Affinage

MYCN

N-myc proto-oncogene protein · UniProt P04198

Round 2 corrected
Length
464 aa
Mass
49.6 kDa
Annotated
2026-04-29
130 papers in source corpus 39 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MYCN encodes a basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factor that heterodimerizes with Max to bind E-box sequences in target gene promoters, functioning as a master regulator of proliferation, differentiation, and survival in neural progenitors and other developmental contexts (PMID:2006410, PMID:1935896). MYCN protein stability is tightly controlled by sequential Cdk1- and GSK-3β-primed phosphorylation that triggers SCF(Fbxw7)-mediated ubiquitination and proteasomal degradation, counteracted by Aurora A kinase—which stabilizes MYCN in a kinase activity-independent manner—and USP7/HAUSP deubiquitinase, while the Huwe1 E3 ligase promotes MYCN destruction during neural differentiation (PMID:16139224, PMID:19111882, PMID:27618649, PMID:18488021). As a transcriptional activator and repressor, MYCN directly drives expression of MDM2, ODC1, EZH2/PRC2 targets, DR5, and miR-9, while repressing genes such as parkin and EAAT2, and its oncogenic activity is amplified through positive feedback loops involving HDAC5 and bypass of Rb via Id2 (PMID:15644444, PMID:19047152, PMID:27728805, PMID:20173740, PMID:15078880, PMID:23812427, PMID:11782392). MYCN is an essential downstream effector of Sonic hedgehog and Wnt/β-catenin signaling in cerebellar and cortical progenitors, and its deregulated expression—through genomic amplification or post-transcriptional stabilization by the LIN28B/let-7 axis—drives neuroblastoma, medulloblastoma, and neuroendocrine prostate cancer (PMID:16951180, PMID:20215343, PMID:23042116, PMID:27050099).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1984 High

    Identifying the MYCN gene product as a short-lived nuclear phosphoprotein with DNA-binding capacity established its candidacy as a transcription factor and explained why amplification directly increases protein abundance.

    Evidence Immunoprecipitation, subcellular fractionation, DNA-binding assays, and pulse-chase in neuroblastoma cell lines

    PMID:3796607

    Open questions at the time
    • No sequence-specific DNA recognition demonstrated
    • No partner proteins identified
    • Phosphorylation sites and their functional significance unknown
  2. 1986 High

    Sequencing of human and mouse MYCN revealed a conserved bHLH-Zip architecture shared with c-MYC, predicting heterodimerization-dependent DNA binding and transactivation as the core molecular mechanism.

    Evidence Nucleotide sequencing and deduced amino acid comparative analysis of human and mouse N-myc with c-myc

    PMID:2869488 PMID:3015591

    Open questions at the time
    • No dimerization partner identified
    • No DNA-binding specificity determined
    • Functional equivalence with c-MYC not tested
  3. 1985 High

    Demonstrating that MYCN cooperates with activated Ras to transform primary cells and alone transforms established lines proved it is an authentic proto-oncogene, not merely an amplified bystander.

    Evidence Co-transfection transformation assays, soft agar colony formation, and nude mouse tumorigenicity

    PMID:3299052 PMID:4040214

    Open questions at the time
    • Downstream targets mediating transformation unknown
    • Whether transformation requires Max dimerization not tested
  4. 1991 High

    Discovery that MYCN forms an obligate heterodimer with Max through the HLH-Zip domain, and that only the heterodimer binds DNA with sequence specificity, resolved how a single bHLH protein achieves promoter selectivity.

    Evidence Co-immunoprecipitation with domain deletion mapping, EMSA with purified proteins

    PMID:1935896 PMID:2006410

    Open questions at the time
    • Genomic binding sites not mapped
    • Competition with other Max partners (Mad/Mxi) not characterized in vivo
  5. 1998 High

    Establishing that MYCN is degraded through ubiquitin-dependent proteasomal proteolysis explained its extreme instability and opened the search for the specific E3 ligases and kinase signals controlling turnover.

    Evidence Proteasome and calpain inhibitors, pulse-chase, ubiquitin immunoblotting in neuroblastoma cells

    PMID:9528855

    Open questions at the time
    • Specific E3 ligase not identified
    • Phosphodegron signals not mapped
    • Whether ubiquitination is nuclear or cytoplasmic not resolved
  6. 2005 High

    Mapping the Cdk1→GSK-3β sequential phosphorylation cascade as the trigger for MYCN degradation during the terminal cell cycle of cerebellar granule neuron precursors linked MYCN turnover to cell cycle exit and differentiation.

    Evidence Primary cerebellar granule neuron precursor cultures, kinase inhibitors, phospho-specific antibodies, pulse-chase

    PMID:16139224

    Open questions at the time
    • Identity of the E3 ligase downstream of GSK-3β phosphorylation not yet identified in this study
    • Whether the same phosphodegron operates in non-neuronal contexts unknown
  7. 2008 High

    Identification of Huwe1 as a K48-linkage ubiquitin ligase for MYCN, whose genetic loss blocks neural differentiation rescuable by N-myc silencing, placed a specific E3 ligase upstream of MYCN in the differentiation pathway.

