Legewie et al. (2006), Apoptosis
June 2008, model of the month by Melanie I. Stefan
Original model: BIOMD0000000102
Apoptosis, a form of programmed cell death, is crucial in development, as well as for maintaining homoeostasis in adult tissues . There are several pathways resulting in apoptosis, all of which involve Cysteine Aspartyl-specific proteases (caspases) .
The extrinsic apoptotic pathway is triggered by ligand binding to cell-surface receptors, resulting in the recruitment of various proteins to form the death-inducing signalling complex (DISC). This complex promotes activation of caspase-8, which in turn activates caspase-3. Caspase-3 then induces the cellular changes that characterise apoptosis. The intrinsic pathway, in contrast, is triggered by cytotoxic stress, which induces the translocation of pro-apoptotic Bcl-2 family members, such as Bax, to the mitochondria. This leads to the release of mitochondrial cytochrome c into the cytosol, where it promotes the oligomerisation of the pro-apoptotic factor Apaf-1 into a complex called the "apoptosome". The aptoptosome recruits and activates caspase-9, which in turn promotes the activation of caspase-3. This process is further regulated by X-linked inhibitor of apoptosis (XIAP) protein, which inhibits the activity of both caspase-9 and caspase-3. Both extrinsic and intrinsic pathways have been reviewed in  and are shown in figure 1.
Figure 1: Extrinsic and intrinsic apoptosis pathways, figure taken from , modified. Direct positive feedback from caspase-3 on caspase-9 not shown.
The model by Legewie et al. (, BIOMD0000000102) focuses on the intrinsic apoptotic pathway. This pathway displays some properties that make it an interesting target for closer examination with mathematical methods: Depending on cellular context, cytochrome c induces caspase activation either gradually or in an all-or-none fashion. In addition, caspase activation is reversible in some cellular contexts, but irreversible in others. This suggests that the caspase activation pathway is monostable (characterised by a gradual response and reversibility) in some cells, but bistable (characterised by an all-or-none-response and sometimes irreversibility) in others. In order for bistability to occur, the existence of some form of positive (or double negative) feedback loop is a necessary, but not sufficient condition (reviewed in ).
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