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A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis

Kevin A Janes1, John G Albeck, Suzanne Gaudet

  • 1Biological Engineering Division, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Science (New York, N.Y.)
|December 13, 2005
PubMed

Insights

This study models intracellular signaling networks to predict apoptosis. The findings reveal fundamental signaling dimensions that determine cell survival by integrating death and survival signals.

Area of Science:

  • Cellular biology
  • Systems biology
  • Molecular biology

Background:

  • Signal transduction pathways regulate cellular responses.
  • Understanding how molecular information is processed in a network remains a challenge.

Purpose of the Study:

  • To construct a systems model of intracellular signaling events linked to apoptosis.
  • To identify molecular mechanisms connecting signaling to apoptosis and determine factors influencing cell survival.

Main Methods:

  • Developed a systems model of 7980 intracellular signaling events.
  • Linked signaling events to 1440 response outputs for apoptosis.
  • Validated the model using time-dependent apoptotic responses induced by specific cytokines and growth factors.

Main Results:

  • The model accurately predicted apoptotic responses to combined death and survival factors.
  • Identified novel autocrine circuits involving transforming growth factor-alpha and interleukin-1alpha.
  • Derived two fundamental dimensions (basis axes) within the apoptotic signaling network.

Conclusions:

  • The derived basis axes capture the entire measured apoptotic network.
  • Cell survival is determined by signaling through these canonical basis axes.
  • Revealed new molecular mechanisms linking signaling pathways to apoptosis.

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