    Evidence Co-immunoprecipitation, ubiquitination assays, Huwe1 knockout ES cells and mouse brain, siRNA epistasis

    PMID:18488021

    Open questions at the time
    • Relationship between Huwe1 and SCF(Fbxw7) pathways not clarified
    • Whether Huwe1 targets the same phosphodegron as Fbxw7 not determined
  8. 2009 High

    Discovery that Aurora A stabilizes MYCN by physically blocking SCF(Fbxw7)-mediated ubiquitination—independently of Aurora A kinase activity—revealed a non-catalytic scaffolding mechanism and a druggable protein–protein interaction.

    Evidence shRNA screen, co-immunoprecipitation of Aurora A/MYCN/Fbxw7 complex, kinase-dead Aurora A mutants, pulse-chase

    PMID:19111882

    Open questions at the time
    • Structural basis of kinase-independent stabilization not resolved at atomic level
    • Relative contributions of Huwe1 vs. Fbxw7 in different tissues unknown
  9. 2013 High

    Pharmacological disruption of the Aurora A–MYCN complex by allosteric Aurora A inhibitors drove MYCN degradation and tumor regression in vivo, validating the non-catalytic stabilization mechanism as a therapeutic target.

    Evidence Co-crystal structures, small-molecule Aurora A inhibitors, TH-MYCN mouse neuroblastoma model

    PMID:23792191 PMID:25175806

    Open questions at the time
    • Clinical efficacy in MYCN-amplified patients not established
    • Whether resistance arises through alternative stabilization pathways not tested
  10. 2016 High

    Identification of USP7/HAUSP as a deubiquitinase that directly stabilizes MYCN added a third layer of post-translational control and provided a second druggable target for destabilizing MYCN protein.

    Evidence Co-immunoprecipitation, in vitro deubiquitination assay, conditional Usp7 knockout in mouse brain, HAUSP inhibitor xenograft studies

    PMID:27618649

    Open questions at the time
    • Whether USP7 opposes Huwe1, Fbxw7, or both is unknown
    • Structural basis of USP7–MYCN interaction not determined
  11. 2002 Medium

    Identification of Id2 as a direct MYCN target that sequesters Rb revealed how MYCN overcomes cell cycle checkpoint control in neural progenitors and neuroblastoma, linking transcriptional output to a specific proliferation mechanism.

    Evidence Immunohistochemistry, transformation assays, siRNA knockdown, Id2-null mouse embryonic fibroblasts

    PMID:11782392

    Open questions at the time
    • Whether Id2 is the sole mediator of Rb inactivation by MYCN not established
    • Direct MYCN binding to Id2 promoter not shown by ChIP in this study
  12. 2005 High

    Demonstration that MYCN directly activates MDM2 transcription via a canonical E-box explained how MYCN dampens p53-dependent apoptosis, resolving the paradox of MYCN simultaneously promoting proliferation and suppressing cell death.

    Evidence ChIP, oligonucleotide pulldown, luciferase reporter, inducible MYCN neuroblastoma lines

    PMID:15644444

    Open questions at the time
    • Relative importance of MYCN-MDM2 vs. Twist-ARF pathways in p53 suppression not quantified
    • Whether MDM2 activation is context-dependent across tumor types not tested
  13. 2006 High

    Conditional knockout experiments placing MYCN as the essential downstream effector of Shh signaling in cerebellar granule neuron precursors established MYCN's non-redundant role in developmental mitogenic signaling and medulloblastoma formation.

    Evidence Conditional N-myc knockout mice, in vitro Shh proliferation assays, compound mutants with ND2:SmoA1

    PMID:16951180

    Open questions at the time
    • How Shh signaling induces MYCN transcription or stabilization not resolved
    • Whether MYCN mediates all Shh proliferative outputs or only a subset is unclear
  14. 2016 High

    Showing that MYCN overexpression activates an EZH2/PRC2-mediated transcriptional program and drives neuroendocrine transdifferentiation of prostate cancer extended MYCN's oncogenic role beyond neural crest-derived tumors.

    Evidence Genetically engineered MYCN-overexpressing prostate mouse model, ChIP-seq for EZH2, human NEPC transcriptome validation

    PMID:27050099 PMID:27728805

    Open questions at the time
    • Whether EZH2 is a direct MYCN transcriptional target or indirectly upregulated not fully resolved
    • Mechanism by which MYCN suppresses androgen receptor signaling unknown
  15. 2012 High

    Establishing the LIN28B/let-7/MYCN post-transcriptional axis as sufficient to initiate neuroblastoma in vivo identified an amplification-independent mechanism for pathological MYCN elevation.

    Evidence let-7 quantification, MYCN protein analysis, LIN28B transgenic mouse model in sympathetic adrenergic lineage

    PMID:23042116

    Open questions at the time
    • Whether let-7 directly targets MYCN mRNA or acts through intermediate regulators not fully dissected
    • Clinical relevance of LIN28B overexpression relative to MYCN amplification not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MYCN integrates its multiple post-translational stabilization inputs (Aurora A, USP7, YAP/TAZ) with transcriptional and post-transcriptional regulation (BRD4, LIN28B/let-7, miR-34a) to set threshold protein levels in normal development versus cancer, and whether these distinct inputs can be simultaneously targeted therapeutically, remains unresolved.
  • No integrated quantitative model of MYCN protein homeostasis exists
  • Structural basis of MYCN–Aurora A and MYCN–USP7 interactions at atomic resolution lacking
  • Therapeutic combination strategies targeting multiple stabilization axes untested in clinical trials

