Abstract
High-risk neuroblastomas often harbor structural chromosomal alterations, including amplified MYCN, and usually have a near-di/tetraploid DNA index, but the mechanisms creating tetraploidy remain unclear. Gene-expression analyses revealed that certain MYCN/MYC and p53/pRB-E2F target genes, especially regulating mitotic processes, are strongly expressed in near-di/tetraploid neuroblastomas. Using a functional RNAi screening approach and live-cell imaging, we identified a group of genes, including MAD2L1, which after knockdown induced mitotic-linked cell death in MYCN-amplified and TP53-mutated neuroblastoma cells. We found that MYCN/MYC-mediated overactivation of the metaphase-anaphase checkpoint synergizes with loss of p53-p21 function to prevent arrest or apoptosis of tetraploid neuroblastoma cells.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
MeSH terms
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Apoptosis*
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Blotting, Western
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cell Cycle
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Differentiation
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Cell Proliferation
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
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E2F Transcription Factors / genetics
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E2F Transcription Factors / metabolism
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Flow Cytometry
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Fluorescent Antibody Technique, Indirect
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Humans
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In Situ Hybridization, Fluorescence
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Infant
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Mad2 Proteins
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N-Myc Proto-Oncogene Protein
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Neuroblastoma / genetics
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Neuroblastoma / pathology*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Ploidies*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Salivary Proline-Rich Proteins / genetics
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Salivary Proline-Rich Proteins / metabolism
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Spindle Apparatus / genetics*
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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CDKN1A protein, human
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Calcium-Binding Proteins
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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E2F Transcription Factors
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MAD2L1 protein, human
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MYCN protein, human
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Mad2 Proteins
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N-Myc Proto-Oncogene Protein
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Nuclear Proteins
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Oncogene Proteins
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PRB1 protein, human
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Repressor Proteins
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Salivary Proline-Rich Proteins
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TP53 protein, human
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Tumor Suppressor Protein p53