title: ON/OFF and beyond--a boolean model of apoptosis.
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-alpha, UV-B irradiation, interleukin-1beta 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.
authors.affiliation: Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de
authors.forename: Rebekka
authors.initials: R
authors.lastname: Schlatter
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schmich
authors.forename: Ima
authors.initials: I
authors.lastname: Avalos Vizcarra
authors.forename: Peter
authors.initials: P
authors.lastname: Scheurich
authors.forename: Thomas
authors.initials: T
authors.lastname: Sauter
authors.forename: Christoph
authors.initials: C
authors.lastname: Borner
authors.forename: Michael
authors.initials: M
authors.lastname: Ederer
authors.forename: Irmgard
authors.initials: I
authors.lastname: Merfort
authors.forename: Oliver
authors.initials: O
authors.lastname: Sawodny
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D019295:Computational Biology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D015398:Signal Transduction