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 12 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-4839726 Chromatin organization 1
Partners
AURKAFBXW7HDAC5HUWE1MAXUSP7YAP1
Complex memberships
MYC-MAX heterodimer

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 N-myc encodes nuclear phosphoproteins (65 kDa and 67 kDa) that bind both single- and double-stranded DNA, are exceptionally unstable, and are located in the nucleus; their abundance correlates with N-myc amplification extent. Protein identification by immunoprecipitation, subcellular fractionation, DNA-binding assays, pulse-chase stability assays Molecular and cellular biology High 3796607
1986 N-myc and c-myc share similar intron/exon structure (three exons with coding elements in exons 2 and 3), long 5' UTRs, and encode related proteins with conserved C-terminal basic helix-loop-helix leucine zipper domains and N-terminal transactivation regions, suggesting related biochemical functions. Nucleotide sequencing, deduced amino acid sequence comparison, exon-intron mapping Proceedings of the National Academy of Sciences of the United States of America High 2869488
1986 Mouse N-myc encodes a 462 amino acid protein rich in proline; sequence comparison with c-myc reveals eight conserved regions (four in N-terminal half, four in C-terminal half including HLH-Zip), with a distinctive stretch of 13 consecutive acidic amino acids in one conserved N-terminal region. Genomic cloning, nucleotide sequencing, deduced amino acid sequence analysis The EMBO journal High 3015591
1985 N-myc cooperates with mutant c-Ha-ras to transform secondary rat embryo cells, and N-myc alone transforms established Rat-1 fibroblasts, causing morphological transformation, anchorage-independent growth, and tumorigenicity, demonstrating it is an authentic proto-oncogene with neoplastic transformation activity. Co-transfection transformation assay, soft agar colony formation, nude mouse tumorigenicity assay Nature High 3299052 4040214
1986 Overexpression of N-myc in a rat neuroblastoma cell line causes down-modulation of MHC class I histocompatibility antigen expression and increases in vivo growth rate and metastatic ability; this effect is cell-type-specific (not observed in fibroblasts) and reversible by interferon treatment without affecting N-myc mRNA levels. Gene transfer/transfection, flow cytometry for MHC class I, in vivo tumor growth and metastasis assays Cell High 3096575
1991 N-Myc protein forms a hetero-oligomeric complex in vivo with Max (p20/p22) in human neuroblastoma cells; the HLH-Zip region of N-Myc is essential for complex formation, and both Max proteins are phosphorylated by casein kinase II in vitro. Co-immunoprecipitation with monoclonal antibody, partial proteolytic mapping, in vitro kinase assay, deletion/point mutation analysis of N-Myc The EMBO journal High 1935896
1991 Max specifically associates with N-Myc, c-Myc, and L-Myc through their HLH-Zip domains, and the Myc-Max complex binds DNA in a sequence-specific manner; neither Max nor Myc alone exhibits appreciable DNA binding under these conditions. cDNA library screen with Myc bHLH-Zip bait, co-immunoprecipitation, electrophoretic mobility shift assay (EMSA), domain mutagenesis Science (New York, N.Y.) High 2006410
1993 N-Myc protein transitions from nuclear to cytoplasmic localization during differentiation of specific neuronal classes (retinal ganglion cells, spinal ganglia neurons, cerebellar Purkinje cells), revealing a novel regulated localization mechanism for Myc family proteins in maturing neurons. Immunohistochemistry, immunofluorescence on embryonic neural tissues with anti-N-Myc antibodies Neuron Medium 8427698
1998 N-myc protein is degraded in vivo via the 26S proteasome through ubiquitin-dependent proteolysis; proteasome inhibitors (ALLnL, lactacystin) stabilize N-myc and increase its polyubiquitination, while calpain and cathepsin inhibitors do not affect degradation; fluorescence microscopy shows N-myc is exclusively nuclear during proteasome inhibition. Proteasome/calpain inhibitor treatment, pulse-chase experiments, ubiquitin Western blotting, fluorescence microscopy Oncogene High 9528855
2000 N-myc is directly recruited to the promoters of telomerase and prothymosin target genes in living neuroblastoma cells; N-myc competes with other Max partners for promoter binding, and overexpression of N-myc increases N-myc occupancy at these promoters while Max remains constitutively bound. Chromatin immunoprecipitation (ChIP) in living cells with formaldehyde crosslinking Molecular carcinogenesis Medium 11074604
2002 N-Myc drives Id2 overexpression to bypass Rb tumor suppressor function; an N-Myc-Id2 pathway persists during late nervous system development and parallels rising levels of active Rb in withdrawing neuronal precursors; overexpression of Id2 mediates cellular transformation and is required to maintain neuroblastoma malignancy. Immunohistochemistry of primary neuroblastomas, transformation assays, siRNA knockdown, embryonic fibroblast proliferation from Id2-null mice Cancer research Medium 11782392
2002 N-myc expression in postmitotic sympathetic neurons induces S-phase re-entry while protecting against apoptosis caused by nerve growth factor withdrawal; N-myc-induced cell cycle entry (but not survival) is blocked by constitutively hypophosphorylated Rb, indicating N-myc uses separate pathways for proliferation and survival. Neuronal microinjection/transfection, BrdU incorporation, cell cycle marker analysis, epistasis with constitutively active Rb The Journal of neuroscience Medium 11826111
2002 N-Myc directly activates Pax-3 promoter activity via a noncanonical E-box site in the 5' promoter region; N-Myc-Max heterodimer drives Pax-3 transcription, and the E-box is required for cell cycle-dependent Pax-3 expression. Transient transfection luciferase reporter assays, RT-PCR, site-directed mutagenesis of E-box The Journal of biological chemistry Medium 12095979
