Nitric oxide inhibits apoptosis via AP-1-dependent CD95L transactivation

Gerry Melino, Francesca Bernassola, Maria Valeria Catani, Antonello Rossi, Marco Corazzari, Stefania Sabatini, Francis Vilbois, Douglas R. Green

Research output: Contribution to journalArticle

Abstract

Several inducers of cytotoxic stress promote apoptotic cell death, which, at least in some cases, involves the CD95/CD95 ligand (CD95L) pathway. The induction of the CD95/CD95L pathway can be activated by the activator protein-1 (AP-1)-mediated up-regulation of the CD95L promoter, which is responsible for the induction of apoptosis elicited by stimuli such as etoposide. We show that nitric oxide (NO) represents a regulatory element able to block apoptosis by interfering with this loop. Etoposide- and C6- ceramide-induced apoptosis in Jurkat T cells with different kinetics. Cell death was accompanied by an increase in DNA-binding activity of the transcription factor AP-1, transactivation of the AP-1 site-containing CD95L promoter, and caspase 3-like protease activation. Using different NO- releasing compounds, we found that apoptosis was prevented in a dose- dependent manner. Furthermore, in both models of apoptosis, NO-releasing compounds dose-dependently reduced: (a) the number of the titratable thiol groups (cysteine residues) of c-Jun; (b) induction of AP-1 DNA-binding activity; (c) AP-1-driven transactivation of the CD95L promoter; and (d) caspase activation. In conclusion, our data demonstrate that NO can modulate cell death at an upstream level, by interfering with the ability of AP-1 to induce CD95L expression.

Original languageEnglish
Pages (from-to)2377-2383
Number of pages7
JournalCancer Research
Volume60
Issue number9
Publication statusPublished - May 1 2000

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Melino, G., Bernassola, F., Catani, M. V., Rossi, A., Corazzari, M., Sabatini, S., Vilbois, F., & Green, D. R. (2000). Nitric oxide inhibits apoptosis via AP-1-dependent CD95L transactivation. Cancer Research, 60(9), 2377-2383.