Abstract
N-Myc oncogene amplification is a frequent event in neuroblastoma and is strongly correlated with advanced disease stage and treatment failure. Similarly to c-Myc oncogenic activation, N-Myc deregulation promotes both cell proliferation and p53-dependent apoptosis by sensitizing cells to a variety of insults. Intriguingly, p53 mutations are uncommon in neuroblastomas, strongly suggesting that an alternative cooperating event circumvents this safeguard against oncogene-driven neoplasia. By performing a pangenomic cDNA microarray analysis, we demonstrate that human Twist is constantly overexpressed in N-Myc-amplified neuroblastomas. H-Twist overexpression is responsible for the inhibition of the ARF/p53 pathway involved in the Myc-dependent apoptotic response. This oncogenic cooperation of two key regulators of embryogenesis causes cell transformation and malignant outgrowth.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology
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Blotting, Northern
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Blotting, Western
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Caspase 3
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Caspase 8
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Caspases / metabolism
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics*
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p21
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Fibroblasts / pathology
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Flow Cytometry
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Gene Amplification
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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In Situ Nick-End Labeling
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Mice
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Neuroblastoma / genetics
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Neuroblastoma / metabolism
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Neuroblastoma / pathology*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oligonucleotide Array Sequence Analysis
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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Proto-Oncogenes / genetics
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RNA, Small Interfering / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transfection
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Tumor Stem Cell Assay
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Tumor Suppressor Protein p14ARF / genetics
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Tumor Suppressor Protein p53 / metabolism
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Twist-Related Protein 1
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Nuclear Proteins
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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TWIST1 protein, human
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Transcription Factors
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53
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Twist-Related Protein 1
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CASP3 protein, human
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CASP8 protein, human
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Casp3 protein, mouse
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Casp8 protein, mouse
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Caspase 3
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Caspase 8
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Caspases