2004 N-myc directly binds the parkin promoter and represses parkin transcription; parkin expression is inversely correlated with N-myc levels in developing brain, neuroblastoma cell lines with varying N-myc amplification, and in an inducible N-myc cell line. Chromatin immunoprecipitation, luciferase reporter assays, inducible N-myc cell line, developmental expression analysis The Journal of biological chemistry Medium 15078880
2004 H-Twist overexpression cooperates with N-Myc oncogenesis by inhibiting the ARF/p53 apoptotic pathway activated by N-Myc; N-Myc deregulation promotes both proliferation and p53-dependent apoptosis, and H-Twist is constitutively overexpressed in N-Myc-amplified neuroblastomas as an escape mechanism. cDNA microarray, transfection-based transformation assays, ARF/p53 pathway reporter assays Cancer cell Medium 15607966
2005 N-myc is recruited to the EAAT2 glutamate transporter promoter in response to TNFα and mediates TNFα-dependent transcriptional repression; N-myc overexpression inhibits both basal and NF-κB/p65-induced EAAT2 activation, and N-myc binding sites within the EAAT2 promoter are required for repression. Chromatin immunoprecipitation, promoter reporter assays, overexpression studies, site-directed mutagenesis The EMBO journal Medium 15660126
2005 Methylation of the CpG dinucleotide within the E-box (CACGTG) prevents N-Myc access to gene promoters in vivo; N-Myc is a direct regulator of several target genes identified by ChIP and methylation-sensitive restriction analysis, and differential E-box methylation generates cell-type-specific patterns of N-Myc-dependent transcription. Chromatin immunoprecipitation, methylation-sensitive restriction analysis, E-box methylation mapping Proceedings of the National Academy of Sciences of the United States of America Medium 16093321
2005 Cdk1 complex phosphorylates N-myc as a priming event for subsequent GSK-3β phosphorylation and proteasomal degradation in mitosis; degradation of N-myc during the final cell division cycle is required for cerebellar granule neuron precursor growth arrest and differentiation. Primary mouse cerebellar granule neuron precursor cultures, kinase inhibitors, phosphorylation-specific antibodies, pulse-chase, genetic loss-of-function Developmental cell High 16139224
2005 N-Myc directly upregulates TRAIL receptor DR5/KILLER and Bid by binding noncanonical E-boxes in the DR5 promoter, sensitizing neuroblastoma cells to TRAIL-induced apoptosis; TRAIL-induced apoptosis in N-Myc-overexpressing cells proceeds through Smac/DIABLO but not cytochrome c-mediated caspase-9 activation. DR5 promoter luciferase reporter with E-box mutagenesis, overexpression studies, Western blotting for caspase pathway components, siRNA knockdown The Journal of biological chemistry Medium 15632181
2005 MDM2 is a direct transcriptional target of MYCN; MYCN binds a consensus E-box in the MDM2 promoter (confirmed by ChIP and oligonucleotide pulldown), upregulates MDM2 mRNA and protein in inducible neuroblastoma lines, and MYCN inhibition decreases MDM2 expression with concomitant p53 stabilization and apoptosis. ChIP cloning screen, ChIP with MYCN antibodies, oligonucleotide pulldown, luciferase reporter assays, quantitative RT-PCR, Western blot in inducible MYCN cell lines Proceedings of the National Academy of Sciences of the United States of America High 15644444
2006 N-myc acts as an essential downstream effector of Sonic hedgehog (Shh) signaling in cerebellar granule neuron precursors; conditional deletion of N-myc (but not c-myc) abolishes Shh-induced proliferation, and in vivo compound mutants show that N-myc is required for medulloblastoma formation downstream of constitutively active Smoothened. Conditional knockout (N-myc floxed mice), in vitro Shh response assay, in vivo compound mutants with ND2:SmoA1 transgene Cancer research High 16951180
2008 Huwe1 (HECT-domain ubiquitin ligase) ubiquitinates N-Myc via K48-linked chains and targets it for proteasomal degradation; Huwe1 inactivation prevents N-Myc degradation, blocks cell cycle exit, and impairs neural differentiation; silencing N-myc in Huwe1-deficient cells rescues both phenotypes, placing Huwe1 upstream of N-Myc in the neural differentiation pathway. Co-immunoprecipitation, ubiquitination assay, genetic knockout (mouse and ES cells), RNA interference, cell cycle analysis, neural differentiation markers Nature cell biology High 18488021
2009 Aurora A kinase interacts directly with N-Myc and counteracts SCF(Fbxw7)-mediated ubiquitination and proteasomal degradation of N-Myc; N-Myc degradation normally requires sequential phosphorylation by cyclin B/Cdk1 and GSK-3; Aurora A stabilizes N-Myc independently of its catalytic kinase activity, uncoupling N-Myc stability from PI3-kinase/growth factor signals. shRNA screen, co-immunoprecipitation of Aurora A/N-Myc/Fbxw7 complex, kinase-dead Aurora A mutants, cyclin B/Cdk1 and GSK-3 phosphorylation assays, pulse-chase Cancer cell High 19111882
2010 MYC and MYCN directly bind the mir-9-3 locus to activate miR-9 transcription; miR-9 directly targets CDH1 (E-cadherin) mRNA, leading to increased cell motility and invasiveness and activation of β-catenin/VEGF signaling. ChIP for MYCN/MYC at mir-9-3 locus, luciferase reporter for miR-9 targeting of CDH1, gain/loss-of-function in breast cancer cells Nature cell biology High 20173740
2010 Wnt signaling acts upstream of N-myc to regulate basal progenitor production and neuronal fate commitment in the neocortex; stabilized β-catenin or N-myc overexpression increases basal progenitors in vivo, while conditional N-myc deletion reduces basal progenitor numbers and neocortical neuron output. Conditional N-myc knockout (nestin-Cre), stabilized β-catenin overexpression, in vivo and in vitro progenitor quantification Development (Cambridge, England) Medium 20215343
