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J. Biol. Chem., Vol. 280, Issue 10, 9474-9481, March 11, 2005

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Linking of N-Myc to Death Receptor Machinery in Neuroblastoma Cells^*

Hongjuan Cui, Tai Li, and Han-Fei Ding

From the Department of Biochemistry and Cancer Biology, Medical College of Ohio, Toledo, Ohio 43614

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-9 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.

Received for publication, September 10, 2004 , and in revised form, December 13, 2004.

^* This work was supported in part by the Howard Temin award from the NCI, National Institutes of Health (to H.-F. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry and Cancer Biology, Medical College of Ohio, Health Sciences Bldg., Rm. 468, 3035 Arlington Ave., Toledo, OH 43614-5804. Tel.: 419-383-6653; Fax: 419-383-6228; E-mail: hding{at}mco.edu.

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