Scheme for induction of apoptosis in response to the cytokines tumor necrosis factor α and the Fas (APO-1) ligand. Both cytokines bind to specific membrane receptors (such as TNFR and Fas) and allow for the interaction of the receptors with specific proteins (such as TRADD and FADD/MORT). This may result in activation of a protease (Mach/Flice) that somehow launches the apoptotic response. Downstream mediators of this response may include sphingomyelinase causing the accumulation of ceramide, phospholipase A2 with accumulation of arachidonate, and other mediators such the Fast kinase.94 Eventually, this results in activation of downstream proteases such as prICE/CPP-32, which cleaves PARP and possibly other protein substrates. This then appears to induce the terminal and irreversible phase of apoptosis characterized by macromolecular breakdown and cellular fragmentation.