2013 Aurora A inhibitors MLN8054 and MLN8237 disrupt the Aurora A/N-Myc protein complex and promote Fbxw7-mediated proteasomal degradation of N-Myc; stabilization of N-Myc by Aurora A does not require Aurora A catalytic activity; complex disruption inhibits N-Myc-dependent transcription and causes tumor regression in a MYCN-driven mouse neuroblastoma model. Co-immunoprecipitation, N-Myc protein stability assays, transcription profiling, in vivo mouse neuroblastoma model (TH-MYCN), small molecule inhibitors Cancer cell High 23792191
2013 HDAC5 forms a protein complex with N-Myc to repress a common subset of target genes; HDAC5 represses NEDD4 ubiquitin ligase expression, increases Aurora A expression, and consequently stabilizes N-Myc protein; conversely, N-Myc upregulates HDAC5 expression, establishing a positive feedback loop. Co-immunoprecipitation, genome-wide gene expression analysis, ChIP, Western blotting, siRNA knockdown Oncogene Medium 23812427
2014 An allosteric class of Aurora A inhibitors disrupts the native conformation of Aurora A and drives proteasomal degradation of MYCN; co-crystal structures reveal an Aurora A conformation-specific mechanism distinct from simple kinase inhibition, explaining how these inhibitors promote MYCN degradation across MYCN-driven cancers. Co-crystal structures of Aurora A/inhibitor complexes, structure-activity relationships, biochemical proteasome degradation assays, mutagenesis Cancer cell High 25175806
2016 HAUSP/USP7 deubiquitinase interacts with N-Myc, deubiquitinates it, and stabilizes the protein; USP7 knockdown or genetic ablation in mouse brain destabilizes N-Myc and inhibits its function; small-molecule HAUSP inhibitors suppress growth of MYCN-amplified neuroblastoma xenografts. Co-immunoprecipitation, deubiquitination assay, RNAi knockdown, conditional mouse Usp7 knockout, xenograft mouse model with HAUSP inhibitors Nature medicine High 27618649
2016 N-Myc overexpression drives neuroendocrine prostate cancer by inducing an EZH2-mediated transcriptional program; N-Myc overexpression abrogates androgen receptor signaling and activates Polycomb Repressive Complex 2 (PRC2/EZH2) signaling, as established in a genetically engineered mouse model confirmed against human NEPC transcriptomics. Genetically engineered mouse model (MYCN overexpression in prostate), gene expression profiling, ChIP-seq for EZH2, human NEPC transcriptome validation Cancer cell High 27728805
2016 N-Myc and activated AKT1 are sufficient to transform human prostate epithelial cells into prostate adenocarcinoma and neuroendocrine prostate cancer; N-Myc is required for tumor maintenance (demonstrated by inducible N-myc knockdown), and Aurora A kinase inhibition destabilizes N-Myc and reduces tumor burden. Lentiviral transformation of human prostate epithelial cells, organoid and xenograft models, inducible N-myc knockdown, Aurora A kinase inhibitor treatment Cancer cell High 27050099
2019 N-Myc differentially regulates the miR-421/ATM pathway in a cell-context-dependent manner: in LNCaP cells, N-Myc overexpression suppresses ATM by upregulating miR-421, relieving ADT-induced senescence; in C4-2 cells, N-Myc upregulates ATM to promote migration and Enzalutamide resistance, which is reversed by ATM inhibition or CRISPR-Cas9 ATM knockout. Stable N-Myc overexpressing cell lines, CRISPR-Cas9 ATM knockout, miR-421 modulation, SA-β-gal senescence assay, xenograft model Molecular cancer Medium 30657058
2021 Coactivation of ALK F1174C and N-Myc is sufficient to transform mouse prostate basal stem cells into aggressive neuroendocrine prostate cancer; ALK F1174C and ALK/N-Myc tumors display Wnt/β-catenin pathway activation; ALK inhibition suppresses Wnt/β-catenin signaling and cooperates with Wnt inhibition to suppress NEPC growth and metastasis. Tissue recombination model, gene expression profiling, chemical and genetic ALK inhibition, Wnt pathway reporter/inhibitor studies, in vivo metastasis assay Cancer research Medium 33637566
2023 Activated YAP/TAZ bind and stabilize N-Myc protein in mesangial cells; YAP/TAZ-mediated N-Myc stabilization leads to enhanced N-Myc transcriptional activity and mesangial cell impairments characteristic of diabetic nephropathy. Immunoprecipitation for YAP/TAZ-N-Myc interaction, protein stability assays, conditional mouse Lats1/2 knockout model, RiboTag RNA-seq Journal of the American Society of Nephrology : JASN Medium 36724799
2008 MYCN-amplified neuroblastomas coordinately deregulate multiple polyamine biosynthesis enzymes (ODC1, SRM, SMS, AMD1, OAZ2, SMOX); ODC1 is a direct downstream effector of MYCN oncogenesis, and pharmacological ODC inhibition with DFMO suppresses neuroblastoma in TH-MYCN mice and inhibits neuroblast proliferation in vitro. Transcriptome analysis of MYCN-amplified tumors, TH-MYCN mouse model pharmacology, in vitro proliferation assays, in vivo survival analysis Cancer research Medium 19047152
2012 LIN28B elevates MYCN protein expression in neuroblastoma by suppressing let-7 microRNAs; this LIN28B-let-7-MYCN axis blocks neuroblast differentiation and is sufficient to induce neuroblastoma in a mouse model expressing LIN28B in the sympathetic adrenergic lineage. let-7 miRNA quantification, MYCN protein expression analysis, mouse transgenic model, neuroblast differentiation assays Nature genetics High 23042116
2013 BRD4 bromodomain-containing protein acts as a transcriptional regulator of MYCN expression; BET bromodomain inhibition downregulates MYCN transcription and its transcriptional program; BRD4 knockdown phenocopies BET inhibitor effects, suppressing MYCN-amplified neuroblastoma growth in vivo. BET bromodomain inhibitor (JQ1) treatment, BRD4 siRNA knockdown, genome-wide expression analysis, in vivo neuroblastoma models Cancer discovery High 23430699
2008 The MYCN oncogene is a direct target of miR-34a; miR-34a directly suppresses MYCN expression in neuroblastoma cells with MYCN amplification, inducing apoptosis and decreasing DNA synthesis; miR-34a maps to the 1p36 region commonly deleted alongside MYCN amplification. Luciferase reporter with MYCN 3'UTR, quantitative RT-PCR, cell growth and apoptosis assays, gene expression profiling Oncogene Medium 18504438

