myc and immunoprecipitation of the 62-64 kDa protein from neuroblastoma cells\",\n      \"pmids\": [\"3510398\", \"3008339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence kinship did not establish DNA-binding specificity or partner requirements\", \"No functional transcriptional assay in these studies\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Demonstrating that N-Myc transforms fibroblasts alone or with Ha-ras assigned it bona fide oncogenic activity equivalent to c-Myc.\",\n      \"evidence\": \"Co-transfection transformation and soft-agar/tumorigenicity assays in rat fibroblasts\",\n      \"pmids\": [\"3860871\", \"3299052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transformation readout did not define the transcriptional targets responsible\", \"Fibroblast context differs from the neural lineage where N-Myc normally acts\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Showing IL-7-driven N-myc induction occurs via release of a transcriptional attenuation block clarified how its expression is gated in a developmental-stage-specific manner.\",\n      \"evidence\": \"Nuclear run-on transcription assays in normal pre-B cells\",\n      \"pmids\": [\"1730410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Attenuation mechanism characterized in B-lineage, not neural cells\", \"Did not identify the trans-acting factors controlling attenuation\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Knock-in complementation and ChIP recruitment together showed N-Myc shares c-Myc's core function and physically engages target promoters through Max-competitive binding.\",\n      \"evidence\": \"c-myc/N-myc coding-sequence knock-in mice and formaldehyde-crosslinking ChIP at telomerase/prothymosin promoters\",\n      \"pmids\": [\"10837031\", \"11074604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ChIP limited to two target genes\", \"Did not establish genome-wide occupancy or repression mechanisms\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping direct activating and repressing targets defined how N-Myc converts promoter binding into specific phenotypes spanning adhesion, apoptosis sensitization, metabolism, and pluripotency.\",\n      \"evidence\": \"EMSA/ChIP/reporter and promoter-mutagenesis studies on FAK, DR5/Bid, parkin, LIF, ASCT2, and pluripotency genes\",\n      \"pmids\": [\"17327229\", \"15632181\", \"15078880\", \"12153570\", \"19495417\", \"25142020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most targets validated in single labs on individual promoters\", \"LIF repression via a Max-independent N-terminal domain was not structurally resolved\", \"Relative contribution of each target to tumor phenotype unquantified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic epistasis placed N-Myc as the proliferative effector downstream of Shh and Wnt/\\u03b2-catenin that drives neural progenitor expansion by suppressing CDK inhibitors.\",\n      \"evidence\": \"Conditional N-myc knockouts, \\u03b2-catenin gain-of-function, p18/p27 double-mutant rescue, and Rb-dependent S-phase re-entry assays\",\n      \"pmids\": [\"16322694\", \"16864777\", \"20215343\", \"11826111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDK-inhibitor suppression is direct transcriptional repression not fully resolved\", \"Survival pathway separable from cell-cycle re-entry remains molecularly undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying the Cdk1/GSK3-Fbxw7 degradation axis and its antagonists Aurora A and USP7 established N-Myc protein abundance as a druggable control point.\",\n      \"evidence\": \"Co-IP, ubiquitination/phospho-mutagenesis assays, a 1.72 \\u00c5 Aurora A\\u2013N-Myc crystal structure, and in vivo USP7 ablation/inhibitor studies\",\n      \"pmids\": [\"19111882\", \"27837025\", \"27618649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Aurora A's stabilizing function is fully kinase-independent versus structural is incompletely separated\", \"NEDD4 and other ligases noted but not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking N-Myc to chromatin cofactors GCN5 and HDAC5 connected its transcriptional output to histone acetylation and a feed-forward loop reinforcing its own stability.\",\n      \"evidence\": \"Co-IP, conditional GCN5 knockout phenocopy, histone-acetylation ChIP, and HDAC5 knockdown differentiation assays\",\n      \"pmids\": [\"22745758\", \"23812427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only a subset of N-Myc target genes shown to be cofactor-dependent\", \"Direct versus indirect effects of HDAC5 on Aurora A/NEDD4 not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending N-Myc oncogenesis to neuroendocrine prostate cancer showed it cooperates with AKT1, ALK, and Wnt/\\u03b2-catenin and remains required for tumor maintenance and Aurora A-targetable.\",\n      \"evidence\": \"Genetically engineered and tissue-recombination mouse models, human prostate epithelial transformation, and Aurora A/ALK/Wnt pharmacologic inhibition\",\n      \"pmids\": [\"27728805\", \"27050099\", \"33637566\", \"30657058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-context-dependent miR-421/ATM regulation not mechanistically unified\", \"Single-lab models for each cooperating oncogene\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How N-Myc's genome-wide target selection, repressive (Max-independent) activities, and cofactor switching are integrated to specify distinct lineage outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of N-Myc/Max/cofactor complexes on chromatin\", \"Determinants of activation versus repression at individual promoters undefined\", \"Role of the intron-1 antisense RNA duplex in regulating N-myc expression uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 8, 9, 16, 17, 18, 21]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [8, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 8, 9, 16, 17, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 11, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 19, 20, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAX\", \"AURKA\", \"USP7\", \"FBXW7\", \"HDAC5\", \"GCN5\", \"ATF4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}