German Cancer Research Centre, University of Heidelberg, Heidelberg.
This is the reduced model (model 8) described in: Dynamics within the CD95 death-inducing signaling complex decide life and death of cells. Leo Neumann, Carina Pforr, Joel Beaudouin, Alexander Golks, Peter H. Krammer, Inna N. Lavrik and Roland Eils (German Cancer Research Center (DKFZ), http://www.dkfz.de ); Mol Sys Biol 2010; 6 :352. doi: 10.1038/msb.2010.6 ; Abstract: This study explores the dilemma in cellular signaling that triggering of CD95 (Fas/APO-1) in some situations results in cell death and in others leads to the activation of NF-κB. We established an integrated kinetic mathematical model for CD95-mediated apoptotic and NF-κB signaling. Systematic model reduction resulted in a surprisingly simple model well approximating experimentally observed dynamics. The model postulates a new link between c-FLIP L cleavage in the death-inducing signaling complex (DISC) and the NF-κB pathway. We validated experimentally that CD95 stimulation resulted in an interaction of p43-FLIP with the IKK complex followed by its activation. Furthermore, we showed that the apoptotic and NF-κB pathways diverge already at the DISC. Model and experimental analysis of DISC formation showed that a subtle balance of c-FLIP L and procaspase-8 determines life/death decisions in a nonlinear manner. We present an integrated model describing the complex dynamics of CD95-mediated apoptosis and NF-κB signaling. The original was taken from the MSB article supplementary material site msb20106-s2.xml . All the species ids were changed since the model was not a valid SBML with its original ids - Lukas. Notes added to the species [L] (the initial concentration of Anti-CD95), regarding changes to be made in the initial concentration of [L], to obtain figure 5D. This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels Team. For more information see the terms of use . To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.
Initial concentration of anti-CD95 = 113.22nM is equivalent to 1500ng/ml. The model as such reproduces the figure 5D (black plot: i.e. anti-CD95=1500ng/ml). To obtain the blue (anti-CD95=500ng/ml) and red (250ng/ml) plot of figure 5D, the model parameter [L] (initial concentration of anti-CD95 [L]) should be set as 37.74nM and 18.87nM respectively.