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1984 Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science (New York, N.Y.) 2112 6719137
1985 Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. The New England journal of medicine 1945 4047115
1991 Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science (New York, N.Y.) 1807 2006410
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2010 miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nature cell biology 1112 20173740
2017 Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science (New York, N.Y.) 934 28473536
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1985 Decreased expression of N-myc precedes retinoic acid-induced morphological differentiation of human neuroblastoma. Nature 634 3855502
2010 A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 565 20946988
2013 Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer discovery 521 23430699
1984 Expression and amplification of the N-myc gene in primary retinoblastoma. Nature 483 6728001
2009 Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer cell 472 19111882
2016 N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer. Cancer cell 470 27728805
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2016 N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells. Cancer cell 336 27050099
1986 N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma. Cell 328 3096575
1992 Loss of N-myc function results in embryonic lethality and failure of the epithelial component of the embryo to develop. Genes & development 323 1459449
2012 LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nature genetics 322 23042116
1984 Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc. Nature 309 6700732
1985 Human N-myc gene contributes to neoplastic transformation of mammalian cells in culture. Nature 295 4040214
2013 Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. The Lancet. Oncology 292 23498719
1992 Embryonic lethality in mice homozygous for a targeted disruption of the N-myc gene. Genes & development 281 1459450
2012 Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer cell 270 22439933
1986 Human N-myc is closely related in organization and nucleotide sequence to c-myc. Nature 256 3510398
2020 Target gene-independent functions of MYC oncoproteins. Nature reviews. Molecular cell biology 250 32071436
2013 Histone H3.3. mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer discovery 245 23539269
2010 The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 243 20667976
2013 Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma. Cancer cell 242 23792191
2008 The MYCN oncogene is a direct target of miR-34a. Oncogene 239 18504438
1990 Frequent activation of N-myc genes by hepadnavirus insertion in woodchuck liver tumours. Nature 237 2205804
2008 The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nature cell biology 230 18488021
2014 Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer cell 229 25175806
2018 A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers. Clinical cancer research : an official journal of the American Association for Cancer Research 228 30232224
2018 Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry. Nature genetics 223 30127528
2008 ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma. Cancer research 220 19047152
1986 Nucleotide sequence of the human N-myc gene. Proceedings of the National Academy of Sciences of the United States of America 216 2869488
2010 Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clinical cancer research : an official journal of the American Association for Cancer Research 211 20719933
2013 Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia (New York, N.Y.) 208 23358695
2008 Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas. Genome biology 208 18851746
2004 Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer cell 208 15607966
2005 The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. Proceedings of the National Academy of Sciences of the United States of America 204 15644444
2012 Functional genomics identifies therapeutic targets for MYC-driven cancer. Proceedings of the National Academy of Sciences of the United States of America 203 22623531
2005 Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression. The EMBO journal 201 15660126
1993 Defects of embryonic organogenesis resulting from targeted disruption of the N-myc gene in the mouse. Development (Cambridge, England) 187 8404543
2012 Distinct neural stem cell populations give rise to disparate brain tumors in response to N-MYC. Cancer cell 172 22624711
1991 The N-Myc oncoprotein is associated in vivo with the phosphoprotein Max(p20/22) in human neuroblastoma cells. The EMBO journal 172 1935896
2016 HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma. Nature medicine 170 27618649
1993 Defects in heart and lung development in compound heterozygotes for two different targeted mutations at the N-myc locus. Development (Cambridge, England) 163 8287798
1998 Dissecting the role of N-myc in development using a single targeting vector to generate a series of alleles. Current biology : CB 160 9635194
