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Effects of Bcl-2 Levels on Fas Signaling-Induced Caspase-3 Activation: Molecular Genetic Tests of Computational Model Predictions¹

Fei Hua^2,*, Melanie G. Cornejo^*, Michael H. Cardone, Cynthia L. Stokes and Douglas A. Lauffenburger^*,

^* Center for Cancer Research and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139; Merrimack Pharmaceuticals, Cambridge, MA 02142; and Entelos, Foster City, CA 94404

Fas-induced apoptosis is a critical process for normal immune system development and function. Although many molecular components in the Fas signaling pathway have been identified, a systematic understanding of how they work together to determine network dynamics and apoptosis itself has remained elusive. To address this, we generated a computational model for interpreting and predicting effects of pathway component properties. The model integrates current information concerning the signaling network downstream of Fas activation, through both type I and type II pathways, until activation of caspase-3. Unknown parameter values in the model were estimated using experimental data obtained from human Jurkat T cells. To elucidate critical signaling network properties, we examined the effects of altering the level of Bcl-2 on the kinetics of caspase-3 activation, using both overexpression and knockdown in the model and experimentally. Overexpression was used to distinguish among alternative hypotheses for inhibitory binding interactions of Bcl-2 with various components in the mitochondrial pathway. In comparing model simulations with experimental results, we find the best agreement when Bcl-2 blocks the release of cytochrome c by binding to both Bax and truncated Bid instead of Bax, truncated Bid, or Bid alone. Moreover, although Bcl-2 overexpression strongly reduces caspase-3 activation, Bcl-2 knockdown has a negligible effect, demonstrating a general model finding that varying the expression levels of signal molecules frequently has asymmetric effects on the outcome. Finally, we demonstrate that the relative dominance of type I vs type II pathways can be switched by varying particular signaling component levels without changing network structure.

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The JI 2005 175: 631-632. [Full Text]  

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