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J. Biol. Chem., Vol. 280, Issue 32, 29199-29207, August 12, 2005

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TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism^*

Jean-François Lavoie¶||, Lynne LeSauteur¶, Judi Kohn¶, Josee Wong¶, Olivia Furtoss, Carol J. Thiele**, Freda D. Miller¶, and David R. Kaplan¶¶¶

From the Cancer Research Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, the Institute of Medical Science and the Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, the ^¶Brain Tumor Research Centre, Montreal Neurological Institute, and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada, and the ^**Pediatric Oncology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892

Neuroblastoma (NB) is the most frequent solid extracranial tumor in children. Its clinical prognosis correlates with the expression of members of the Trk neurotrophin receptor family, which includes TrkA and TrkB. TrkA expression is associated with favorable prognosis, whereas TrkB expression is associated with poor prognosis. Here we show that TrkA expression induces the apoptosis of NB cells and does so by modulating the levels or activities of a number of proteins involved in regulating cell survival and apoptosis, including p53, Bcl-2, and caspase-3. TrkA increased the expression of p53 target proteins and failed to induce apoptosis in cells where p53 was inactivated by mutation or via expression of dominant inhibitory p53 or E1B55K, indicating that TrkA mediates apoptosis, at least in part, through p53. Treatment with a caspase inhibitor or overexpression of Bcl-X_L also prevented TrkA from inducing apoptosis. In contrast, elevated expression of TrkA in non-transformed sympathetic neurons resulted in the suppression of p53 levels and enhanced survival. These results identify apoptosis as a novel biological response of TrkA in NB cells and imply that TrkA is a good prognosis marker for NB due in part to its ability to mediate apoptosis when expressed at sufficient levels.

Received for publication, March 2, 2005 , and in revised form, May 23, 2005.

^* This work was funded in part by grants from the National Cancer Research Institute of Canada and the James Fund for Neuroblastoma Research at Sick Kids (to D. R. K.) and the Canadian Institute of Health Research (to F. D. M.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

^|| Funded by a fellowship from the University of Toronto.

Recipients of Senior Canada Research Chairs.

^¶¶ To whom correspondence should be addressed: Cancer Research Program, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-7654 (ext. 1433); Fax: 416-813-2212; E-mail: dkaplan{at}sickkids.ca.

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