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 [1]. There are several pathways resulting in apoptosis, all of which involve Cysteine Aspartyl-specific proteases (caspases) [1]. 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 [2] and are shown in figure 1. | Figure 1: Extrinsic and intrinsic apoptosis pathways, figure taken from [2], modified. Direct positive feedback from caspase-3 on caspase-9 not shown. |
The model by Legewie et al. ([3], 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 [4]).
Bibliographic References
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- G.S. Salvesen and C.S. Duckett. IAP proteins: blocking the road to death's door. Nat Rev Mol Cell Biol. 3(6):401-410, 2002. [SRS@EBI]
- S. Legewie, N. Blüthgen, H. Herzel. Mathematical modeling identifies inhibitors of apoptosis as mediators of positive feedback and bistability. PLoS Comput Biol. 2(9):e120, 2006. [SRS@EBI]
- J.E. Ferrell Jr. Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr Opin Cell Biol. 14(2):140-148, 2002. [SRS@EBI]
- J. Cui, C. Chen, H. Lu, T. Sun, P. Shen. Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch. PLoS ONE 3(1):e1469, 2008. [SRS@EBI]