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, Emilio Clementi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)15466-15472
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number22
DOIs
Publication statusPublished - May 28 1999

ASJC Scopus subject areas

  • Biochemistry

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