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