Research Article: ON/OFF and Beyond – A Boolean Model of Apoptosis

Date Published: December 11, 2009

Publisher: Public Library of Science

Author(s): Rebekka Schlatter, Kathrin Schmich, Ima Avalos Vizcarra, Peter Scheurich, Thomas Sauter, Christoph Borner, Michael Ederer, Irmgard Merfort, Oliver Sawodny, Denis Thieffry

Abstract: Apoptosis is regulated by several signaling pathways which are extensively linked by crosstalks. Boolean or logical modeling has become a promising approach to capture the qualitative behavior of such complex networks. Here we built a large-scale literature-based Boolean model of the central intrinsic and extrinsic apoptosis pathways as well as pathways connected with them. The model responds to several external stimuli such as Fas ligand, TNF-α, UV-B irradiation, interleukin-1β and insulin. Timescales and multi-value node logic were used and turned out to be indispensable to reproduce the behavior of the apoptotic network. The coherence of the model was experimentally validated. Thereby an UV-B dose-effect is shown for the first time in mouse hepatocytes. Analysis of the model revealed a tight regulation emerging from high connectivity and spanning crosstalks and a particular importance of feedback loops. An unexpected feedback from Smac release to RIP could further increase complex II formation. The introduced Boolean model provides a comprehensive and coherent description of the apoptosis network behavior. It gives new insights into the complex interplay of pro- and antiapoptotic factors and can be easily expanded to other signaling pathways.

Partial Text: Apoptosis is the prototype of programmed cell death and an essential process in multicellular organisms. It is necessary during embryogenesis, tissue growth, differentiation and homeostasis as a protective mechanism to remove superfluous or malfunctioning cells from the organism [1]–[5]. Errors in cell death regulation can result in diseases like Alzheimer and Parkinson when uncontrolled apoptosis occurs or cancer if apoptosis is repressed [6],[7]. Apoptosis can be induced by several signal transduction pathways that are tightly regulated and linked to other cellular events such as inflammatory responses and proliferation. The understanding of these signaling pathways is thought to provide novel solutions for the treatment of many diseases. However, a large number of participating components, their complex dependencies and multiple biological stimuli make the analysis of small network parts difficult and often less expressive. Therefore some mathematical models have already been presented covering broader structures.