MYCN-mediated overexpression of mitotic spindle regulatory genes and loss of p53-p21 function jointly support the survival of tetraploid neuroblastoma cells

Cancer Lett. 2013 Apr 30;331(1):35-45. doi: 10.1016/j.canlet.2012.11.028. Epub 2012 Nov 24.

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.

MeSH terms

  • Apoptosis*
  • Blotting, Western
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cell Cycle
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • E2F Transcription Factors / genetics
  • E2F Transcription Factors / metabolism
  • Flow Cytometry
  • Fluorescent Antibody Technique, Indirect
  • Humans
  • In Situ Hybridization, Fluorescence
  • Infant
  • Mad2 Proteins
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / genetics
  • Neuroblastoma / pathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Ploidies*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Salivary Proline-Rich Proteins / genetics
  • Salivary Proline-Rich Proteins / metabolism
  • Spindle Apparatus / genetics*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • CDKN1A protein, human
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • E2F Transcription Factors
  • MAD2L1 protein, human
  • MYCN protein, human
  • Mad2 Proteins
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • PRB1 protein, human
  • Repressor Proteins
  • Salivary Proline-Rich Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53