Sensitivity analysis of programmed cell death and implications for crosstalk phenomena during Tumor Necrosis Factor stimulation

Different methods for analyzing the sensitivity of the direct signal transduction pathway of receptor-induced apoptosis to parameter changes are presented. Apoptosis is a form of programmed cell death, removing unwanted cells within multicellular organisms to maintain a proper balance between cell reproduction and death. The results indicate the importance of controlling activated caspases by direct inhibition to prevent apoptosis. A misregulation of IAP molecules, one of the main inhibitors, appears to be especially critical. The results indicate how an increased production of this molecule promotes survival and might promote cancer progression, while a reduced degradation might not, thereby providing insight of potential pharmaceutical relevance and also stimulating experimental verification. The different engineering methods applied, nicely complement each other to provide valuable insight into this important process. Because IAPs, among others, are also an important connection to other signaling pathways, the results will enable a more efficient extension of the current model. This is outlined at the example of Tumor Necrosis Factor induced signaling pathways.