1992 A targeted mutation reveals a role for N-myc in branching morphogenesis in the embryonic mouse lung. Genes & development 156 1577267
1993 Detection of N-myc gene amplification by fluorescence in situ hybridization. Diagnostic utility for neuroblastoma. The American journal of pathology 144 7684192
2006 N-myc is an essential downstream effector of Shh signaling during both normal and neoplastic cerebellar growth. Cancer research 139 16951180
1986 Human proto-oncogene N-myc encodes nuclear proteins that bind DNA. Molecular and cellular biology 131 3796607
2005 The Cdk1 complex plays a prime role in regulating N-myc phosphorylation and turnover in neural precursors. Developmental cell 130 16139224
1987 Neoplastic transformation by the human gene N-myc. Molecular and cellular biology 127 3299052
1995 Identification of subsets of neuroblastomas by combined histopathologic and N-myc analysis. Journal of the National Cancer Institute 120 7674334
2005 N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury. The Journal of biological chemistry 117 16314423
2002 Id2 is critical for cellular proliferation and is the oncogenic effector of N-myc in human neuroblastoma. Cancer research 117 11782392
2007 The N-Myc down regulated Gene1 (NDRG1) Is a Rab4a effector involved in vesicular recycling of E-cadherin. PloS one 106 17786215
1991 Embryonic lethality resulting from disruption of both N-myc alleles in mouse zygotes. The New biologist 106 1931830
1987 Analysis of N-myc amplification in relation to disease stage and histologic types in human neuroblastomas. Cancer 106 3594401
2005 In vivo transcriptional regulation of N-Myc target genes is controlled by E-box methylation. Proceedings of the National Academy of Sciences of the United States of America 105 16093321
1989 N-myc is frequently activated by proviral insertion in MuLV-induced T cell lymphomas. The EMBO journal 103 2653809
2009 N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer. Neoplasia (New York, N.Y.) 97 19649210
2019 N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway. Molecular cancer 95 30657058
1989 Amplified N-myc in human neuroblastoma cells is often arranged as clustered tandem repeats of differently recombined DNA. Molecular and cellular biology 92 2601700
1993 Transition of localization of the N-Myc protein from nucleus to cytoplasm in differentiating neurons. Neuron 89 8427698
2004 Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. Proceedings of the National Academy of Sciences of the United States of America 86 14983023
2006 Neural precursor cycling at sonic speed: N-Myc pedals, GSK-3 brakes. Cell cycle (Georgetown, Tex.) 80 16322694
2010 Wnt signaling and its downstream target N-myc regulate basal progenitors in the developing neocortex. Development (Cambridge, England) 78 20215343
2008 N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma. Oncogene 78 18278068
2008 N-Myc downstream-regulated gene 2 is involved in p53-mediated apoptosis. Nucleic acids research 78 18689861
2011 Antitumor activity of sustained N-myc reduction in rhabdomyosarcomas and transcriptional block by antigene therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 76 22065083
2017 TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours. Molecular cancer 70 28327152
1985 Retinoic acid treatment of human neuroblastoma cells is associated with decreased N-myc expression. Biochemical and biophysical research communications 70 3977910
2009 Nmi (N-Myc interactor) inhibits Wnt/beta-catenin signaling and retards tumor growth. International journal of cancer 64 19358268
2002 N-myc promotes survival and induces S-phase entry of postmitotic sympathetic neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 64 11826111
1993 Preferential amplification of the paternal allele of the N-myc gene in human neuroblastomas. Nature genetics 64 8102299
2011 Conditional deletion of N-Myc disrupts neurosensory and non-sensory development of the ear. Developmental dynamics : an official publication of the American Association of Anatomists 63 21448975
2016 Emerging role of N-myc downstream-regulated gene 2 (NDRG2) in cancer. Oncotarget 62 26506239
2014 microRNA-29 negatively regulates EMT regulator N-myc interactor in breast cancer. Molecular cancer 62 25174825
2004 Nitric oxide negatively regulates proliferation and promotes neuronal differentiation through N-Myc downregulation. Journal of cell science 60 15331636
2007 Overexpression of N-Myc rapidly causes acute myeloid leukemia in mice. Cancer research 55 18006809
1994 The biological effects of antisense N-myc expression in human neuroblastoma. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 54 8180130
1986 Increased N-myc expression following progressive growth of human neuroblastoma. Cancer research 53 3731081
2000 Direct recruitment of N-myc to target gene promoters. Molecular carcinogenesis 52 11074604
1992 Isolation and structural analysis of a 1.2-megabase N-myc amplicon from a human neuroblastoma. Molecular and cellular biology 51 1448086
1998 In vivo degradation of N-myc in neuroblastoma cells is mediated by the 26S proteasome. Oncogene 50 9528855
