Schematic model of the CD95/CD95L pathway and NO interference with cellular stress-pathway of apoptosis. Schematic model of the CD95/CD95L pathway and.

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Schematic model of the CD95/CD95L pathway and NO interference with cellular stress-pathway of apoptosis. Schematic model of the CD95/CD95L pathway and NO interference with cellular stress-pathway of apoptosis. Ligation of CD95 or activation by CD95L activates two main pathways: (a) downstream caspase activation via a direct or mitochondria-mediated activation; and (b) production of ceramide, which might activate the downstream caspases. DNA-damaging agents might link up to this second path and/or use the activation of AP-1 to trigger CD95L. Two inducers of apoptosis tested in this study, etoposide (1) and ceramide (2) , all induced AP-1-dependent CD95L transactivation. NO inhibits this mechanism, thus preventing apoptosis. NO is also able to S-nitrosylate caspases and tTG, or inactivate the mitochondrial respiratory chain, as indicated by the dashed arrows. Not all pathways and connections are represented in this simplified scheme. Gerry Melino et al. Cancer Res 2000;60:2377-2383 ©2000 by American Association for Cancer Research