Regulation of Apoptosis via the NFκB Pathway: Modeling and Analysis

Programmed cell death (or apoptosis) has an essential biological function, enabling successful embryonic development, as well as maintenance of a healthy living organism [6]. Apoptosis is a physiological process which enables an organism to remove unwanted or damaged cells. Malfunctioning apoptotic pathways can lead to many diseases, including cancer and inflammatory or immune system related problems. A family of proteins called caspases are primarily responsible for execution of the apoptotic process: basically, in response to appropriate stimuli, initiator caspases (for instance, caspases 8, 9) activate effector caspases (for instance, caspases 3, 7), which will then cleave various cellular substrates to accomplish the cell death process [22]. Nuclear factor κB (NFκB) is a transcription factor for a large group of genes which are involved in several different pathways. For instance, NFκB activates its own inhibitor (IκB) [14] as well as groups of pro-apoptotic and anti-apoptotic genes [21]. Among the latter, NFκB activates transcription of a gene encoding for inhibitor of apoptosis protein (IAP). This protein in turn contributes to downregulate the activity of the caspase cascade which forms the core of the apoptotic pathway [6, 8]. The canonical NFκB pathway is induced, among other stimuli, by the cytokine tumor necrosis factor α (TNFα) [21]. Binding of TNFα to death receptor TNFR1 forms a first complex which eventually activates NFκB. A second complex is later formed, which will activate the initiator caspase 8 [6], and hence activate the apoptotic process. The same signal (TNFα stimulation) thus triggers two parallel but contrary pathways: the pro-apoptotic caspase cascade and the anti-apoptotic NFκB-IκB-IAP pathway. These two pathways, together with the interactions among their components, form a