1988 Characterization of N-myc amplification units in human neuroblastoma cells. Molecular and cellular biology 50 2832725
2021 Activated ALK Cooperates with N-Myc via Wnt/β-Catenin Signaling to Induce Neuroendocrine Prostate Cancer. Cancer research 49 33637566
1994 Aggressive medulloblastoma with high-level N-myc amplification. Mayo Clinic proceedings 48 8170180
2011 N-myc controls proliferation, morphogenesis, and patterning of the inner ear. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 21562282
2007 Activities of N-Myc in the developing limb link control of skeletal size with digit separation. Development (Cambridge, England) 47 17360777
2004 N-myc regulates parkin expression. The Journal of biological chemistry 47 15078880
1988 N-myc amplification at chromosome band 1p32 in neuroblastoma cells as investigated by in situ hybridization. Journal of cancer research and clinical oncology 44 3204111
2010 c-myc and N-myc promote active stem cell metabolism and cycling as architects of the developing brain. Oncotarget 43 20651942
2011 Didymin induces apoptosis by inhibiting N-Myc and upregulating RKIP in neuroblastoma. Cancer prevention research (Philadelphia, Pa.) 42 22174364
1997 Modulation of N-myc expression alters the invasiveness of neuroblastoma. Clinical & experimental metastasis 42 9062389
2005 N-Myc functions in transcription and development. Birth defects research. Part C, Embryo today : reviews 41 16425253
1986 Nucleotide sequence of the coding region of the mouse N-myc gene. The EMBO journal 40 3015591
2002 The expression of the developmentally regulated proto-oncogene Pax-3 is modulated by N-Myc. The Journal of biological chemistry 38 12095979
2000 Role of N-myc in the developing mouse kidney. Developmental biology 38 10837121
2000 Multiple genomic alterations including N-myc amplification in a primary large cell medulloblastoma. Pediatric neurosurgery 38 10940769
1990 Inverse correlation between N-myc amplification and catecholamine metabolism in children with advanced neuroblastoma. Surgery 38 2404349
1991 In vivo modulation of N-myc expression by continuous perfusion with an antisense oligonucleotide. Antisense research and development 37 1821655
1986 Amplification of N-myc in a rhabdomyosarcoma. Japanese journal of cancer research : Gann 37 2432051
2013 Histone deacetylase 5 blocks neuroblastoma cell differentiation by interacting with N-Myc. Oncogene 36 23812427
2005 Linking of N-Myc to death receptor machinery in neuroblastoma cells. The Journal of biological chemistry 36 15632181
2020 Beyond the Warburg Effect: N-Myc Contributes to Metabolic Reprogramming in Cancer Cells. Frontiers in oncology 35 32547946
2014 N-Myc interactor inhibits prototype foamy virus by sequestering viral Tas protein in the cytoplasm. Journal of virology 35 24719420
1992 The N-myc proto-oncogene: developmental expression and in vivo site-directed mutagenesis. Brain pathology (Zurich, Switzerland) 35 1341949
2017 N-myc regulates growth and fiber cell differentiation in lens development. Developmental biology 34 28716713
1995 pRb is necessary for inhibition of N-myc expression by TGF-beta 1 in embryonic lung organ cultures. Development (Cambridge, England) 32 7555731
2008 N-myc augments death and attenuates protective effects of Bcl-2 in trophically stressed neuroblastoma cells. Oncogene 31 18193081
2011 N-myc downstream-regulated gene 1 (NDRG1) a differentiation marker of human breast cancer. Pathology oncology research : POR 29 21221878
1997 In vivo regulation of single copy and amplified N-myc in human neuroblastoma cells. Oncogene 29 9233765
1990 Expression of the N-myc proto-oncogene during the early development of Xenopus laevis. Development (Cambridge, England) 28 2088727
2015 Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin. Oncotarget 27 25883214
2013 Loss of N-Myc interactor promotes epithelial-mesenchymal transition by activation of TGF-β/SMAD signaling. Oncogene 27 23770854
2010 N-myc downstream regulated 1 gene and its place in the cellular machinery. Acta biochimica Polonica 27 20300662
1993 Protein phosphorylation required for the formation of E2F complexes regulates N-myc transcription during differentiation of human embryonal carcinoma cells. Oncogene 26 8384353
1987 Amplification of IMR-32 clones 8, G21, and N-myc in human neuroblastoma xenografts. Cancer research 25 3034408
2023 Hyperactivation of YAP/TAZ Drives Alterations in Mesangial Cells through Stabilization of N-Myc in Diabetic Nephropathy. Journal of the American Society of Nephrology : JASN 24 36724799
1993 Determination of N-myc gene amplification in neuroblastoma by differential polymerase chain reaction. Molecular and cellular probes 24 8366868
1989 N-myc activation by proviral insertion in MCF 247-induced murine T-cell lymphomas. Oncogene 24 2548143
1986 Amplification of the N-myc oncogene in an adenocarcinoma of the lung. Journal of cellular biochemistry 24 3020069
2015 Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea. Development (Cambridge, England) 23 26160903
2002 N-myc modulates expression of p73 in neuroblastoma. Neoplasia (New York, N.Y.) 22 12192602