The role of CD95/Fas ligand (CD95L/FasL) in the induction of CD95-mediated extrinsic apoptosis is well characterized. Trimerized, membrane-bound CD95L ligates the CD95 receptor activating downstream signaling resulting in the execution of cells by caspase proteins. However, the expression of CD95L has been reported to induce cell death in contexts in which this pathway is unlikely to be activated, such as in cell autonomous activation induced cell death (AICD) and in CD95-resistant cancer cell lines. Recent data suggests that the CD95L mRNA exerts toxicity through death induced by survival gene elimination (DISE). DISE results from the targeting of networks of survival genes by toxic short RNA (sRNA)s in the RNA-induced silencing complex (RISC). CD95L mRNA contributes to this death directly, through the processing of its mRNA into toxic sRNAs that are loaded into the RISC, and indirectly, by promoting the loading of other toxic sRNAs. Interestingly, CD95L is not the only mRNA that is processed and loaded into the RISC. Protein-coding mRNAs involved in protein translation are also selectively loaded. We propose a model in which networks of mRNA-derived sRNAs modulate DISE, with networks of genes providing non-toxic RISC substrate sRNAs that protect against DISE, and opposing networks of stress-activated genes that produce toxic RISC substrate sRNAs that promote DISE.

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