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.
%0 Journal Article
%1 Schlatter2009
%A Schlatter, Rebekka
%A Schmich, Kathrin
%A Vizcarra, Ima Avalos
%A Scheurich, Peter
%A Sauter, Thomas
%A Borner, Christoph
%A Ederer, Michael
%A Merfort, Irmgard
%A Sawodny, Oliver
%D 2009
%J PLoS Computational Biology
%K 2009 izi scheuric
%N 12
%P e1000595
%R 10.1371/journal.pcbi.1000595
%T ON/OFF and beyond - A Boolean model of apoptosis
%U https://www.ncbi.nlm.nih.gov/pubmed/20011108
%V 5
%X 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.
%7 2009/12/17
%@ 1553-7358 (Electronic)$\backslash$n1553-734X (Linking)
@article{Schlatter2009,
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.},
added-at = {2018-02-01T16:04:27.000+0100},
author = {Schlatter, Rebekka and Schmich, Kathrin and Vizcarra, Ima Avalos and Scheurich, Peter and Sauter, Thomas and Borner, Christoph and Ederer, Michael and Merfort, Irmgard and Sawodny, Oliver},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/2e2d80fa424a48562f954906260cd748c/cristiano},
doi = {10.1371/journal.pcbi.1000595},
edition = {2009/12/17},
interhash = {1438ea99c89c7d2994771791c9a79f80},
intrahash = {e2d80fa424a48562f954906260cd748c},
isbn = {1553-7358 (Electronic)$\backslash$n1553-734X (Linking)},
issn = {1553734X},
journal = {PLoS Computational Biology},
keywords = {2009 izi scheuric},
number = 12,
pages = {e1000595},
pmid = {20011108},
timestamp = {2018-07-25T12:31:54.000+0200},
title = {{ON/OFF and beyond - A Boolean model of apoptosis}},
url = {https://www.ncbi.nlm.nih.gov/pubmed/20011108},
volume = 5,
year = 2009
}
