title: Nitric oxide inhibits apoptosis via AP-1-dependent CD95L transactivation.
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.
authors.affiliation: IDI-IRCCS, Department of Experimental Medicine, University of Rome Tor Vergata, Italy. gerry.melino@uniroma2.it
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.forename: F
authors.initials: F
authors.lastname: Bernassola
authors.forename: M V
authors.initials: MV
authors.lastname: Catani
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: M
authors.initials: M
authors.lastname: Corazzari
authors.forename: S
authors.initials: S
authors.lastname: Sabatini
authors.forename: F
authors.initials: F
authors.lastname: Vilbois
authors.forename: D R
authors.initials: DR
authors.lastname: Green
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002518:Ceramides / Q000494:pharmacology; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D002518:Ceramides; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D020030:Nitric Oxide Donors; D019384:Nucleic Acid Synthesis Inhibitors; D016755:Proto-Oncogene Proteins c-jun; C110881:S-nitro-N-acetylpenicillamine; D018808:Transcription Factor AP-1; C101954:N-caproylsphingosine; D009569:Nitric Oxide; D005047:Etoposide; D011065:Poly(ADP-ribose) Polymerases; D010396:Penicillamine