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Inactivation of multiple targets by nitric oxide in CD95‐triggered apoptosis

Nitric oxide (NO) plays an important anti‐apoptotic role by inactivating both upstream and downstream apoptotic molecules. We now report that exogenously supplied NO protected Jurkat T cells from anti‐CD95‐stimulated apoptosis. We have recently shown that nitrosation of the activator protein‐1 (AP‐1) transcriptional factor is crucial for NO‐mediated inhibition of cell death triggered by etoposide or ceramide. Since the inhibition of apoptosis by NO has been reported to involve AP‐1, we evaluated its involvement in in CD95‐mediated cell death. Cross‐linking of CD95 enhanced AP‐1 DNA binding activity and AP‐1‐dependent CD95L transactivation, which were both significantly reduced by different NO‐donors compounds. However, AP‐1 induction does not seem to significantly contribute to anti‐CD95‐triggered apoptosis, as cell death could not be prevented by using the recombinant Fas‐Fc fusion protein which inhibits the CD95/CD95L interaction. We observed that caspase 3‐like activity was negatively modulated by several NO‐donors in vitro and that titratable thiol groups of purified caspases 3, 7, and 9 decreased in the presence of NO‐releasing compounds. In conclusion, we demonstrated that NO‐mediated inhibition of other targets, possibly caspases, but not AP‐1, is a crucial event responsible for protection against anti‐CD95‐stimulated apoptosis. Even though NO affects multiple molecular mechanisms, the relevant target for exerting the cellular effects, may vary among different models. J. Cell. Biochem. 82: 123–133, 2001. © 2001 Wiley‐Liss, Inc.