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Science 310 (5754): 1646-1653

Copyright © 2005 by the American Association for the Advancement of Science

A Systems Model of Signaling Identifies a Molecular Basis Set for Cytokine-Induced Apoptosis

Kevin A. Janes,1,2* John G. Albeck,2,3* Suzanne Gaudet,2,3 Peter K. Sorger,1,2,3 Douglas A. Lauffenburger,1,2,3 Michael B. Yaffe1,2,3{dagger}

Abstract: Signal transduction pathways control cellular responses to stimuli, but it is unclear how molecular information is processed as a network. We constructed a systems model of 7980 intracellular signaling events that directly links measurements to 1440 response outputs associated with apoptosis. The model accurately predicted multiple time-dependent apoptotic responses induced by a combination of the death-inducing cytokine tumor necrosis factor with the prosurvival factors epidermal growth factor and insulin. By capturing the role of unsuspected autocrine circuits activated by transforming growth factor–{alpha} and interleukin-1{alpha}, the model revealed new molecular mechanisms connecting signaling to apoptosis. The model derived two groupings of intracellular signals that constitute fundamental dimensions (molecular "basis axes") within the apoptotic signaling network. Projection along these axes captures the entire measured apoptotic network, suggesting that cell survival is determined by signaling through this canonical basis set.

1 Biological Engineering Division, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2 Center for Cell Decision Processes, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3 Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: myaffe{at}mit.edu

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