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Nitric Oxide Inhibits Apoptosis via AP-1-dependent CD95L Transactivation¹

Biochemistry Laboratory, IDI-IRCCS, Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy [G. M., F. B., M. V. C., A. R., M. C., S. S.]; Serono Pharmaceutical Research Institute, 1228 Plan-les-Ouates, Switzerland [F. V.]; and Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121 [D. R. G.]

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.

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