The N-myc paradox: N-myc overexpression in neuroblastomas is associated with sensitivity as well as resistance to apoptosis.
Neuroblastomas are characterized by defects in tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induced apoptosis, especially down-regulation and methylation of Caspase-8 (CASP8). This defect is associated with amplification of N-myc. However, N-myc has also been implicated in induction of apoptosis, especially activation of CASP9 mediated apoptosis. Here we found that ectopic N-myc expression induces TRAIL susceptibility, both by CASP8 and CASP9 mediated apoptosis. N-myc did not modify CASP8 expression and methylation. CASP8 defects therefore represent an independent event in neuroblastoma, counteracting the N-myc induced susceptibility to apoptosis. Analysis of the CASP9 mediated route in a series of neuroblastoma cell lines, we found normal expression and no aberrant methylation of four apoptotic intermediates, including CASP9 itself.
van Noesel
Max M
MM
Department of Human Genetics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Pieters
Rob
R
Voûte
P A
PA
Versteeg
Rogier
R
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005784:Gene Amplification; D016259:Genes, myc / Q000502:physiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases