MycN and IFNgamma cooperate in apoptosis of human neuroblastoma cells.
Neuroblastomas undergo spontaneous regression at an unusually high rate. The mechanisms are not clear, but apoptosis may be involved. A large proportion of neuroblastomas is characterized by amplification of MYCN. Using human neuroblastoma cells harbouring tetracycline controlled expression of MYCN we have analysed the role of the MycN protein and IFNgamma in cell death decision. Neither conditional expression of MYCN nor treatment with IFNgamma alone was sufficient to trigger cell death. However, when acting in concert MycN and IFNgamma efficiently triggered cell death, which was accompanied by DNA fragmentation and required caspase activity, two hallmarks of apoptosis. MycN and IFNgamma may cooperate along at least two different pathways. First, IFNgamma increased the CD95 cell surface expression while MycN enhanced the cellular susceptibility for the CD95 mediated death signal. Second, IFNgamma treatment induced expression of BAK mRNA while MycN and IFNgamma in combination increased the amount of Bax protein, another activator of apoptosis, without a concomitant increase in BAX mRNA. MycN also increased cell death in response to TRAIL and TNFalpha, suggesting that enforced MYCN expression in general increases the susceptibility of neuroblastoma cells towards a variety of death stimuli.
Department of Cytogenetics-0825, German Cancer Research Center, Heidelberg.
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Lutz
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Fulda
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Jeremias
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Debatin
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Schwab
D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis; D002460:Cell Line; D017931:DNA Primers; D005784:Gene Amplification; D016259:Genes, myc; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008565:Membrane Proteins / Q000096:biosynthesis; D009447:Neuroblastoma; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019014:fas Receptor / Q000096:biosynthesis
D015703:Antigens, CD; C494819:BAD protein, human; C494772:BAK1 protein, human; C494826:BAX protein, human; D002352:Carrier Proteins; D017931:DNA Primers; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019014:fas Receptor; D007371:Interferon-gamma