Linking of N-Myc to death receptor machinery in neuroblastoma cells

Hongjuan Cui, Tai Li, Hanfei Ding

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

The oncogene MYCN is amplified in aggressive neuroblastomas in which caspase-8, an essential component of death receptor pathways, is frequently inactivated, suggesting a critical role of death receptor-mediated apoptosis in suppression of N-Myc oncogenic activity. Elevated levels of N-Myc sensitize neuroblastoma cells to apoptosis induced by various death ligands. Using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as a model, we define the mechanism underlying the sensitization effect. In neuroblastoma cells with increased expression of N-Myc, TRAIL triggers high levels of caspase-8 activation and Bid cleavage, leading to release of cytochrome c and Smac/DIABLO from mitochondria. However, the apoptotic process requires Smac/DIABLO, but not cytochrome c-mediated caspase-8 activation. N-Myc sensitizes neuroblastoma cells to TRAIL by up-regulating TRAIL receptor-2/DR5/KILLER and Bid. Moreover, DR5 mRNA is increased after N-Myc overexpression, and the human DR5 promoter contains two noncanonical E-boxes critical for the transcriptional activation by N-Myc. These findings establish a mechanistic link between N-Myc and death receptor machinery, which may serve as a checkpoint to guard the cell from N-Myc-initiated tumorigenesis.

Original languageEnglish (US)
Pages (from-to)9474-9481
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number10
DOIs
StatePublished - Mar 11 2005

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Death Domain Receptors
Neuroblastoma
Machinery
Caspase 8
Apoptosis
Chemical activation
Cytochromes c
Guards (shields)
TNF-Related Apoptosis-Inducing Ligand Receptors
Ligands
Mitochondria
Oncogenes
Transcriptional Activation
Carcinogenesis
Tumor Necrosis Factor-alpha
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Linking of N-Myc to death receptor machinery in neuroblastoma cells. / Cui, Hongjuan; Li, Tai; Ding, Hanfei.

In: Journal of Biological Chemistry, Vol. 280, No. 10, 11.03.2005, p. 9474-9481.

Research output: Contribution to journalArticle

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