FIG. 6.

Proteasome inhibition and subsequent reduced degradation of active caspases can lead to autoactivation. Shown is a mathematical model of apoptotic cell death through spontaneous (spont.) activation and imbalance of protein turnover. (A) Model schematic assuming a 0.1% initial, spontaneous caspase-3 activity which gets amplified by caspase-3 autofeedback. Cleavage of the cellular substrate is prevented through heterodimerization and inhibition of caspase-3 by XIAP (indicated by “XIAP ∼ Caspase-3”). The model further considered caspase-3 cleavage (solid arrows) of XIAP to its fragments BIR12 and BIR3R (neglected). Dashed arrows indicate the constant turnover of endogenous proteins XIAP and procaspase-3, as well as the decay of proteins that are activated in the signaling cascade. (B) Cellular substrate cleavage as a consequence of the deregulation of protein turnover balance induced by proteasome (prot.) inhibition. With inhibition higher than 90%, a robust cleavage of cellular substrate was predicted with onset of 5% substrate cleavage at approximately 10 to 30 h. Inhibitions less than 80% led to a complete abolishment of robust caspase-3 activation and therefore no substrate cleavage. admin, administration.