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J Biol Chem, Vol. 274, Issue 22, 15466-15472, May 28, 1999

The p75^NTR-induced Apoptotic Program Develops through a Ceramide-Caspase Pathway Negatively Regulated by Nitric Oxide

Jean-Philippe Lièvremont, Clara Sciorati, Elena Morandi, Clara Paolucci, Giuseppe Bunone^**, Giuliano Della Valle^**, Jacopo Meldolesi, and Emilio Clementi^¶¶

From the  Department of Pharmacology and the Bruno Ceccarelli Center, University of Milan, the Consiglio Nazionale delle Ricerche Center of Molecular and Cellular Pharmacology, and DIBIT, Department of Neuroscience, San Raffaele Institute, 20132 Milan, Italy, the ^** Department of Genetics and Microbiology, University of Pavia, 27100 Pavia, Italy, the  National Cancer Institute, 20129 Milan, Italy, the  Department of Biology, University of Bologna, 40126 Bologna, Italy, and the ^¶¶ Department of Pharmacology, School of Pharmacy, University of Calabria, 87036 Arcavacata di Rende, Italy

SK-N-BE neuroblastoma cell clones transfected with p75^NTR and lacking Trk neurotrophin receptors, previously reported to undergo extensive spontaneous apoptosis and to be protected by nerve growth factor (NGF) (Bunone, G., Mariotti, A., Compagni, A., Morandi, E., and Della Valle, G. (1997) Oncogene 14, 1463-1470), are shown to exhibit (i) increased levels of the pro-apoptotic lipid metabolite ceramide and (ii) high activity of caspases, the proteases of the cell death cascade. In the p75^NTR-expressing cells, these parameters were partially normalized by prolonged NGF treatment, which, in addition, decreased apoptosis, similar to caspase blockers. Conversely, exogenous ceramide increased caspase activity and apoptosis in both wild-type and p75^NTR-expressing cells. A new p75^NTR-expressing clone characterized by low spontaneous apoptosis exhibited high endogenous ceramide and low caspase levels. A marked difference between the apoptotic and resistant clones concerned the very low and high activities of nitric-oxide (NO) synthase, respectively. Protection from apoptosis by NO was confirmed by results with the NO donor S-nitrosoacetylpenicillamine and the NO-trapping agent hemoglobin. We conclude that the p75^NTR receptor, while free of NGF, triggers a cascade leading to apoptosis; the cascade includes generation of ceramide and increased caspase activity; and the protective role of NO occurs at step(s) in between the latter events.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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