title: MYCN-mediated overexpression of mitotic spindle regulatory genes and loss of p53-p21 function jointly support the survival of tetraploid neuroblastoma cells.
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.
authors.affiliation: Division of Tumor Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Gogolin
authors.forename: Richa
authors.initials: R
authors.lastname: Batra
authors.forename: Nathalie
authors.initials: N
authors.lastname: Harder
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Tobias
authors.initials: T
authors.lastname: Paffhausen
authors.forename: Nicolle
authors.initials: N
authors.lastname: Diessl
authors.forename: Vitaliya
authors.initials: V
authors.lastname: Sagulenko
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Stephan
authors.initials: S
authors.lastname: Gade
authors.forename: Ingo
authors.initials: I
authors.lastname: Nolte
authors.forename: Karl
authors.initials: K
authors.lastname: Rohr
authors.forename: Rainer
authors.initials: R
authors.lastname: König
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D064246:Mad2 Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011003:Ploidies; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D055273:Salivary Proline-Rich Proteins / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050684:E2F Transcription Factors; C577697:MAD2L1 protein, human; C459801:MYCN protein, human; D064246:Mad2 Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C524744:PRB1 protein, human; D012097:Repressor Proteins; D055273:Salivary Proline-Rich Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53