This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Melino, G. Articles by Green, D. R. Search for Related Content PubMed PubMed Citation Articles by Melino, G. Articles by Green, D. R.

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.

This article has been cited by other articles:

				J. Zhang, S. Wang, R. A. Wesley, and R. L. Danner Adjacent Sequence Controls the Response Polarity of Nitric Oxide-sensitive Sp Factor Binding Sites J. Biol. Chem., August 1, 2003; 278(31): 29192 - 29200. [Abstract] [Full Text] [PDF]

				R. Weller, A. Schwentker, T. R. Billiar, and Y. Vodovotz Autologous nitric oxide protects mouse and human keratinocytes from ultraviolet B radiation-induced apoptosis Am J Physiol Cell Physiol, May 1, 2003; 284(5): C1140 - C1148. [Abstract] [Full Text] [PDF]

				S.-K. LEONG, R.-S. RUAN, and Z. ZHANG A Critical Assessment of the Neurodestructive and Neuroprotective Effects of Nitric Oxide Ann. N.Y. Acad. Sci., May 1, 2002; 962(1): 161 - 181. [Abstract] [Full Text] [PDF]

				A. Almeida, J. Almeida, J. P. Bolanos, and S. Moncada Different responses of astrocytes and neurons to nitric oxide: The role of glycolytically generated ATP in astrocyte protection PNAS, December 6, 2001; (2001) 261560998. [Abstract] [Full Text] [PDF]

				F. Feger, H. Ferry-Dumazet, M. M. Matsuda, J. Bordenave, M. Dupouy, A. K. Nussler, M. Arock, L. Devevey, J. Nafziger, J.-J. Guillosson, et al. Role of Iron in Tumor Cell Protection from the Pro-Apoptotic Effect of Nitric Oxide Cancer Res., July 1, 2001; 61(13): 5289 - 5294. [Abstract] [Full Text] [PDF]

				A. Almeida, J. Almeida, J. P. Bolanos, and S. Moncada Different responses of astrocytes and neurons to nitric oxide: The role of glycolytically generated ATP in astrocyte protection PNAS, December 18, 2001; 98(26): 15294 - 15299. [Abstract] [Full Text] [PDF]