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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.

20011108

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PLoS Comput. Biol.
PLoS Comput. Biol. 5(12): e1000595
2nd Jul 2009

Rebekka Schlatter, Kathrin Schmich, Ima Avalos Vizcarra, Peter Scheurich, Thomas Sauter, Christoph Borner, Michael Ederer, Irmgard Merfort, Oliver Sawodny

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[Christoph Borner] [Michael Ederer] [Irmgard Merfort] [Oliver Sawodny]

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Views: 2277
  • Created: 3rd Dec 2010 at 09:59
  • Last updated: 24th Oct 2013 at 16:21

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