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Published 13 September 2004. doi:10.1083/jcb.200404158
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 6, 839-851
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Article

Mathematical modeling reveals threshold mechanism in CD95-induced apoptosis



M. Bentele1, I. Lavrik2, M. Ulrich1, S. Stößer2, D.W. Heermann3, H. Kalthoff4, P.H. Krammer2, and R. Eils1

1 Division Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
2 Immunogenetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
3 Institute for Theoretical Physics, University of Heidelberg, 69120 Heidelberg, Germany
4 Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University of Kiel, 24098 Kiel, Germany

Address correspondence to R. Eils, DKFZ, Division Theoretical Bioinformatics, Im Neuenheimer Feld 580, Heidelberg 69120, Germany. Tel.: (49) 6221-423600; Fax: (49) 6221-423610; email: r.eils{at}dkfz.de

Mathematical modeling is required for understanding the complex behavior of large signal transduction networks. Previous attempts to model signal transduction pathways were often limited to small systems or based on qualitative data only. Here, we developed a mathematical modeling framework for understanding the complex signaling behavior of CD95(APO-1/Fas)-mediated apoptosis. Defects in the regulation of apoptosis result in serious diseases such as cancer, autoimmunity, and neurodegeneration. During the last decade many of the molecular mechanisms of apoptosis signaling have been examined and elucidated. A systemic understanding of apoptosis is, however, still missing. To address the complexity of apoptotic signaling we subdivided this system into subsystems of different information qualities. A new approach for sensitivity analysis within the mathematical model was key for the identification of critical system parameters and two essential system properties: modularity and robustness. Our model describes the regulation of apoptosis on a systems level and resolves the important question of a threshold mechanism for the regulation of apoptosis.

Key Words: mathematical modeling; CD95-induced apoptosis; sensitivity analysis; parameter estimation; threshold mechanism

M. Bentele and I. Lavrik contributed equally to this work.

Abbreviations used in this paper: CHX, cyclohexamide; DD, death domain; DISC, death-inducing signaling complex.


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